Metformin: May 'Revolutionize' Cancer Therapies: Unexpected T-cell Breakthr
 

Possible need to monitor B12 ?
http://www.diabetesselfmanagement.co...12_deficiency/





Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Breakthrough

http://www.sciencedaily.com/releases/2009/06/
090603131433.htm

ScienceDaily (June 3, 2009) — Researchers at McGill University and the University of Pennsylvania have discovered that a widely used anti-diabetic drug can boost the immune system and increase the potency of vaccines and cancer treatments. Their findings will be published June 3 in the journal Nature.
The discovery was made by Dr. Russell Jones, an assistant professor at McGill's Goodman Cancer Centre and the Department of Physiology, Faculty of Medicine, Yongwon Choi, PhD, professor of pathology and laboratory medicine, and postdoctoral fellow Erika Pearce, PhD, of the University of Pennsylvania. They discovered that the widely prescribed diabetes treatment metformin increases the efficiency of the immune system's T-cells, which in turn makes cancer and virus-fighting vaccines more effective.
The specialized white blood cells of the human immune system known as "T-cells" remember pathogens they have encountered from previous infections or vaccinations, enabling them to fight subsequent infections much faster. This "immunological memory" has been the subject of intense study for many years, but until now the underlying cellular mechanisms behind it were not well understood. Now, the researchers say, they can use diabetic therapies to manipulate T-cell response and enhance the immune system's response to infections and cancer alike.
"Many genes involved in diabetes regulation also play a role in cancer progression," Jones explained. "There is also a significant body of data suggesting that diabetics are more prone to certain cancers. However, our study is the first to suggest that by targeting the same metabolic pathways that play a role in diabetes, you can alter how well your immune system functions."
"We serendipitously discovered that the metabolizing, or burning, of fatty acids by T-cells following the peak of infection is critical to establishing immunological memory," Pearce added. "We used metformin, which is known to operate on fatty-acid metabolism, to enhance this process, and have shown experimentally in mice that metformin increases T-cell memory as well as the ensuing protective immunity of an experimental anti-cancer vaccine."
Few talk about cancer and diabetes in the same breath. However, recent advances have uncovered common links between cancer and diabetes, in particular how metabolic pathways, the basic chemical reactions that happen in our cells, are controlled in these diseases. The recent findings suggest a new link between the metabolic pathways deregulated in cancer and diabetes and their role in immune cell function. The results suggest that common diabetic therapies which alter cellular metabolism may enhance T-cell memory, providing a boost to the immune system. This could lead to novel strategies for vaccine and anti-cancer therapies.
"Our findings were unanticipated, but are potentially extremely important and could revolutionize current strategies for both therapeutic and protective vaccines," Choi said.
<hr> Journal reference:

• Erika L. Pearce, Matthew C. Walsh, Pedro J. Cejas, Gretchen M. Harms, Hao Shen, Li-San Wang, Russell G. Jones & Yongwon Choi. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature, 2009; DOI: 10.1038/nature08097

Adapted from materials provided by McGill University, via EurekAlert!, a service of AAAS. Retrieved June 3, 2009, from http://www.sciencedaily.com* /releases/2009/06/090603131433.htm
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Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission

FULL TEXT
<nobr>Heather A. Hirsch¹</nobr>, <nobr>Dimitrios Iliopoulos¹</nobr>, <nobr>Philip N. Tsichlis²</nobr> and <nobr>Kevin Struhl¹</nobr> ¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and ² Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts
Requests for reprints: Kevin Struhl, Harvard University, 240 Longwood Avenue, Boston, MA 02115. Phone: 617-432-2104; Fax: 617-432-2529; E-mail: kevin@hms.harvard.edu<script type="text/javascript"><!-- var u = "kevin", d = "hms.harvard.edu"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>.


<!-- ABS --> The cancer stem cell hypothesis suggests that, unlike most cancercells within a tumor, cancer stem cells resist chemotherapeuticdrugs and can regenerate the various cell types in the tumor,thereby causing relapse of the disease. Thus, drugs that selectivelytarget cancer stem cells offer great promise for cancer treatment,particularly in combination with chemotherapy. Here, we showthat low doses of metformin, a standard drug for diabetes, inhibitscellular transformation and selectively kills cancer stem cellsin four genetically different types of breast cancer. The combinationof metformin and a well-defined chemotherapeutic agent, doxorubicin,kills both cancer stem cells and non–stem cancer cellsin culture. Furthermore, this combinatorial therapy reducestumor mass and prevents relapse much more effectively than eitherdrug alone in a xenograft mouse model. Mice seem to remain tumor-freefor at least 2 months after combinatorial therapy with metforminand doxorubicin is ended. These results provide further evidencesupporting the cancer stem cell hypothesis, and they providea rationale and experimental basis for using the combinationof metformin and chemotherapeutic drugs to improve treatmentof patients with breast (and possibly other) cancers. [CancerRes 2009;69(19):7507–11]





Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer
FULL TEXT: http://jco.ascopubs.org/cgi/content/full/27/20/3297

<nobr>Sao Jiralerspong</nobr>, <nobr>Shana L. Palla</nobr>, <nobr>Sharon H. Giordano</nobr>, <nobr>Funda Meric-Bernstam</nobr>, <nobr>Cornelia Liedtke</nobr>, <nobr>Chad M. Barnett</nobr>, <nobr>Limin Hsu</nobr>, <nobr>Mien-Chie Hung</nobr>, <nobr>Gabriel N. Hortobagyi</nobr>, <nobr>Ana M. Gonzalez-Angulo</nobr> From the Departments of Breast Medical Oncology, Biochemistry and Molecular Biology, Quantitative Sciences, Surgical Oncology, Pharmacy, Molecular and Cellular Oncology, and Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Department of Gynecology and Obstetrics, University of Muenster, Muenster, Germany.
Corresponding author: Ana M. Gonzalez-Angulo, MD, Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: agonzalez@mdanderson.org<script type="text/javascript"><!-- var u = "agonzalez", d = "mdanderson.org"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>.
<!-- ABS --> Purpose Population studies have suggested that metformin use in diabeticpatients decreases cancer incidence and mortality. Metformininhibits the growth of cancer cells in vitro and tumors in vivo.However, there is little clinical data to support this. Ourpurpose was to determine whether metformin use was associatedwith a change in pathologic complete response (pCR) rates indiabetic patients with breast cancer receiving neoadjuvant chemotherapy.
Patients and Methods We identified 2,529 patients who received neoadjuvant chemotherapyfor early-stage breast cancer between 1990 and 2007. Patientswere compared by groups: 68 diabetic patients taking metformin,87 diabetic patients not taking metformin, and 2,374 nondiabeticpatients. pCR rates were compared between the three groups usinghttp://jco.ascopubs.org/math/chi.gif² tests of independence and compared pair- wise using a binomialtest of proportions. Factors predictive of pCR were assessedusing a multivariate logistic regression model.
Results The rate of pCR was 24% in the metformin group, 8.0% in thenonmetformin group, and 16% in the nondiabetic group (P = .02).Pairwise comparisons between the metformin and nonmetformingroups (P = .007) and the nonmetformin and nondiabetic groups(P = .04) were significant. Comparison of the pCR rates betweenthe metformin and nondiabetic groups trended toward but didnot meet significance (P = .10). Metformin use was independentlypredictive of pCR (odds ratio, 2.95; P = .04) after adjustmentfor diabetes, body mass index, age, stage, grade, receptor status,and neoadjuvant taxane use.
Conclusion Diabetic patients with breast cancer receiving metformin andneoadjuvant chemotherapy have a higher pCR rate than do diabeticsnot receiving metformin. Additional studies to evaluate thepotential of metformin as an antitumor agent are warranted.




Metformin As an Addition to Conventional Chemotherapy in Breast Cancer

TO THE EDITOR: We were most interested to read the article by Jiralerspong et al.1 This study showed that patients with breast cancer and diabetes who received metformin plus neoadjuvant therapy had a higher pathologic complete response rate than patients with diabetes who were not in receipt of metformin did. Jiralerspong et al1 and Goodwin et al,2 who wrote the accompanying editorial, suggest that the possible beneficial action of metformin in breast cancer may be related to activation of adenosine monophosphate–activated protein kinase, which may ultimately result in a rapid inhibition of cellular protein synthesis and growth of tumor cells. We suggest, however, that additional mechanisms may play a part.
It is a well-accepted fact that chronic inflammation is a major contributory factor to cancer development and progression, and elevated levels of various nonspecific markers of inflammation in the serum have been shown to be associated with poor survival in a number of different cancers. Pierce et al3 have recently assessed the relationship between circulating levels of C-reactive protein and serum amyloid A and breast cancer survival. They showed that raised levels of these inflammatory markers were associated with a significantly reduced overall survival and a trend toward a reduced diseasefree survival. Patients with type 2 diabetes mellitus tend to have higher C-reactive protein concentrations than those without it, suggesting that inflammation may contribute to the higher risk of breast cancer and worse prognosis of malignant disease in these patients.4 There is evidence to suggest that metformin has a positive impact on inflammation and endothelial dysfunction. Metformin was compared with another oral hypoglycaemic agent, repaglinide, in nonobese patients with type 2 diabetes and shown to be more effective in reducing levels of tumor necrosis factor alpha, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, vonWillebrand factor, soluble intercellular adhesion molecule-1, and soluble E-selectin.5 A further study has shown that metformin is capable of producing a significant decrease in the levels of vascular endothelial growth factor and plasminogen activator inhibitor-1.6 Because an inflammatory component is present in the microenvironment of most neoplastic tissues, this in itself is a logical target for drug intervention. It thus follows that metformin maybe of value as an adjunct to conventional chemotherapy, in a wide spectrum of malignant diseases, and not only in patients with diabetes.
Tal Grenader, Anthony Goldberg, and Linda Shavit
Department of Oncology, Department of Medicine, Sha’are Zedek Medical
Center, Jerusalem, Israel
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Jiralerspong S, Palla SL, Giordano SH, et al: Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297-3302, 2009
2. Goodwin PJ, Ligibel JA, Stambolic V: Metformin in breast cancer: Time for action. J Clin Oncol 27:3271-3273, 2009
3. Pierce BL, Ballard-Barbash R, Bernstein L, et al: Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients.
J Clin Oncol 27:3437-3444, 2009
4. Dandona P: Effects of antidiabetic and antihyperlipidemic agents on C-reactive protein. Mayo Clin Proc 83:333-342, 2008
5. Lund SS, Tarnow L, Stehouwer CD, et al: Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 158:631-641, 2008
6. Ersoy C, Kiyici S, Budak F, et al: The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Diabetes Res Clin Pract 81:56-60, 2008
DOI: 10.1200/JCO.2009.25.4110; published online ahead of print at www.jco.org on November 2, 2009
■ ■ ■
JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E
Journal of Clinical Oncology, Vol 27, 2009 © 2009 by American Society of Clinical Oncology 1
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1...O.2009.25.4110






<table cellpadding="0" cellspacing="2" width="100%"><tbody><tr><td>Cancer abolishes the tissue-type specific differences in the phenotype of energetic metabolism
</td></tr> <tr><td>Acebo Paloma, Daniel Giner, Piedad Calvo, Blanco-Rivero Amaya, Alvaro D Ortega, Pedro L Fernández, Giovanna Roncador, Fernández-Malavé Edgar, Margarita Chamorro and José M Cuezva
</td></tr> <tr><td>Abstract Full Article</td></tr></tbody></table>
"Unexpectedly, we find that tumors from different tissues and/or histological subtypes have the same cellular content of these markers and, therefore, the same bioenergetic signature. It seems that cancer alters the expression of the markers of energetic metabolism of the cell in a tissue-specific manner (Table 1), consistent with the variable cellular response that oncogenes [3,24,25] and tumor suppressors [2,5,26] have on the phenotype of energetic metabolism. However, it is noteworthy that the bioenergetic signature is basically the same regardless of the tissue of origin and the histological type of the tumor (see β-F1/GAPDH ratio in Table 1 and Figure 2F). These findings could support that a common origin for tumors arises from an undifferentiated progenitor cell and that cancer cells undergo a process of dedifferentiation to acquire the traits of embryonic stem cells[27]. In this regard, we suggest that the bioenergetic signature of the tumors and, hence, the expression of markers of energetic metabolism partially respond to the installment of the reductive metabolic program (mainly glycolytic) that sustains cellular proliferation [15,28]. Conversely, the suppression of the tissue-specific differences in the bioenergetic signature of the tumors and its drastic reduction in certain tissues (Table 1) strongly support that containment of the mitochondrial bioenergetic activity in the cancer cell is an event required for tumor progression. Indeed, tumors with a low bioenergetic signature have a worse prognosis [6–8,10] and the activity of mitochondria has been shown to act as a tumor suppressor [12,14,29].
Owing to the convergence of breast, lung, and esophageal tumors on the same bioenergetic signature, it seems that energetic metabolism affords a common target for cancer therapy. In this regard, several groups and biotech companies are currently targeting the proteins of energetic metabolism as a promising approach to eradicate different types of tumors especially in combined therapy [30–33]. Overall, and because the bioenergetic signature provides a predictive marker of the response of tumors to chemotherapy [9], in agreement with the role of mitochondrial oxidative phosphorylation in the execution of cell death [11,13,14], we suggest that its translation to the clinics will benefit cancer patients."
....
the results support that energetic metabolism represents an additional hallmark of the phenotype of the cancer cell and a promising target for the treatment of diverse neoplasias




The following 2 studies do not necessarily contradict previously noted synergistic (beyond glucose) efficacy against multiple BC types. Instead, it suggests it can work by itself in triple negative breast cancer due to it's heavier reliance on glucose:


Cell Cycle. 2009 Jul 1;8(13):2031-40. Epub 2009 Jul 21.
Metformin induces unique biological and molecular responses in triple negative breast cancer cells.

Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, Thor AD.
Department of Pathology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
Comment in:

• Cell Cycle. 2009 Sep 1;8(17):2681.

Triple negative (TN) breast cancer is more frequent in women who are obese or have type II diabetes, as well as young women of color. These cancers do not express receptors for the steroid hormones estrogen or progesterone, or the type II receptor tyrosine kinase (RTK) Her-2 but do have upregulation of basal cytokeratins and the epidermal growth factor receptor (EGFR). These data suggest that aberrations of glucose and fatty acid metabolism, signaling through EGFR and genetic factors may promote the development of TN cancers. The anti-type II diabetes drug metformin has been associated with a decreased incidence of breast cancer, although the specific molecular subtypes that may be reduced by metformin have not been reported. Our data indicates that metformin has unique anti-TN breast cancer effects both in vitro and in vivo. It inhibits cell proliferation (with partial S phase arrest), colony formation and induces apoptosis via activation of the intrinsic and extrinsic signaling pathways only in TN breast cancer cell lines. At the molecular level, metformin increases P-AMPK, reduces P-EGFR, EGFR, P-MAPK, P-Src, cyclin D1 and cyclin E (but not cyclin A or B, p27 or p21), and induces PARP cleavage in a dose- and time-dependent manner. These data are in stark contrast to our previously published biological and molecular effects of metformin on luminal A and B, or Her-2 type breast cancer cells. Nude mice bearing tumor xenografts of the TN line MDA-MB-231, treated with metformin, show significant reductions in tumor growth (p = 0.0066) and cell proliferation (p = 0.0021) as compared to untreated controls. Metformin pre-treatment, before injection of MDA-MB-231 cells, results in a significant decrease in tumor outgrowth and incidence. Given the unique anti-cancer activity of metformin against TN disease, both in vitro and in vivo, it should be explored as a therapeutic agent against this aggressive form of breast cancer.

PMID: 19440038 [PubMed - indexed for MEDLINE]





5154] Selective Effects of Glucose, Insulin and Leptin by Molecular Breast Cancer Subtype.

Deng X-S, Liu B, Fan Z, Edgerton SM, Lind SE, Thor AD University of Colorado Denver, Aurora, CO

Background: Type II diabetes and obesity are important risk factors for post-menopausal luminal A (LA) and triple negative (TN) pre-menopausal breast cancers, particularly in African American (AA) and Hispanic women. Breast cancer patients with these chronic metabolic diseases also have a worse prognosis, independent of other factors. We have published that metformin inhibits cell growth (S phase arrest) and induces apoptosis, only in TN cell lines in vivo and in vitro. It is less active, growth inhibitory (G1 arrest) and does not induce apoptosis in other breast cancer cell subtypes (Cell Cycle, 2009).
Methods: We investigated the effects of glucose as a mitogen at physiologic (5mM), metabolic syndrome (7mM) or diabetic levels (10mM), with or without insulin (100 ng/ml) or leptin (100 ng/ml) using cell lines representing all molecular subtypes of breast cancer. Metformin was then used in combination with the above, to determine whether it would block the mitogenic or signaling effects of supraphysiological glucose, insulin or leptin.
Results: The LA (MCF-7) and 2 of 5 TN cell lines (derived from AA patients; HCC 1806 and MDA 468) showed the most cell growth in response to glucose >5mM (75% for MCF-7, 30-50% for AA TN lines). Three TN cell lines from Caucasians (MDA231, HCC1937, BT20), the HER2 (SKBR3) and luminal B (BT-474) cells showed less growth induction with glucose >5mM. In TN lines only, glucose associated mitogenesis was associated with increased EGFR, pEGFR, IGF1R, pIGF1R, AKT and pAKT and decreases in AMPK, pAMPK, p38, IRS2, and the cyclins D1, E and A in a dose dependent manner. Metformin abrogated glucose induced cell growth and the aforementioned protein expression/phosphorylation changes involving EGFR, IGF1R, and AKT, increased AMPK and pAMPK and induced a profound reduction in Cyclin D1 across all glucose concentrations in TN cell lines from AA women. It reduced but did not eliminate glucose associated mitogenesis in the TN cell lines from Caucasian patients. Metformin had a more variable effect on cell lines of other molecular subtypes grown under high glucose conditions. The 5 TN breast cancer cell lines were uniformly resistant to both leptin and insulin associated mitogenesis, across a wide range of glucose concentrations. In contrast, both leptin and insulin significantly promoted LA breast cancer cell growth. These effects were resistant to metformin treatment. Leptin and insulin had the least growth promoting effects on HER2 breast cancer cell lines, whereas they induced modest growth induction in LB cell lines.
Conclusions: All TN cell lines showed significant mitogenesis in response to glucose >5mM, whereas they were uniformly resistant to both leptin and insulin. The glucose associated mitogenesis was more pronounced in lines derived from AA patients, as were the anti-mitgenic effects of metformin. LA cells showed marked growth induction by glucose, leptin and insulin, whereas HER2 cell lines showed general resistance to all of these factors. These data suggest that metabolic and hormonal shifts with obesity and diabetes, as well as metformin response vary by the molecular subtype of breast cancer cells and ethnicity.

Saturday, December 12, 2009 5:30 PM

Poster Session 5: Tumor Biology: Metabolism and Breast Cancer (5:30 PM-7:30 PM)






Diabetes Drug Kills Cancer Stem Cells in Combination Treatment in Mice
September 14, 2009


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• Metformin is more effective than chemotherapy alone
• Study supports cancer stem cells hypothesis
• Laboratory study focused on breast cancer cells
Listen to a recorded mp3 of the teleconference.
PHILADELPHIA - In a one-two punch, a familiar diabetes drug reduced tumors faster and prolonged remission in mice longer than chemotherapy alone by targeting cancer stem cells, Harvard Medical School researchers reported in the September 14 online first edition of Cancer Research, a journal of the American Association for Cancer Research.
"We have found a compound selective for cancer stem cells," said lead researcher Kevin Struhl, Ph.D., the David Wesley Gaiser professor of biological chemistry and molecular pharmacology at Harvard Medical School. "What's different is that ours is a first-line diabetes drug."
These findings add to a growing body of preliminary evidence in cells, mice and people that metformin may improve breast cancer outcomes in people. In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.
The results fit within the cancer stem cell hypothesis, an intensely studied idea that small subsets of cancer cells have a special power to initiate tumors, fuel tumor growth and promote recurrence of cancer. Cancer stem cells appear to resist conventional chemotherapies, which kill the bulk of the tumor.
"There is a big desire to find drugs specific to cancer stem cells," said Struhl. "The cancer stem cell hypothesis says you cannot cure cancer unless you also get rid of the cancer stem cells. From a purely practical point of view, this could be tested in humans. It's already [in use as] a first-line diabetes drug."
The possible usefulness of a diabetes drug against cancer lends credence to an emerging idea that, in the vast and complex alphabet soup of molecular interactions within cells, a relatively few biological pathways will turn out to be most important for many different diseases, Struhl suggested.
In experiments led by postdoctoral fellows Heather Hirsch, Ph.D., and Dimitrios Iliopoulos, Ph.D., the combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture. The researchers used four genetically distinct breast cancer cell lines.
In mice, pretreatment with metformin prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors. In other mice where tumors took hold for 10 days, the combination therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone. In the two months between the end of treatment and the end of the experiment, tumors regrew in the mice treated with chemotherapy alone, but not in those who received both drugs. Metformin was ineffective in treating tumors when used alone.
"This is an exciting study," said Jennifer Ligibel, M.D., a medical oncologist at the Dana-Farber Cancer Institute and a Harvard Medical School instructor in medicine. Ligibel and colleagues at the National Cancer Institute of Canada Clinical Trials Group are developing a large-scale phase II trial and will study its metformin's impact on recurrence in women treated for early stage breast cancer.
"There is a lot of interest in studying metformin in breast cancer, but so far we do not have direct evidence that metformin will improve outcomes in patients," said Ligibel, who was not involved in the current study "That's what this trial is for."
So far, observational studies have suggested a lower risk of cancers, including breast cancer, and better response to chemotherapy in patients with diabetes who are treated with metformin, she said. Results of basic science studies have also suggested plausible biological mechanisms. The study from the Struhl lab suggests a potential new pathway through which metformin could have an effect on breast cancer cells, according to Ligibel.
In their search for compounds that selectively destroy cancer stem cells, researchers hope to improve cancer outcomes. But the story is never as simple in human cancers, according to Kornelia Polyak, M.D., Ph.D., a breast cancer researcher at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School.
Cancer stem cells are a shifty target, said Polyak, who was not involved in the current study. For example, any cancer cell can acquire the properties of a cancer stem cell, and cancer stem cells can change into non-stem cancer cells, which can be just as deadly. Clinical trials in people are needed to test these ideas, according to Polyak.
The study by Struhl and colleagues is an offshoot of a larger project in his lab to systematically track how gene activity changes when cells transform into cancer. These changes were remarkably similar to gene dynamics in diabetes and other inflammatory conditions.
The researchers reasoned that if a common genetic pathway underlies different diseases, drugs that work against one disease might work against another. In a screen, the most effective drug inhibiting the transformation of cells into cancer was metformin, which led to the experiments in this study. They were further encouraged by the low dose of metformin needed for the effect in the laboratory, compared to the amount needed for analogous molecular experiments in basic diabetes research. The relative dosage for treating or preventing cancer is unknown and untested in people.
Struhl and Harvard Medical School have applied for a patent for a combined therapy of metformin and a lower dose of chemotherapy, which is being tested in animals. The National Institutes of Health and the American Cancer Society funded this research.


News Briefing: The American Association for Cancer Research hosted a news briefing about the results of this study Monday, Sept. 14, 2009.
Download* the mp3 of the press briefing (8.74 MB, 38 minutes and 11 seconds)

*On a PC, right mouse click on the "Download" link and select "Save link as..." in Firefox or "Save Target as..." in Internet Explorer.

Panelists:
Moderator - Frank Rauscher, III, Ph.D.
Editor in Chief, Cancer Research
Professor, Gene Expression and Regulation Program
The Wistar Institute
Kevin Struhl, Ph.D.
David Wesley Gaiser Professor of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
George Prendergast, Ph.D.
President, CEO and Professor
Lankenau Institute for Medical Research
Jennifer Ligibel, M.D.
Medical Oncologist
Dana-Farber Cancer Institute
Download panelist photos through the following links

Frank Rauscher, III, Ph.D.
Kevin Struhl, Ph.D.
George Prendergast, Ph.D.
Jennifer Ligibel, M.D.
Read the full Cancer Research study here.

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Media Contacts:
Jeremy Moore
(267) 646-0557
jeremy.moore@aacr.org
Harvard Medical School
Carol Cruzan Morton
(617) 432-0442
communications@hms.harvard.edu
# # #



<style> .ExternalClass .ecxhmmessage P {padding:0px;} .ExternalClass body.ecxhmmessage {font-size:10pt;font-family:Verdana;} </style> Cancer Stem Cell Teleconference (August 14, 2009)

Sponsored by Cancer Research
A variety of researchers involved in the discussion but..

Foreword and comments by:
Frank Rauscher III, editor of Cancer Research

Interesting article/profile on Rauscher: LINK
Frank J. Rauscher III, Ph.D.
Professor
Gene Expression and Regulation Program
215-898-0995, Office
215-898-3929, Fax


A familiar diabetes drug reduced tumors faster and prolonged remission in mice longer than chemotherapy alone by targeting cancer stem cells, Harvard Medical School researchers reported in Cancer Research. The American Association for Cancer Research hosted a news briefing about the results of this study on Monday, Sept. 14, 2009. Read the press release and listen to the teleconference below for more information on the study and panelists.

Download* the mp3 of the press briefing (8.74 MB, 38 minutes and 11 seconds)

NOTES:

CSC hypothesis
Metformin: well known and safe, kills CSCs at low concentrations (lower than diabetes dose). Works on all breast cancer phenotypes, not connected to diabetes.
Synergizes with chemo (Doxo). Combination: regression quicker, no relapse for 3 months (as of teleconference). Could mean chemo could be lower dose. Safety profile means trials could start immediately.
Should be considered for cancer prevention.

Cancer cells are gluttons for glucose.

Metformin may produce immune memory to stave off cancer.

Inflammatory/immune response involved are important.

Metformin may be useful as low toxicity way to deplete dormant cancer cells i.e. CSCs.

Patients with higher insulin have increased breast cancer and mortality.
Diabetics on Metformin less on both accounts and better response rate to chemo.

Metformin may also have direct impact outside insulin (AMPK, MTOR)

NCI Canada MA32, post adjuvant Metformin monotherapy trial, available through cooperative groups in US (eg Dana Farber), enrollment in 2010?

Neoadjuvant Metformin trial in works.

Q&A

5-10% cancer stem cells. CSC far more tumor forming when injected.
Concentrations in experiments much lower than what diabetics use.
Less glucose response but more immune response, possibly inflammatory response.

Q: Why doesn't metformin monotherapy not show effect?
A: tried on fully formed tumor. At concentrations used, little effect on formed tumors. Other non cancer stem cells continue growing.

Italian study looking at Metformin in metastatic setting.

Principles involved not specific to breast cancer.

------------------------------------------------------------------------------




Breast Cancer Res Treat. 2010 Feb 5. [Epub ahead of print]
Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells.

Zakikhani M, Blouin MJ, Piura E, Pollak MN.
Department of Oncology, McGill University, Montreal, QC, Canada.
Rapamycin and its analogues inhibit mTOR, which leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5'- monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions, in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. As mTOR inhibition by rapamycin is associated with attenuation of negative feedback to IRS-1, rapamycin is known to increase activation of AKT, which may reduce its anti-neoplastic activity. We observed that metformin exposure decreases AKT activation, an action opposite to that of rapamycin. We show that metformin (but not rapamycin) exposure leads to increased phosphorylation of IRS-1 at Ser(789), a site previously reported to inhibit downstream signaling and to be an AMPK substrate phosphorylated under conditions of cellular energy depletion. siRNA methods confirmed that reduction of AMPK levels attenuates both the IRS-1 Ser(789) phosphorylation and the inhibition of AKT activation associated with metformin exposure. Although both rapamycin and metformin inhibit mTOR (the former directly and the latter through AMPK signaling), our results demonstrate previously unrecognized differences between these agents. The data are consistent with the observation that maximal induction of apoptosis and inhibition of proliferation are greater for metformin than rapamycin.

PMID: 20135346


Article LINK

Contact: Dama Kimmon
dama.kimmon@uc.edu
513-558-4519
University of Cincinnati Academic Health Center
Popular diabetes drug works differently than thought

CINCINNATI—The popular diabetes medication metformin works in different fashion than the current widely accepted view. This new finding could lead to wider use of the drug—particularly in people with cancer and diseases linked to TSC deficiency like tuberous sclerosis and lymphangioleiomyomatosis (LAM).
The results of this study, led by George Thomas, PhD, scientific director of UC's Metabolic Diseases Institute, are published in the May 5 edition of Cell Metabolism.
Metformin, marketed first by Bristol-Myers Squibb as Glucophage and now available in generic form and a number of combinations, is widely prescribed to people with type 2 diabetes and may be extended to the treatment of certain cancers. The drug blocks the production of glucose (sugar) and increases sensitivity to insulin—a hormone that converts sugar and other foods into energy within the body.
Researchers have thought that metformin, an energy-deprivation agent, disables the mTOR (mammalian target of rapamycin) complex by first activating the tuberous sclerosis complex (TSC) proteins through the enzyme AMPK.
Thomas' team determined that mTOR could actually be disabled without AMPK, and even without TSC. The team was able to determine that metformin works to knock out mTOR through another enzyme, RAG GTPase.
"We've poked a hole in dogma," says Thomas, a professor in the cancer and cell biology department. "Scientists can and should go back and ask about things they had crossed off their list."
The importance of this finding, says Thomas, is the possibility it holds for broader use of metformin.
"Metformin is already prescribed to 100 million people worldwide, and our study raises the question, 'Could this drug be used even more widely?'"
A drug like metformin, which improves insulin sensitivity, could be seen as a possible viable alternative to drugs that target mTOR, but that may have long-term deleterious effects on insulin production. Type 2 diabetes results from the body's inability to properly use insulin. If left unmanaged, diabetes can lead to vision loss, kidney failure, heart attack, stroke and nerve or blood vessel damage.



J Angiogenes Res. 2010 Feb 19;2(1):5.
Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors.

(available as user injectable Relistor)

Singleton PA, Mambetsariev N, Lennon FE, Mathew B, Siegler JH, Moreno-Vinasco L, Salgia R, Moss J, Garcia JG.
Department of Medicine, University of Chicago, 5841 S Maryland Avenue, W604, Chicago, IL 60637, USA. psinglet@medicine.bsd.uchicago.edu

Free text

Abstract

BACKGROUND: Recent cancer therapies include drugs that target both tumor growth and angiogenesis including mammalian target of rapamycin (mTOR) inhibitors. Since mTOR inhibitor therapy is associated with significant side effects, we examined potential agents that can reduce the therapeutic dose. METHODS: Methylnaltrexone (MNTX), a peripheral mu opioid receptor (MOR) antagonist, in combination with the mTOR inhibitors temsirolimus and/or rapamycin, was evaluated for inhibition of VEGF-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration as well as in vivo angiogenesis (mouse Matrigel plug assay). RESULTS: MNTX inhibited VEGF-induced EC proliferation and migration with an IC50 of approximately 100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation and migration from approximately 10 nM to approximately 1 nM and from approximately 50 to approximately 10 nM respectively. We observed similar effects with rapamycin. On a mechanistic level, we observed that MNTX increased EC plasma membrane-associated tyrosine phosphate activity. Inhibition of tyrosine phosphatase activity (3,4-dephostatin) blocked the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR Complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR Complex 1 (rapamycin and temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events. CONCLUSIONS: Our data indicate that MNTX exerts a synergistic effect with rapamycin and temsirolimus on inhibition of VEGF-induced human EC proliferation and migration and in vivo angiogenesis. Therefore, addition of MNTX could potentially lower the dose of mTOR inhibitors which could improve therapeutic index.

PMID: 20298531 [PubMed]PMCID: PMC2831839Free PMC Article




Regarding track record of using Metformin in non-diabetics:

Role of Metformin for Weight Management in Patients Without Type 2 Diabetes 2008
http://www.theannals.com/cgi/reprint/42/6/817



Oncogene. 2010 Feb 15. [Epub ahead of print]
Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation.

Zhang H, Fagan DH, Zeng X, Freeman KT, Sachdev D, Yee D.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Insulin receptor (IR) and the type I IGF receptor (IGF1R) are structurally and functionally related. The function of IGF1R in cancer has been well documented and anti-IGF1R strategies to treat cancer have shown initial positive results. However, the role of IR in tumor biology, independent of IGF1R, is less clear. To address this issue, short hairpin RNA (shRNA) was used to specifically downregulate IR in two cancer cell lines, LCC6 and T47D. Cells with reduced IR showed reduced insulin-stimulated Akt activation, without affecting IGF1R activation. Cells with reduced IR formed fewer colonies in anchorage-independent conditions. LCC6 IR shRNA xenograft tumors in mice had reduced growth, angiogenesis and lymphangiogensis when compared with LCC6 wild-type cells. Accordingly, LCC6 IR shRNA clones produced less hypoxia-inducible factor-1alpha, vascular endothelial growth factor (VEGF)-A and VEGF-D. Furthermore, LCC6 IR shRNA cells formed fewer pulmonary metastases when compared with LCC6 wild-type cells. Using in vivo luciferase imaging, we have shown that LCC6 IR shRNA cells have less seeding and colonization potential in the lung and liver of mice than LCC6 cells. In conclusion, downregulation of IR inhibited cancer cell proliferation, angiogenesis, lymphangiogenesis and metastasis. Our data argue that IR should also be targeted in cancer therapy.

Oncogene advance online publication, 15 February 2010; doi:10.1038/onc.2010.17.




Cancer Res. 2009 Aug 15;69(16):6539-45.
Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth.

Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E.
Departments of Medicine, CURE, Digestive Diseases Research Center, Molecular Biology Institute, University of California at Los Angeles, 90095-1786, USA.
Recently, we identified a novel crosstalk between insulin and G protein-coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTOR. Here, we determined whether metformin disrupts the crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, and BxPC-3) with insulin (10 ng/mL) for 5 minutes markedly enhanced the increase in intracellular [Ca(2+)] induced by GPCR agonists (e.g., neurotensin, bradykinin, and angiotensin II). Metformin pretreatment completely abrogated insulin-induced potentiation of Ca(2+) signaling but did not interfere with the effect of GPCR agonists alone. Insulin also enhanced GPCR agonist-induced growth, measured by DNA synthesis, and the number of cells cultured in adherent or nonadherent conditions. Low doses of metformin (0.1-0.5 mmol/L) blocked the stimulation of DNA synthesis, and the anchorage-dependent and anchorage-independent growth induced by insulin and GPCR agonists. Treatment with metformin induced striking and sustained increase in the phosphorylation of AMPK at Thr(172) and a selective AMPK inhibitor (compound C, at 5 micromol/L) reversed the effects of metformin on [Ca(2+)](i) and DNA synthesis, indicating that metformin acts through AMPK activation. In view of these results, we tested whether metformin inhibits pancreatic cancer growth. Administration of metformin significantly decreased the growth of MIAPaCa-2 and PANC-1 cells xenografted on the flank of nude mice. These results raise the possibility that metformin could be a potential candidate in novel treatment strategies for human pancreatic cancer.

PMID: 19679549 [PubMed - indexed for MEDLINE]

PMID: 20154728 [PubMed - as supplied by publisher]v



Cancer Res. 2010 Mar 9. [Epub ahead of print]
Targeting Cancer Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis in Prostate Cancer Cells.

Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F.
Authors' Affiliations: Institut National de la Sante et de la Recherche Medicale (INSERM), U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 7, Cellular and Molecular Physiopathology of Obesity and Diabetes; Université de Nice Sophia-Antipolis, Faculté de Médecine, Institut Signalisation et Pathologies; INSERM, U895, C3M, Team 1; INSERM, U576; INSERM, U634; Université de Nice Sophia-Antipolis, Centre Commun de Microscopie Appliquée; and INSERM, U895, C3M, Team 2, Nice, France.
Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, exerts antitumoral and antiproliferative action. In this study, the addition of metformin to 2-deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to 96% inhibition of cell viability in LNCaP prostate cancer cells. In contrast, a moderate effect on cell viability was observed in normal prostate epithelial cells. At the cellular level, the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase, and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity. In addition to apoptosis, the combination of metformin and 2DG arrested prostate cancer cells in G(2)-M. This G(2)-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug. Finally, metformin inhibited 2DG-induced autophagy, decreased beclin 1 expression, and triggered a switch from a survival process to cell death. Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment. Cancer Res; 70(6); 2465-75.

PMID: 20215500 [PubMed - as supplied by publisher]


Autophagy. 2010 Jul 21;6(5). [Epub ahead of print]
The combination of metformin and 2-deoxyglucose inhibits autophagy and induces AMPK dependent apoptosis in prostate cancer cells.

Sahra IB, Tanti JF, Bost F.
INSERM, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 7, Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France; Université de Nice Sophia-Antipolis, Faculté de Médecine, Institut Signalisation et pathologies, Nice, France.
Abstract

Targeting cancer cell metabolism is a promising new strategy to fight cancer. Metformin, a widely used antidiabetic agent, and 2-deoxyglucose (2DG) drastically affect cancer cell metabolism. Recently, we showed that the combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone. At the cellular level, this combination leads to p53- and AMPK-dependent apoptosis. Furthermore, we showed that metformin inhibits 2DG-induced autophagy, decreases beclin 1 expression and triggers a switch from a survival process to cell death.

PMID: 20559023 [PubMed - as supplied by publisher]






Breast Cancer Res Treat. 2010 Mar 19. [Epub ahead of print]
Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase.

Brown KA, Hunger NI, Docanto M, Simpson ER.
Prince Henry's Institute of Medical Research, P.O. Box 5152, Clayton, VIC, 3168, Australia, Kristy.Brown@princehenrys.org.
AMP-activated protein kinase (AMPK) is recognized as a master regulator of energy homeostasis. In concert with the AMPK-kinase LKB1, it has been shown to provide a molecular link between obesity and postmenopausal breast cancer via its actions to inhibit aromatase expression, hence estrogen production, within the breast. The anti-diabetic drug metformin is known to increase the activity of AMPK and was therefore hypothesized to inhibit aromatase expression in primary human breast adipose stromal cells. Results demonstrate that metformin significantly decreases the forskolin/phorbol ester (FSK/PMA)-induced expression of aromatase at concentrations of 10 and 50 muM. Consistent with the hypothesized actions of metformin to increase AMPK activity, treatment with 50 muM metformin results in a significant increase in phosphorylation of AMPK at Thr172. Interestingly, metformin also causes a significant increase in LKB1 protein expression and promoter activity, thereby providing for the first time an additional mechanism by which metformin activates AMPK. Furthermore, metformin inhibits the nuclear translocation of CRTC2, a CREB-coactivator known to increase aromatase expression which is also a direct downstream target of AMPK. Overall, these results suggest that metformin would reduce the local production of estrogens within the breast thereby providing a new key therapeutic tool that could be used in the neoadjuvant and adjuvant settings and conceivably also as a preventative measure in obese women.

PMID: 20300828 [PubMed - as supplied by publisher]






Cell Cycle. 2010 Mar 21;9(6). [Epub ahead of print]
Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena.

Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA.
Catalan Institute of Oncology (ICO) and Girona Biomedical Research Institute (IdIBGi), Girona, Catalonia, Spain.
In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs ("metabolic rehabilitation"). In the early 2000s, Anisimov's experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients' survival in type 2 diabetics. At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may constitute a novel "hybrid anti-cancer pill" physically combining both the long-lasting effects of antibodies-by persistently lowering levels of blood insulin and glucose-and the immediate potency of a cancer cell-targeting molecular agent-by suppressing the pivotal AMPK/mTOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER1 and HER2-. In this scenario, we discuss the relevance of metformin doses in pre-clinical models regarding metformin's mechanisms of action in clinical settings. We examine recent landmark studies demonstrating metformin's ability to specifically target the cancer-initiating stem cells from which tumor cells develop, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion hypothesis). We present the notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self-maintenance and repair (hormesis) might trigger counterintuitive detrimental effects. Ongoing chemopreventive, neoadjuvant and adjuvant trials should definitely establish whether metformin's ability to kill the "dandelion root" beneath the "cancer soil" likely exceeds metformin-related dangers of hormesis.

PMID: 20305377 [PubMed - as supplied by publisher]


Curr Mol Med. 2010 Aug 16. [Epub ahead of print]
Metformin and Energy Metabolism in Breast Cancer: From Insulin Physiology to Tumour-initiating Stem Cells.

Vazquez-Martin A, Oliveras-Ferraros C, CufÃ* S, Martin-Castillo B, Menendez JA.
Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain. jmenendez@iconcologia.net.
Abstract

A whole new area of investigation has emerged recently with regards to the anti-diabetic drug metformin and breast cancer. Metformin's anti-breast cancer actions, observed in population studies, in rodents and in cultured tumour cells, are especially encouraging because they attack not only the most common bulk of the tumour cells but also the more rare tumour-initiating stem cells. Here, we illustrate the multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and cellular levels constitutes a novel and valuable strategy to prevent and treat breast cancer disease.

PMID: 20712585 [PubMed - as supplied by publisher]

</form>

More on metformin
 

<table border="0" cellpadding="0" cellspacing="0" width="100%"> <tbody><tr><td align="left" valign="middle">http://www.sciencedaily.com/releases/2009/05/
090514153136.htm</td> <td id="printbutton" align="right" valign="middle"><input value="Print this page" onclick="window.print()" type="button"></td> </tr></tbody> </table> Old Diabetes Drug Teaches Experts New Tricks

ScienceDaily (May 20, 2009) — Research from the Johns Hopkins Children's Center reveals that the drug most commonly used in type 2 diabetics who don't need insulin works on a much more basic level than once thought, treating persistently elevated blood sugar — the hallmark of type 2 diabetes — by regulating the genes that control its production.
Reporting in the May 15 issue of Cell, investigators say they have zeroed in on a specific segment of a protein called CBP made by the genetic switches involved in overproduction of glucose by the liver that could present new targets for drug therapy of the disease.
In healthy people, the liver produces glucose during fasting to maintain normal levels of cell energy production. After people eat, the pancreas releases insulin, the hormone responsible for glucose absorption. Once insulin is released, the liver should turn down or turn off its glucose production, but in people with type 2 diabetes, the liver fails to sense insulin and continues to make glucose. The condition, known as insulin resistance, is caused by a glitch in the communication between liver and pancreas.
Metformin, introduced as frontline therapy for uncomplicated type 2 diabetes in the 1950s, up until now was believed to work by making the liver more sensitive to insulin. The Hopkins study shows, however, that metformin bypasses the stumbling block in communication and works directly in the liver cells.
"Rather than an interpreter of insulin-liver communication, metformin takes over as the messenger itself," says senior investigator Fred Wondisford, M.D., who heads the metabolism division at Hopkins Children's. "Metformin actually mimics the action of CBP, the critical signaling protein involved in the communication between the liver and the pancreas that's necessary for maintaining glucose production by the liver and its suppression by insulin."
To test their hypothesis, researchers induced insulin resistance in mice by feeding them a high-fat diet over several months. Mice on high-fat diets developed insulin resistance, and their high blood glucose levels did not drop to normal after eating. Once treated with metformin, however, CBP was activated to the levels of nondiabetic mice, and their blood glucose levels returned to normal. However, when given to diabetic mice with defective copies of CBP, metformin had no effect on blood glucose levels, a proof that metformin works through CBP.
Researchers further were able to determine that metformin worked on one particular section of CBP by studying the drug's effects in mice with normal CBP and in mice missing this section of their CBP. The mice with normal CBP responded to metformin with a drop in their fasting blood glucose — much like diabetes patients do — while the mice missing that section in their CBP had no decrease in their blood sugar.
Because CBP is involved in growth and development and a variety of metabolic processes in other organs, this newly discovered pathway may hold therapeutic promise for conditions like growth retardation, cancer and infertility, investigators say.
Another important finding in the study: Investigators have discovered a biomarker that can predict how well a person will respond to treatment with metformin and help doctors determine the optimal therapeutic dose, which can vary widely from person to person. The Hopkins team has found that in mice, metformin changes CBP in white bloods cells — just as it does in liver cells — creating a molecular marker that is easily measured via a standard blood test.
"This is the quintessence of individualized medicine: We have found an easily obtainable biomarker with great predictive power that can tell us whether and how well an individual will respond to treatment and help us determine the best dose right away instead of trying to do it by trial and error," Wondisford says.
Researchers caution that, while promising, their findings must be first replicated in humans.
Diabetes (type 1 and type 2) is a leading cause of kidney failure, eye disease and amputations, and one of the main causes of heart disease and stroke. Nearly 24 million Americans have type 2 diabetes, according to the U.S. Centers for Disease Control.
Lead author of the paper is Ling He.
Other investigators in the study include Amin Sabet, Stephen Djedjos, Ryan Miller, Mehboob Hussain and Sally Radovick, all of Hopkins, and Xiaojian Sun, of the University of Chicago.
The research was funded by the National Institutes of Health and by the Baltimore Diabetes Research and Training Center, a joint endeavor between Johns Hopkins and the University of Maryland for basic science, clinical research and community outreach on diabetes and obesity in both adults and children.
<hr> Adapted from materials provided by Johns Hopkins Medical Institutions, via EurekAlert!, a service of AAAS.
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Johns Hopkins Medical Institutions (2009, May 20). Old Diabetes Drug Teaches Experts New Tricks. ScienceDaily. Retrieved June 3, 2009, from http://www.sciencedaily.com* /releases/2009/05/090514153136.htm

J Nucl Med. 2007; 48 (Supplement 2):184P
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</td></tr> </tbody></table> </td></tr></tbody></table> <table cellpadding="0" cellspacing="0"><tbody><tr><td><hr noshade="noshade" size="1">Oncology: Clinical Diagnosis-Solid Tumors
Miscellaneous Tumors and Clinical Problems

</td></tr></tbody></table> Alteration of FDG uptake associated with metformin: Pitfall and opportunity

<nobr>Bahar Dasgeb¹</nobr> and <nobr>Eliot Siegel¹</nobr> ¹ Radiology/Nuclear Medicine, University of Maryland, Baltimore, Maryland
<!-- ABS --> 627
Objectives: Metformin, a biguanide molecule with 15 hour halflife, is commonly utilized in the treatment of non-insulin-dependentdiabetes mellitus. The major effect of metformin is postulatedto be enhanced glucose utilization. In vivo and in vitro studieshave demonstrated that metformin stimulates the insulin-inducedglucose uptake into skeletal muscle and adipocytes in both diabeticindividuals and animal models. It has also been shown that insulin-mediatedvisceral fat glucose uptake (VFGU) is enhanced by metforminmonotherapy which is believed to be related to enhanced VF insulinsensitivity. Administration of metformin is routinely discontinuedprior to administration of contrast for a CT study. The purposeof the study was to demonstrate and quantify the alterationin FDG uptake in subcutaneous tissue and peripheral striatedmuscle associated with the use of metformin. Methods: PET imageswere obtained on fifteen patients who had taken metformin eitherwithin four hours prior to an FDG PET examination, between fourand twelve hours, or more than twelve hours prior to the study.Subjective and quantitative analysis was made of the distributionand ratio of uptake in the striated muscles and subcutaneoustissue. Results: Patients who received metformin within 12 hoursof a PET study were found to have significantly increased uptakein their peripheral musculature and in their subcutaneous fatdiffusely as judged subjectively and utilizing ratios of uptakewith that in the liver and lungs in comparison to those thatdid not receive metformin within that time period. Conclusions:Metformin should be discontinued at least 12 hours prior toperforming a PET study regardless of whether intravenous CTcontrast material is administered. PET may also help quantifythe impact of metformin therapy on diabetic patients which couldhave treatment selection implications.




Free Radic Biol Med. 2010 Jan 15. [Epub ahead of print]
Paclitaxel Combined with Inhibitors of Glucose and Hydroperoxide Metabolism Enhances Breast Cancer Cell Killing Via H(2)O(2)-Mediated Oxidative Stress.

Hadzic T, Aykin-Burns N, Zhu Y, Coleman MC, Leick K, Jacobson GM, Spitz DR.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA.
Cancer cells (relative to normal cells) demonstrate alterations in oxidative metabolism characterized by increased steady-state levels of reactive oxygen species [i.e. hydrogen peroxide, H(2)O(2)] that may be compensated for by increased glucose metabolism but the therapeutic significance of these observations is unknown. In the current study, inhibitors of glucose [i.e., 2-deoxy-D-glucose, 2DG] and hydroperoxide [i.e., L-buthionine-S, R-sulfoximine, BSO] metabolism were utilized in combination with a chemotherapeutic agent paclitaxel [PTX], thought to induce oxidative stress, to treat breast cancer cells. 2DG+PTX were found to be more toxic than either agent alone in T47D and MDA-MB231 human breast cancer cells, but not in normal human fibroblasts or normal human mammary epithelial cells. Increases in parameters indicative of oxidative stress, including steady-state levels of H(2)O(2), total glutathione, and glutathione disulfide accompanied the enhanced toxicity of 2DG+PTX in cancer cells. Antioxidants, including N-acetyl-cysteine [NAC], polyethylene glycol-conjugated catalase [PEG-CAT] and superoxide dismutase [PEG-SOD], inhibited the toxicity of 2DG+PTX and suppressed parameters indicative of oxidative stress in cancer cells, while inhibition of glutathione synthesis using BSO further sensitized breast cancer cells to 2DG+PTX. These results show that combining inhibitors of glucose [2DG] and hydroperoxide [BSO] metabolism with PTX selectively (relative to normal cells) enhances breast cancer cell killing via H(2)O(2)-induced metabolic oxidative stress, and suggests that this biochemical rationale may be effectively utilized to treat breast cancers. Copyright © 2010. Published by Elsevier Inc.

PMID: 20083194 [PubMed - as supplied by publisher]





A treatment that capitalizes on the PET/Glucose mechanism:

http://www.antiagingmedicine.com/procedures_insulin.htm

Controlling Cancer Growth
At the Nevada Center we use a form of chemotherapy called Insulin Potentiation Therapy (IPT). IPT is a simple, safe medical treatment that exploits the fact that cancer cells, unlike healthy cells, are not able to metabolize fat for energy. They rely completely on glucose (sugar/carbohydrates) for their energy supply. This is a weakness of cancer cells, and we use this weakness to control them. We use the hormone insulin to do this.
When insulin is injected it has the effect of causing the patient’s blood sugar to drop. As the blood sugar drops, the patient’s healthy cells simply shift over to fat metabolism, but the patient’s cancer cells become seriously compromised. Since they rely entirely on sugar metabolism, they go into an emergency mode and open all of their membranes in an effort to get sugar. In this state they are very vulnerable to chemotherapy drugs.
Once the blood sugar has reached a low enough level for the treatment to be effective, we then inject the chemotherapy drugs. This is immediately followed by an intravenous infusion of large amounts of sugar. What happens next is that the cancer cells, weakened and starved for sugar, take up the chemotherapy drugs in large amounts as they take up the sugar they so desperately need.
The effect of this technique is two-fold. First, the cancer cells will take up much larger amounts of chemotherapy medications than they ordinarily would without the insulin application. Secondly, since they are in such a weakened and vulnerable state from the lack of sugar, they are much more sensitive to the toxic effects of the drugs. The result is a level of cancer cell death and growth control comparable to standard chemotherapy. But there is one very big difference.
IPT Is Gentle
Because the IPT technique results in a higher concentration of the chemo-therapeutic drugs in the cancer cells, we are able to use much lower chemo-therapy doses than are normally used to get the same intracellular levels. In general, we usually use about one tenth of the standard dose. A recent soon to be published review of patients treated with IPT shows that the cancer growth controlling effect of IPT is equal to that of standard chemotherapy.
The fact that we can use a lower dose of medication and yet have the same results leads to two very important advantages to IPT. First, the lower dose means that there are little to no side effects. Our patients typically feel as good as ever – even immediately after the treatments. Secondly, and perhaps more importantly, because the doses are so low, IPT treatments can be used as long as they are needed without the concern of long-term toxicity to healthy cells and tissues.



Cancer Res. 2009 Aug 15;69(16):6539-45.
Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth.

Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E.
Departments of Medicine, CURE, Digestive Diseases Research Center, Molecular Biology Institute, University of California at Los Angeles, 90095-1786, USA.
Recently, we identified a novel crosstalk between insulin and G protein-coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTOR. Here, we determined whether metformin disrupts the crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, and BxPC-3) with insulin (10 ng/mL) for 5 minutes markedly enhanced the increase in intracellular [Ca(2+)] induced by GPCR agonists (e.g., neurotensin, bradykinin, and angiotensin II). Metformin pretreatment completely abrogated insulin-induced potentiation of Ca(2+) signaling but did not interfere with the effect of GPCR agonists alone. Insulin also enhanced GPCR agonist-induced growth, measured by DNA synthesis, and the number of cells cultured in adherent or nonadherent conditions. Low doses of metformin (0.1-0.5 mmol/L) blocked the stimulation of DNA synthesis, and the anchorage-dependent and anchorage-independent growth induced by insulin and GPCR agonists. Treatment with metformin induced striking and sustained increase in the phosphorylation of AMPK at Thr(172) and a selective AMPK inhibitor (compound C, at 5 micromol/L) reversed the effects of metformin on [Ca(2+)](i) and DNA synthesis, indicating that metformin acts through AMPK activation. In view of these results, we tested whether metformin inhibits pancreatic cancer growth. Administration of metformin significantly decreased the growth of MIAPaCa-2 and PANC-1 cells xenografted on the flank of nude mice. These results raise the possibility that metformin could be a potential candidate in novel treatment strategies for human pancreatic cancer.

PMID: 19679549 [PubMed - indexed for MEDLINE]



Clin Cancer Res. 2010 Apr 13. [Epub ahead of print]
Crosstalk between Insulin/Insulin-like Growth Factor-1 Receptors and G Protein-Coupled Receptor Signaling Systems: A Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer.

Rozengurt E, Sinnett-Smith J, Kisfalvi K.
Authors' Affiliation: Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles California.
Abstract

Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine-paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between insulin/IGF-1 receptors and GPCR signaling systems in pancreatic cancer cells, leading to enhanced signaling, DNA synthesis, and proliferation. Crosstalk between these signaling systems depends on mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTORC1. Recent results show that metformin-induced activation of AMPK disrupts crosstalk between insulin/IGF-1 receptor and GPCR signaling in pancreatic cancer cells and inhibits the growth of these cells in xenograft models. Given that insulin/IGF-1 and GPCRs are implicated in other malignancies, a similar crosstalk mechanism may be operative in other cancer cell types. Recent epidemiological studies linked administration of metformin with a reduced risk of pancreatic, breast, and prostate cancer in diabetic patients. We posit that crosstalk between insulin/IGF-1 receptor and GPCR signaling is a mechanism for promoting the development of certain types of cancer and a target for the prevention and therapy of these diseases via metformin administration. Clin Cancer Res; 16(9); OF1-7. (c)2010 AACR.

PMID: 20388847 [PubMed - as supplied by publisher]


</form>

Link to carbs and blood sugar??

Might help explain why cancer and diabetes are on the rise.
I know for the last couple years when my Dad has had UTIs, they monitor his blood sugar and give insulin as needed though he is not considered diabetic. I was shocked the first time but they said it was to boost the immune system.

I wonder how connected the IGFR issue is:
http://en.wikipedia.org/wiki/Insulin...tor_1_receptor

<dl class="AbstractPlusReport"><dt class="head">
</dt><dt class="head">REFERENCE: Toleration of Metformin in non-diabetic patients.
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">1: Arch Physiol Biochem. 2009 May;115(2):86-96.http://www.ncbi.nlm.nih.gov/corehtml...-FULL_TEXT.gif
</dt><dd class="abstract"> Obesity related hyperinsulinaemia and hyperglycaemia and cancer development.

<!--AuthorList-->Becker S, Dossus L, Kaaks R.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Excess body weight in combination with physical inactivity is a major determinant for the development of insulin resistance with associated hyperglycaemia and hyperinsulinaemia and further leads to tumour development. Several prospective epidemiological studies have shown a direct association between excess weight and common malignancies, such as colon, breast (post-menopausal), endometrial, gallbladder, pancreatic, kidney and oesophageal cancers, but also less frequent malignancies, such as leukaemia, multiple myeloma and non-Hodgkin lymphoma. Insulin resistance and hyperinsulinaemia are certainly key biological mechanisms underlying the relationship between adiposity and tumour development. The anti-diabetic drug, metformin, in addition to reduction of insulin resistance has also shown anti-tumour properties, and is increasingly being considered as a drug to prevent and treat obesity-related cancers. Several biological pathways have been involved in the association between excess body weight, insulin resistance and cancer, such as chronic low-grade inflammation, glucose toxicity, AGE product metabolism and the adenosine monophosphate kinase pathway.
PMID: 19485704 [PubMed - in process</dd></dl>

Arch Pediatr Adolesc Med. 2010 Feb;164(2):116-23.
Metformin Extended Release Treatment of Adolescent Obesity: A 48-Week Randomized, Double-Blind, Placebo-Controlled Trial With 48-Week Follow-up.

Glaser Pediatric Research Network Obesity Study Group.
Division of Pediatric Endocrinology and Diabetes, Stanford University and the Lucile Packard Children's Hospital at Stanford, G-313 Medical Center, Stanford, CA 94305-5208. dwilson@stanford.edu.
BACKGROUND: Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported. OBJECTIVE: To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo. DESIGN: Multicenter, randomized, double-blind, placebo-controlled clinical trial. SETTING: The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007. PARTICIPANTS: Obese (BMI>/=95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo. RESULTS: After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed. CONCLUSION: Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program. Trial Registration clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.

PMID: 20124139 [PubMed - in process]

<dl class="AbstractPlusReport"><dt class="head">1: Clin Transl Oncol. 2009 Jul;11(7):455-9.<script language="JavaScript1.2"><!-- var Menu19574203 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1957 4203&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb(R)).

<!--AuthorList-->Vázquez-MartÃ*n A, Oliveras-Ferraros C, Del Barco S, MartÃ*n-Castillo B, Menéndez JA.
The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb(R)) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin(R)). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients.</dd></dl>
Cancer Res. 2009 Aug 15;69(16):6539-45.
Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth.

Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E.
Departments of Medicine, CURE, Digestive Diseases Research Center, Molecular Biology Institute, University of California at Los Angeles, 90095-1786, USA.
Recently, we identified a novel crosstalk between insulin and G protein-coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTOR. Here, we determined whether metformin disrupts the crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, and BxPC-3) with insulin (10 ng/mL) for 5 minutes markedly enhanced the increase in intracellular [Ca(2+)] induced by GPCR agonists (e.g., neurotensin, bradykinin, and angiotensin II). Metformin pretreatment completely abrogated insulin-induced potentiation of Ca(2+) signaling but did not interfere with the effect of GPCR agonists alone. Insulin also enhanced GPCR agonist-induced growth, measured by DNA synthesis, and the number of cells cultured in adherent or nonadherent conditions. Low doses of metformin (0.1-0.5 mmol/L) blocked the stimulation of DNA synthesis, and the anchorage-dependent and anchorage-independent growth induced by insulin and GPCR agonists. Treatment with metformin induced striking and sustained increase in the phosphorylation of AMPK at Thr(172) and a selective AMPK inhibitor (compound C, at 5 micromol/L) reversed the effects of metformin on [Ca(2+)](i) and DNA synthesis, indicating that metformin acts through AMPK activation. In view of these results, we tested whether metformin inhibits pancreatic cancer growth. Administration of metformin significantly decreased the growth of MIAPaCa-2 and PANC-1 cells xenografted on the flank of nude mice. These results raise the possibility that metformin could be a potential candidate in novel treatment strategies for human pancreatic cancer.

PMID: 19679549 [PubMed - indexed for MEDLINE]



Cancer Res. 2010 Feb 9. [Epub ahead of print]
Reduced Levels of IGF-I Mediate Differential Protection of Normal and Cancer Cells in Response to Fasting and Improve Chemotherapeutic Index.

Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, Hwang D, Cohen P, Bianchi G, Longo VD.
Authors' Affiliations: Andrus Gerontology Center, Department of Biological Sciences and Norris Cancer Center, University of Southern California; Pediatric Endocrinology, UCLA, Los Angeles, California; and Laboratory of Oncology, Giannina Gaslini Institute, Genova, Italy.
Inhibitors of the insulin-like growth factor-I (IGF-I) receptor have been widely studied for their ability to enhance the killing of a variety of malignant cells, but whether IGF-I signaling differentially protects the host and cancer cells against chemotherapy is unknown. Starvation can protect mice, but not cancer cells, against high-dose chemotherapy [differential stress resistance (DSR)]. Here, we offer evidence that IGF-I reduction mediates part of the starvation-dependent DSR. A 72-hour fast in mice reduced circulating IGF-I by 70% and increased the level of the IGF-I inhibitor IGFBP-1 by 11-fold. LID mice, with a 70% to 80% reduction in circulating IGF-I levels, were protected against three of four chemotherapy drugs tested. Restoration of IGF-I was sufficient to reverse the protective effect of fasting. Sixty percent of melanoma-bearing LID mice treated with doxorubicin achieved long-term survival whereas all control mice died of either metastases or chemotherapy toxicity. Reducing IGF-I/IGF-I signaling protected primary glia, but not glioma cells, against cyclophosphamide and protected mouse embryonic fibroblasts against doxorubicin. Further, S. cerevisiae lacking homologs of IGF-I signaling proteins were protected against chemotherapy-dependent DNA damage in a manner that could be reversed by expressing a constitutively active form of Ras. We conclude that normal cells and mice can be protected against chemotherapy-dependent damage by reducing circulating IGF-I levels and by a mechanism that involves downregulation of proto-oncogene signals. Cancer Res; 70(4); 1564-72.

PMID: 20145127 [PubMed - as supplied by publisher]

Cancer Therapies
 

If we must have oncologists and radiologists stacking the cards for our treatments as the primary decision-makers sitting on our tumor boards, wouldn't it make sense for medical schools to at least start training endocrinologists to help them (AND us) out?

AlaskaAngel

I have seen research in cancer being done by specialists in primarily non-oncology fields.

And it does seem that cancer treatment decisions get complicated by many areas of potential importance.

I remember hearing a while back about thyroid issues being related to cancer incidences. I still wonder if my mom's parathyroid issues that preceded recurrence were connected.

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

<table id="post209566" class="tborder" width="100%" align="center" border="0" cellpadding="6" cellspacing="0"><tbody><tr valign="top"><td class="alt1" id="td_post_209566" style="border-right: 1px solid rgb(204, 0, 51);">Diabetes drug also kills cancer stem cells
BOSTON, Sept. 14 (UPI) -- U.S. scientists say they've found that in human breast cancer cell tumors in mice, a diabetes drug worked better than chemotherapy in prolonging remission.
Researchers led by Harvard Medical School Professor Kevin Struhl said the mice appeared tumor-free for two months after treatment before the end of the experiment. The drug, metformin, appears to selectively kill cancer stem cells in culture dishes and in mice.
The scientists said their findings provide additional rationale for testing metformin in combination with chemotherapy in people with breast cancer and perhaps other cancers.
The scientists said their findings add to a growing body of preliminary evidence in cells, mice, and people that metformin may improve breast cancer outcomes in people. In the new study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes, the researchers said.
The study that included Heather Hirsch and Dimitrios Iliopoulos, along with Dr. Philip Tsichlis of Tufts University Medical Center, is reported in the early online edition of the journal Cancer Research.
<!-- / message --> </td> </tr> <tr> <td class="alt2" style="border-style: none solid solid; border-color: -moz-use-text-color rgb(204, 0, 51) rgb(204, 0, 51); border-width: 0px 1px 1px;"> http://her2support.org/vbulletin/ima...ser_online.gif http://her2support.org/vbulletin/ima...ons/report.gif </td> <td class="alt1" style="border-style: none solid solid none; border-color: -moz-use-text-color rgb(204, 0, 51) rgb(204, 0, 51) -moz-use-text-color; border-width: 0px 1px 1px 0px;" align="right"> <!-- controls --> http://her2support.org/vbulletin/ima...c/progress.gif http://her2support.org/vbulletin/ima...ttons/edit.gif</td></tr></tbody></table>

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Combo with anti-diabetes drug found effective against cancer
(AFP) – 1 day ago
SAN FRANCISCO — An anti-diabetes drug reduced tumors faster and prolonged remission further than chemotherapy when tested on mice, apparently by targeting cancer stem cells, a new report by Harvard Medical School found.
The report, published Monday in the online journal Cancer Research, argued that the drug metformin may improve breast cancer outcomes in people.
"We have found a compound selective for cancer stem cells," said senior author Kevin Struhl, a professor of biological chemistry and molecular pharmacology at Harvard Medical School. "What's different is that ours is a first-line diabetes drug."
In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.
The combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture, the report said. The researchers used four genetically distinct breast cancer cell lines.
In mice, pretreatment with the diabetes drug prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors.
In other mice where tumors were allowed to take hold for 10 days, the dual therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone, accordign to the study.
In the two months between the end of treatment and the end of the experiment, tumors regrew in mice treated with chemotherapy alone, but not in mice that had received both drugs.
By itself, metformin was ineffective in treating tumors.
"There is a big desire to find drugs specific to cancer stem cells," Struhl explained.
"The cancer stem cell hypothesis says you cannot cure cancer unless you also get rid of the cancer stem cells. From a purely practical point of view, this could be tested in humans. It's already used as a first-line diabetes drug."



Diabetes drug kept breast tumors away in mice

Mon Sep 14, 2009 7:45pm BST
By Julie Steenhuysen
CHICAGO (Reuters) - Adding the common diabetes drug metformin to chemotherapy helped shrink breast cancer tumors faster in mice and keep them away longer than chemotherapy alone, raising hope for a more effective way to treat cancer, U.S. researchers said on Monday.
They said metformin appeared to target breast cancer stem cells -- a kind of master cancer cell that resists conventional treatment and may be the source of many tumors that grow back.
"What's exciting here is we now have something that is mechanistically a different kind of killer of cancer that can synergize with chemotherapy," Kevin Struhl of Harvard Medical School, whose study appears in the journal Cancer Research, said in a telephone briefing.
Many teams have been looking for ways to destroy the master cancer cells in the hope of making cancer easier to cure.
Last month, a team at the Broad Institute of Harvard and the Massachusetts Institute of Technology reported that a chemical called salinomycin could kill breast cancer stem cells.
What is different with his study, Struhl said, is that metformin is a widely used drug with a long safety track record. "There are tens of millions of people who take this drug," he said.
"Although our studies are limited to mice and cells, metformin has a history of anti-cancer effects," he said.
Metformin has already been shown to reduce the risk of some cancers, including pancreatic and breast cancer, in large studies of people with diabetes.
Struhl said metformin's affect on cancer stem cells appeared to be separate from its ability to help the body use insulin and lower blood sugar -- which also can improve breast cancer survival.
His team studied metformin and the cancer drug doxorubicin in lab dishes and found they killed both human cancer stem cells and non-stem cancer cells.
Mice that had tumors and got metformin and chemotherapy were less likely to have tumors grow back two months after treatment compared with mice that got chemotherapy alone.
"When we had both drugs together, we lost the tumors faster, but more importantly, there was no relapse," Struhl said.
He said with metformin, it may be possible to reduce the chemotherapy dose and still get the same benefit.
That will need to be studied in people and a study is getting under way. Dr. Jennifer Ligibel, at Dana-Farber Cancer Institute and Harvard, is organizing a large trial with colleagues in Canada to study metformin in women with early stage breast cancer.

<dl class="AbstractPlusReport"><dt class="head">1: Cancer Res. 2009 Sep 14. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...anres_full.gif <script language="JavaScript1.2"><!-- var Menu19752085 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1975 2085&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission.

<!--AuthorList-->Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent, doxorubicin, kills both cancer stem cells and non-stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2 months after combinatorial therapy with metformin and doxorubicin is ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers. [Cancer Res 2009;69(19):OF1-5]. <table class="content_box_inner_table"><tbody><tr><td class="content_box_space_between_sections" colspan="2">http://cancerres.aacrjournals.org/icons/spacer.gif</td></tr> <tr><td class="content_box_arrow" valign="top" width="4">http://cancerres.aacrjournals.org/ic...arrowTtrim.gif</td><td class="content_box_item"> Full Text </td></tr> <tr><td class="content_box_arrow" valign="top" width="4">http://cancerres.aacrjournals.org/ic...arrowTtrim.gif</td><td class="content_box_item"> Full Text (PDF) </td></tr> <tr><td class="content_box_arrow" valign="top" width="4">http://cancerres.aacrjournals.org/ic...arrowTtrim.gif</td><td class="content_box_item"> Correction </td></tr> <tr><td class="content_box_arrow" valign="top" width="4">http://cancerres.aacrjournals.org/ic...arrowTtrim.gif</td><td class="content_box_item"> All Versions of this Article:
0008-5472.CAN-09-2994v1
69/19/7507 most recent</td></tr></tbody></table> </dd></dl>

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

http://www.pharmacorama.com/en/Sections/Insulin_4.php

Enhancers of insulin effects, metformin

The drugs which potentiate the effects of insulin are metformin and thiazolidinediones derivatives.
Metformin is a biguanide. It decreases hyperglycemia without risk of hypoglycemia because it does not lower glycemia in healthy subjects. It has an antihyperglycemic effect. Contrary to sulfonylureas, metformin does not stimulate insulin secretion. It can thus be regarded as a potentialisator of insulin.
Its mechanism of action is complex. It acts in the presence of insulin:

• by increasing glucose uptake and utilization by tissues, in particular by skeletal muscles
• by decreasing hepatic glucose production: it decreases hepatic gluconeogenesis, i.e. formation of glycogen from the amino acids and lipids.
• By decreasing intestinal absorption of glucose

Clinical trials show that metformin in diabetics reduces the fasting glycemia, glycosylated hemoglobin, blood cholesterol and triglycerides.
Metformin is not metabolized by biotransformations. It is present in the plasma in a free form, unbound toproteins. Its plasma half-life is about two to four hours. It is eliminated by the kidney and, in the event of renal impairment, risks to accumulating. The renal impairment is thus a contraindication to its prescription.
It is indicated in the treatment of type 2 diabetes mellitus not balanced by an adapted life style, particularly in overweight subjects. It is sometimes used as additive to insulin therapy in the treatment of insulin-dependant diabetes. Metformin could delay the mortality of the diabetics, especially the obese.
The most severe adverse effect of metformin is lactic acidosis, which can be fatal. Its premonitory signs are cramps, digestive disorders, intense abdominal pains, asthenia. These signs must lead to discontinuation of treatment and hospitalization. This lactic acidosis is seen especially in patients with renal or hepatic impairment. The diagnosis is confirmed by determination of blood lactic acid.
It can have other adverse effects: various digestive disorders, nausea, vomiting, diarrhea, especially at the beginning of treatment.
Metformin must be stopped before a radiological examination using iodized contrast agents because they are hyperosmolar and create a cellular dehydration, likely to induce lactic acidosis.



Curr Cancer Drug Targets. 2009 Sep;9(6):748-60.
Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy.

TEXT purchase

van der Veeken J, Oliveira S, Schiffelers RM, Storm G, van Bergen En Henegouwen PM, Roovers RC.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor-1 receptor (IGF-1R) can contribute to tumor development and -progression through their effects on cell proliferation, inhibition of apoptosis, angiogenesis, anchorage-independent growth and tumor-associated inflammation. EGFR-targeting monoclonal antibodies and small molecule tyrosine kinase inhibitors are currently in clinical use for the treatment of several types of cancer. However, primary and acquired resistance to these agents often occurs and thereby limits the clinical efficacy of mono-specific targeted therapy. Results from both in vitro and in vivo studies indicate that cross-talk between EGFR and IGF-1R can lead to acquired resistance against EGFR-targeted drugs.multi-layered cross-talk and its involvement in the induction of resistance to targeted therapies provide a clear rationale for dual targeting of EGFR and IGF-1R. This review describes the interface between the EGFR and IGF-1R signaling networks and the implications of the extensive cross-talk between these two receptor systems for cancer therapy. EGFR and IGF-1R interact on multiple levels, either through a direct association between the two receptors, by mediating the availability of each others ligands, or indirectly, via common interaction partners such as G protein coupled receptors (GPCR) or downstream signaling molecules. This We discuss several (potential) strategies to simultaneously inhibit EGFR and IGF-1R signaling as promising novel therapeutic approaches.

PMID: 19754359 [PubMed - indexed for MEDLINE]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

http://www.diabeteshealth.com/read/2...r-wonder-drug/

Mighty Metformin: The New Cancer Wonder Drug

Sep 25, 2009

Metformin has always been the old reliable for treating new onset type 2 diabetes, but it's beginning to look like it's got a new calling as a cancer treatment. Diabetes Health recently reported on the fact that metformin reduces a type 2 person's risk of pancreatic cancer by up to 62 percent. It's also been observed that people with type 2 who take metformin have a much lower cancer incidence than those who don't. Now it appears that metformin can help with breast cancer treatment as well. A study of mice with breast cancer generated from human breast cancer cells has found that they remained tumor-free for nearly three months on metformin combined with doxorubicin, a standard cancer chemotherapy. In mice given only the doxorubicin, the tumors recurred.
How metformin suppresses cancer has been unclear, but now researchers believe that they may have the answer. According to Dr. Kevin Struhl of Harvard Medical School, the lead researcher of the study, metformin selectively kills cancer stemcells. This is an extremely valuable talent because stem cells, which make up five to ten percent of a tumor's cells, are resistant to chemotherapy. Although standard chemotherapy kills the mature cancer cells that comprise most of the tumor, it can't vanquish the cancer stem cells. Consequently, the tumor is able to regrow after standard chemotherapy. But the combination of standard chemo and metformin appears to be very powerful.
The researchers hope that by adding metformin to the cancer treatment regimen, it will be possible to reduce the dose of standard chemo. According to Dr. Struhl, current chemo regimens load patients up with as much as they can possibly tolerate. With metformin, however, the doses of standard chemo could possibly be reduced, allowing good results with fewer side effects.
Dr. Struhl's study grew out of another project, during which he found that the gene activity changes that occur when cells transform into cancer are a lot like what goes on in diabetes and other inflammatory conditions. He reasoned that if a common genetic pathway underlies different diseases, drugs that work against one disease might also work against another. After screening a number of drugs, he found that metformin was most effective in inhibiting cells from transforming into cancer. Those findings led to his current study, the results of which were published in the September 14 online edition of Cancer Research, a journal of the American Association for Cancer Research.
Although the current research was conducted on mice, their cancer cells were actually of human origin, which is promising. The researchers are now planning clinical trials conducted on humans. This normally lengthy process might be hastened by the fact that metformin is already an accepted drug that is known to be safe. In fact, a clinical trial to see if metformin alone is effective in preventing breast cancer from recurring in early stage breast cancer patients who have already had surgery and chemo will begin enrolling patients next year.
Interestingly, Dr. Struhl and Harvard Medical School have already applied for a patent that would cover a combination of metformin and a lower dose of chemotherapy to treat cancer.



Breast Cancer Res Treat. 2009 Nov 22. [Epub ahead of print]
Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy.

Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP.
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT, 06030-3501, USA.
Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events.

PMID: 20204498 [PubMed - as supplied by publisher]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

http://www.pulsetoday.co.uk/story.as...de=4123806&c=1
Study raises new questions over insulin glargine cancer risk

02 Oct 09
By Lilian Anekwe

A controversial trial by UK researchers has reopened the debate about a possible link between insulin glargine and cancer, after finding a six-fold increase in cancer incidence among patients in the treatment.

Researchers speculated that insulin glargine could cause metabolic changes that might accelerate the growth of pre-existing tumours.
But prescribing Metformin in addition to insulin glargine appeared to have a protective effect, cancelling out the risk of cancer at lower insulin doses and halving it at the highest doses.
In response to the trial’s findings, Sanofi-Aventis, manufacturer of insulin glargine, announced it will launch a new probe that will ‘provide methodologically robust research that will contribute to the debate over insulin safety’.
In July, the European Association for the Study of diabetes (EASD) made ‘an urgent call for more research into a possible link between insulin glargine and increased risk of cancer’, following evidence from studies in Germany, Sweden and the UK.
The latest study, presented in a stormy session last week at the EASD annual meeting in Vienna, analysed cancer incidence at more than 300 GP practices in the UK.
<script language="JavaScript" type="text/javascript"> bust = Math.floor(1000000*Math.random()); document.write('<script language="JavaScript" src="http://ad.doubleclick.net/adj/Pulse.co.uk/site=cmpi;affiliate=pulse;etype=;target=/story.asp;sectioncode=0;navcode=0;pubcode=4;articl eid=4123806;affinity2=no;pagepos=inlinestory;sz=;o rd='+bust+'?" type="text/javascript"></scr' + 'ipt>'); </script><script language="JavaScript" src="http://ad.doubleclick.net/adj/Pulse.co.uk/site=cmpi;affiliate=pulse;etype=;target=/story.asp;sectioncode=0;navcode=0;pubcode=4;articl eid=4123806;affinity2=no;pagepos=inlinestory;sz=;o rd=331270?" type="text/javascript"></script>http://m1.2mdn.net/viewad/817-grey.gif
Researchers analysed data from 5,000 patients with type 2 diabetes on a combination of insulin glargine and metformin, and over 30,000 on insulin alone.
Crude cancer rates at the highest doses of both drugs were 60 per 1,000 person-years in patients treated with insulin alone compared with 10 with metformin alone. The rate fell to 34 cancers per 1,000 person-years when metformin treatment was added.
After adjusting for age, gender and smoking status, insulin monotherapy was associated with a 5.7-fold increase in the risk of any cancer, which fell to 3.2 when metformin was also prescribed.
Study leader Dr Craig Currie, research fellow at the University of Cardiff school of medicine, told delegates: ‘The results are highly statistically valid. There was a dose-dependent association between insulin glargine and cancer in type 2 diabetes – supporting the principle of causality.’
EASD president Professor Ulf Smith said: ‘The epidemiological relationship is clear but association is not the same as cause. What we’re worried about is in patients with already existing cancers their growth may be accelerated in the presence of insulin glargine.’
But Dr Jay Skyler, associate director of the Diabetes Research Institute in Miami and a consultant for Sanofi-Aventis, insisted: ‘

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Metformin as fountain of youth (for mice)..other drugs mentioned

http://www.google.com/hostednews/afp...Iwzgdueus52qFg

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Gynecol Oncol. 2009 Oct 10. [Epub ahead of print]
Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy.

Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, CB #7572, Chapel Hill, NC 27599-7572, USA.
OBJECTIVES: Obesity and diabetes are strong risk factors that drive the development of type I endometrial cancers. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce rates of cancer deaths among diabetic patients. In order to better understand metformin's anti-tumorigenic potential, our goal was to assess the effect of metformin on proliferation and expression of key targets of metformin cell signaling in endometrial cancer cell lines. METHODS: The endometrial cancer cell lines, ECC-1 and Ishikawa, were used. Cell proliferation was assessed after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3 activity. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin. RESULTS: Metformin potently inhibited growth in a dose-dependent manner in both cell lines (IC(50) of 1 mM). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, within 24 h of exposure. In parallel, treatment with metformin decreased phosphorylation of S6 protein, a key target of the mTOR pathway. CONCLUSIONS: We find that metformin is a potent inhibitor of cell proliferation in endometrial cancer cell lines. This effect is partially mediated through AMPK activation and subsequent inhibition of the mTOR pathway. This work should provide the scientific foundation for future investigation of metformin as a strategy for endometrial cancer prevention and treatment.

PMID: 19822355 [PubMed - as supplied by publisher]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

http://cancerres.aacrjournals.org/cg...ct/66/21/10269


doi: 10.1158/0008-5472.CAN-06-1500
© 2006 American Association for Cancer Research


Priority Reports

Metformin Is an AMP Kinase–Dependent Growth Inhibitor for Breast Cancer Cells

<nobr>Mahvash Zakikhani¹</nobr>, <nobr>Ryan Dowling²</nobr>, <nobr>I. George Fantus³</nobr>, <nobr>Nahum Sonenberg²</nobr> and <nobr>Michael Pollak¹</nobr> Departments of ¹ Oncology and ² Biochemistry, McGill University, Montreal, Quebec, Canada and ³ Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Requests for reprints: Michael Pollak, Cancer Prevention Center, Jewish General Hospital, E-763, 3755 Cote Ste. Catherine Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8222, ext. 4139; Fax: 514-340-8600; E-mail: Michael.pollak@mcgill.ca<script type="text/javascript"><!-- var u = "Michael.pollak", d = "mcgill.ca"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>.
<!-- ABS --> Recent population studies provide clues that the use of metforminmay be associated with reduced incidence and improved prognosisof certain cancers. This drug is widely used in the treatmentof type 2 diabetes, where it is often referred to as an "insulinsensitizer" because it not only lowers blood glucose but alsoreduces the hyperinsulinemia associated with insulin resistance.As insulin and insulin-like growth factors stimulate proliferationof many normal and transformed cell types, agents that facilitatesignaling through these receptors would be expected to enhanceproliferation. We show here that metformin acts as a growthinhibitor rather than an insulin sensitizer for epithelial cells.Breast cancer cells can be protected against metformin-inducedgrowth inhibition by small interfering RNA against AMP kinase.This shows that AMP kinase pathway activation by metformin,recently shown to be necessary for metformin inhibition of gluconeogenesisin hepatocytes, is also involved in metformin-induced growthinhibition of epithelial cells. The growth inhibition was associatedwith decreased mammalian target of rapamycin and S6 kinase activationand a general decrease in mRNA translation. These results provideevidence for a mechanism that may contribute to the antineoplasticeffects of metformin suggested by recent population studiesand justify further work to explore potential roles for activatorsof AMP kinase in cancer prevention and treatment. (Cancer Res2006; 66(21): 10269-73)

J Cell Mol Med. 2009 Oct 29. [Epub ahead of print]
Metformin attenuates ovarian cancer cell growth in an AMP- kinase dispensable manner.

Rattan R, Giri S, Hartmann L, Shridhar V.
Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905.
ABSTRACT Metformin, the most widely used drug for type 2 diabetes activates AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Here, we report that ovarian cell lines VOSE, A2780, CP70, C200, OV202, OVCAR3, SKOV3ip, PE01 and PE04 predominantly express -alpha1, -beta1, -gamma1 and -gamma2 isoforms of AMPK subunits. Our studies show that metformin treatment


(1) significantly inhibited proliferation of diverse chemo-responsive and -resistant ovarian cancer cell lines (A2780, CP70, C200, OV202, OVCAR3, SKVO3ip, PE01 and PE04),

(2) caused cell cycle arrest accompanied by decreased cyclin D1 and increased p21 protein expression,

(3) activated AMPK in various ovarian cancer cell lines as evident from increased phosphorylation of AMPKalpha and its downstream substrate; ACC (Acetyl Co-carboxylase) and enhanced beta- oxidation of fatty acid,

(4) attenuated mTOR-S6RP phosphorylation, inhibited protein translational and lipid biosynthetic pathways, thus implicating metformin as a growth inhibitor of ovarian cancer cells. We also show that metformin mediated effect on AMPK is dependent on LKB1(Liver kinase B1) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 null mouse embryo fibroblasts (mefs). This observation was further supported by using siRNA approach to downregulate LKB1 in ovarian cancer cells. In contrast, metformin inhibited cell proliferation in both wild type and AMPKalpha1/2 null mefs as well as in AMPK silenced ovarian cancer cells. Collectively, these results provide evidence on the role of metformin as an anti-proliferative therapeutic that can act through both AMPK dependent as well as independent pathways.

PMID: 19874425 [PubMed - as supplied by publisher]



Oncogene. 2008 Jun 5;27(25):3576-86. Epub 2008 Jan 21.
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F.
INSERM U568, Nice, France.
Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.


J Mol Signal. 2008 Dec 1;3:18.
Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1.

Zhuang Y, Miskimins WK.
Cancer Biology Research Center, Sanford Research/USD, 1400 West 22nd Street, Sioux Falls, South Dakota, 57105, USA. keith.miskimins@usd.edu.
ABSTRACT: BACKGROUND: The antihyperglycemic drug metformin may have beneficial effects on the prevention and treatment of cancer. Metformin is known to activate AMP-activated protein kinase (AMPK). It has also been shown to inhibit cyclin D1 expression and proliferation of some cultured cancer cells. However, the mechanisms of action by which metformin mediates cell cycle arrest are not completely understood. RESULTS: In this study, metformin was found to inhibit proliferation of most cultured breast cancer cell lines. This was independent of estrogen receptor, HER2, or p53 status. Inhibition of cell proliferation was associated with arrest within G0/G1 phase of the cell cycle. As in previous studies, metformin treatment led to activation of (AMPK) and downregulation of cyclin D1. However, these events were not sufficient for cell cycle arrest because they were also observed in the MDA-MB-231 cell line, which is not sensitive to growth arrest by metformin. In sensitive breast cancer lines, the reduction in cyclin D1 led to release of sequestered CDK inhibitors, p27Kip1 and p21Cip1, and association of these inhibitors with cyclin E/CDK2 complexes. The metformin-resistant cell line MDA-MB-231 expresses significantly lower levels of p27Kip1 and p21Cip1 than the metformin-sensitive cell line, MCF7. When p27Kip1 or p21Cip1 were overexpressed in MDA-MB-231, the cells became sensitive to cell cycle arrest in response to metformin. CONCLUSION: Cell cycle arrest in response to metformin requires CDK inhibitors in addition to AMPK activation and cyclin D1 downregulation. This is of interest because many cancers are associated with loss or downregulation of CDK inhibitors and the results may be relevant to the development of anti-tumor reagents that target the AMPK pathway.

PMID: 19046439 [PubMed - in process]




Cell Cycle. 2009 Mar 15;8(6):909-15. Epub 2009 Mar 26.
Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro.

Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, Thor AD.
Department of Pathology, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
The anti-diabetic drug metformin reduces human cancer incidence and improves the survival of cancer patients, including those with breast cancer. We studied the activity of metformin against diverse molecular subtypes of breast cancer cell lines in vitro. Metformin showed biological activity against all estrogen receptor (ER) positive and negative, erbB2 normal and abnormal breast cancer cell lines tested. It inhibited cellular proliferation, reduced colony formation and caused partial cell cycle arrest at the G(1) checkpoint. Metformin did not induce apoptosis (as measured by DNA fragmentation and PARP cleavage) in luminal A, B or erbB2 subtype breast cancer cell lines. At the molecular level, metformin treatment was associated with a reduction of cyclin D1 and E2F1 expression with no changes in p27(kip1) or p21(waf1). It inhibited mitogen activated protein kinase (MAPK) and Akt activity, as well as the mammalian target of rapamycin (mTOR) in both ER positive and negative, erbB2-overexpressing and erbB2-normal expressing breast cancer cells. In erbB2-overexpressing breast cancer cell lines, metformin reduced erbB2 expression at higher concentrations, and at lower concentrations within the therapeutic range, it inhibited erbB2 tyrosine kinase activity evidenced by a reduction of phosphorylated erbB2 (P-erbB2) at both auto- and Src- phosphorylation sites. These data suggest that metformin may have potential therapeutic utility against ER positive and negative, erbB2-overexpressing and erbB2-normal expressing breast cancer cells.

PMID: 19221498 [PubMed - indexed for MEDLINE]






Cancer Res. 2007 Jul 15;67(14):6745-52.
Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth.

Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB.
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
The effect of the antidiabetic drug metformin on tumor growth was investigated using the paired isogenic colon cancer cell lines HCT116 p53(+/+) and HCT116 p53(-/-). Treatment with metformin selectively suppressed the tumor growth of HCT116 p53(-/-) xenografts. Following treatment with metformin, we detected increased apoptosis in p53(-/-) tumor sections and an enhanced susceptibility of p53(-/-) cells to undergo apoptosis in vitro when subject to nutrient deprivation. Metformin is proposed to function in diabetes treatment as an indirect activator of AMP-activated protein kinase (AMPK). Treatment with AICAR, another AMPK activator, also showed a selective ability to inhibit p53(-/-) tumor growth in vivo. In the presence of either of the two drugs, HCT116 p53(+/+) cells, but not HCT116 p53(-/-) cells, activated autophagy. A similar p53-dependent induction of autophagy was observed when nontransformed mouse embryo fibroblasts were treated. Treatment with either metformin or AICAR also led to enhanced fatty acid beta-oxidation in p53(+/+) MEFs, but not in p53(-/-) MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin treatment also suppressed mitochondrial electron transport. Metformin-treated cells compensated for this suppression of oxidative phosphorylation by increasing their rate of glycolysis in a p53-dependent manner. Together, these data suggest that metformin treatment forces a metabolic conversion that p53(-/-) cells are unable to execute. Thus, metformin is selectively toxic to p53-deficient cells and provides a potential mechanism for the reduced incidence of tumors observed in patients being treated with metformin.

PMID: 17638885 [PubMed - indexed for MEDLINE]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Diabetologia. 2005 Dec;48(12):2454-9. Epub 2005 Nov 11.
Contraindications can damage your health--is metformin a case in point?

Holstein A, Stumvoll M.
Clinic Lippe, First Department of Medicine, Detmold, Germany.
Comment in:

• Diabetologia. 2006 May;49(5):1127-8.

Metformin is an effective anti-hyperglycaemic and cardioprotective agent, but a long list of contraindications precludes millions of patients with type 2 diabetes from using it. This is largely due to the historical experience of lactic acidosis with phenformin, despite the fact that metformin does not predispose to this when compared with other therapies. Contraindications such as old age, renal impairment and cardiac insufficiency are increasingly disregarded in clinical practice, yet there is no evidence that the incidence of lactic acidosis has changed. Metformin has been shown to improve metabolic control without causing lactic acidosis in elderly patients with multiple comorbidities, including explicit contraindications, and its use in patients with type 2 diabetes over the age of 70 with mild renal impairment did not produce a clinically relevant increase in plasma lactate. There is no correlation between levels of metformin and lactate in patients with lactic acidosis, and its prognosis is mainly related to the causal hypoxic underlying disease and comorbidities. These findings raise doubts about the pathogenetic significance of metformin in lactic acidosis. We propose that advanced age per se, mild renal impairment and compensated heart failure can no longer be upheld as contraindications for metformin. A clear re-definition of contraindications to metformin will enable more physicians to prescribe within guidelines.

PMID: 16283245 [PubMed - indexed for MEDLINE]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Metformin, insulin, breast cancer and more…
Lev M Bersteinhttp://www.futuremedicine.com/entityImage/?code=200B*
Evaluation of: Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG:

Insulin-lowering effects of metformin in women with early breast cancer.
Clin. Breast Cancer 8(6), 501–505 (2008).

This paper demonstrates that in breast cancer patients without overt diabetes mellitus, the antidiabetic biguanide metformin at a dose of 1500 mg/day reduces initially increased fasting insulinemia by 22.4% on average, 6 months after the onset of treatment. Since the same authors reported earlier on the association between preoperational insulinemia and breast cancer progression rate, an important conclusion from the above publication was that a Phase III randomized trial of metformin is warranted in order to assess the possible antitumor effect of this preparation. The evaluation presented below briefly addresses the history of the issue and possible targets of metformin effects beside its insulin-related action. It is argued that in selecting breast cancer patients for metformin therapy, one should take into account, along with the standard criteria, the pharmacogenetic aspects, estrogen production and specific features of estrogenic signaling, and also the expression of important metformin targets, including AMP-activated protein kinase, in tumor tissue.

<!-- /abstract content --><!-- fulltext content --> <table align="center" cellspacing="10"><tbody><tr><td align="center" nowrap="nowrap">Full Text</td> <td align="center" nowrap="nowrap"> PDF (181 KB) </td> <td align="center" nowrap="nowrap"> PDF Plus (213 KB) </td></tr></tbody></table>

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Ann Oncol. 2009 Nov 2. [Epub ahead of print]
Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemotherapy and trastuzumab: an ongoing clinical-translational research experience at the Catalan Institute of Oncology.

Martin-Castillo B, Dorca J, Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E, Garcia M, Del Barco S, Menendez JA.
Translational Research Unit, Catalan Institute of Oncology.
PMID: 19884247 [PubMed - as supplied by publisher]


Curr Mol Med. 2010 Aug 16. [Epub ahead of print]
Metformin and Energy Metabolism in Breast Cancer: From Insulin Physiology to Tumour-initiating Stem Cells.

Vazquez-Martin A, Oliveras-Ferraros C, CufÃ* S, Martin-Castillo B, Menendez JA.
Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain. jmenendez@iconcologia.net.
Abstract

A whole new area of investigation has emerged recently with regards to the anti-diabetic drug metformin and breast cancer. Metformin's anti-breast cancer actions, observed in population studies, in rodents and in cultured tumour cells, are especially encouraging because they attack not only the most common bulk of the tumour cells but also the more rare tumour-initiating stem cells. Here, we illustrate the multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and cellular levels constitutes a novel and valuable strategy to prevent and treat breast cancer disease.



Eur J Cancer. 2010 Jul 23. [Epub ahead of print]
Metformin: Taking away the candy for cancer?

Jalving M, Gietema JA, Lefrandt JD, Jong SD, Reyners AK, Gans RO, Vries EG.
Department of Medical Oncology, University Medical Centre Groningen, The Netherlands; Department of Internal Medicine, University Medical Centre Groningen, The Netherlands.
Abstract


TEXT

Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformin's anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.

PMID: 20656475 [PubMed - as supplied by publisher]



LKB1 is a master kinase in cancer
Posted: 01 Sep 2010 11:27 AM PDT
"LKB1 is a master kinase"
What a great subheader in a paper last year by Reuben Shaw (journal link below).
Liver kinase B1 (LKB1) first got my attention at the AACR lung cancer meeting in San Diego earlier this year, when a couple of translational researchers mentioned it during informal discussions about how it might play a critical but subtle role in lung cancer and potentially other cancers.
Looking at the literature, LKB1 was first identified as a tumor suppressor gene on human chromosome 19p13, responsible for the inherited cancer disorder Peutz-Jeghers Syndrome (PJS). However, the interest at the AACR meeting centred around it being one of the most commonly mutated genes in sporadic human lung cancer, including some subtypes of non-small cell lung carcinoma (NSCLC).
Of course, being very interested in potential druggable targets, I was trying to get my head around this particular kinase. Several scientists and researchers explained to me patiently that LKB1 is involved in energy levels and metabolism, rather than cell signalling per se, so it kind of went by the wayside as other interesting targets came up lately, associated with small molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies.
Still, the fact that LKB1 and AMPK control cell growth in response to environmental nutrient changes stuck in the back of my mind while I quietly wondered whether it would eventually have it's day.
Fast forward to an AACR press conference this morning about the role of metformin, a biguanide therapy for managing hyperglycemia and diabetes, in the role of chemoprevention. I'm going to write more about that meaty topic in another more detailed post tomorrow, but what fasinated me was the mention by Dr Michael Pollak about metformin altering cell energy levels, ie a control system that senses cell energy supplies and low reserves.
It was also mentioned that the activation of the LKB1-AMPK pathway downregulates gluconeogenesis. This process represents the export of energy from hepatocytes to the organism in the form of glucose. In turn, this reduces blood glucose concentration, which results in a secondary decrease in insulin level.
Essentially, the inhibition of hepatic gluconeogenesis is now felt to be a key process underlying the utility of biguanides in the therapy of type II diabetes.
What is interesting on several levels is:

• Studies showing raised levels of free or circulating IGF1 may be associated with an increased risk of developing cancer
• Epidemiology studies amongst people with diabetes taking metformin who may have a lower risk of developing cancer

Of course, when we look at the broader picture, we can see the interactions across several pathways, which makes the whole situation highly complex:
http://oncochat.typepad.com/.a/6a00d...ab07970c-800wi
Source: University of Dundee
Clearly, there is now enough evidence to warrant researching the effects of metformin in cancer prevention, especially given that it is orally available, has had no long term safety issues and is now generically available. These factors, coupled with a greater understanding of the biology of the involved pathways may make a productive new area of cancer research.
Tomorrow, I will cover the latest research involving metformin for chemoprevention in colorectal and lung cancers in more detail.

http://www.researchblogging.org/publ...large_gray.png Shaw RJ (2009). LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta physiologica (Oxford, England), 196 (1), 65-80 PMID: 19245654
Shackelford DB, & Shaw RJ (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature reviews. Cancer, 9 (8), 563-75 PMID: 19629071

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Cancers' sweet tooth may be weakness

http://www.physorg.com/news177769436.html
<small>November 18th, 2009 in Medicine & Health / Cancer</small>
The pedal-to-the-metal signals driving the growth of several types of cancer cells lead to a common switch governing the use of glucose, researchers at Winship Cancer Institute of Emory University have discovered.
Scientists who study cancer have known for decades that cancer cells tend to consume more glucose, or blood sugar, than healthy cells. This tendency is known as the "Warburg effect," honoring discoverer Otto Warburg, a German biochemist who won the 1931 Nobel Prize in Medicine. Now a Winship-led team has identified a way to possibly exploit cancer cells' taste for glucose.
The results were published this week in the journal Science Signaling.
Normally cells have two modes of burning glucose, comparable to sprinting and long-distance running: glycolysis, which doesn't require oxygen and doesn't consume all of the glucose molecule, and oxidative phosphorylation, which requires oxygen and is more thorough.
Cancer cells often outgrow their blood supply, leading to a lack of oxygen in a tumor, says Jing Chen, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. They also benefit from glycolysis because leftovers from the inefficient consumption of glucose can be used as building blocks for growing cells.
"Even if they have oxygen, cancer cells still prefer glycolysis," Chen says. "They depend on it to grow quickly."
Working with Chen, postdoctoral researcher Taro Hitosugi focused on the enzyme PKM2 (pyruvate kinase M2), which governs the use of glucose and controls whether cells make the switch between glycolysis and oxidative phosphorylation. PKM2 is found predominantly in fetal cells and in tumor cells.
In many types of cancer, mutations lead to over-activation of proteins called tyrosine kinases. Chen's team showed that tyrosine kinases turn off PKM2 in lung, breast, prostate and blood cancers. Introducing a form of PKM2 that is not sensitive to tyrosine kinases into cancer cells forces them to grow slower and be more dependent on oxygen, they found.
Because the active form of PKM2 consists of four protein molecules stuck together, having a tyrosine kinase flip the "off" switch on one molecule can dampen the activity for the others.
"People knew that tyrosine kinases might modify PKM2 for decades but they didn't think it mattered," Chen says. "We showed that such a modification is important and you even don't need that much modification of PKM2 to make a difference in the cells' metabolism."
PKM2 could be a good drug target, because both inhibiting it or activating it can slow down cancer cell growth. Biotechnology companies are already searching for ways to do so, Chen says.
More information: T. Hitosugi et al. Tyrosine phosphorylation inhibits PKM2 to promote the Wargurg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
Source: Emory University (news : web) http://www.physorg.com/news177769436.html


[1133] Metformin Enhances Trastuzumab Efficacy and Overcomes Resistance in HER2 Type Breast Cancer Cells.

Thor AD, Fan Z, Yang X-H, Esteva FJ, Jones FE, Edgerton SM, Lind SE, Liu B University of Colorado Denver, Aurora, CO; University of Oklahoma Health Sciences Center, Oklahoma City, OK; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Tulane University, New Orleans, LA

Background: HER2 alterations occur in one-fourth of breast cancers and are associated with an aggressive tumor phenotype. The anti-HER2 agent trastuzumab reduces cell proliferation, angiogenesis, DNA repair and induces antibody-dependent cellular cytotoxicity. Objective response rates and median duration of response for eligible patients given trastuzumab alone is low (12-34% and 9 months respectively), hence, it is administered in combination with other agents. Mechanisms of trastuzumab resistance include: altered receptor antibody interactions, increased signaling through other EGFR type I growth factor receptors, modulation of p27 ^kip1 and increased insulin-like growth factor 1 receptor (IGF-1) signaling. We have reported that metformin inhibits HER2 expression, tyrosine kinase activity (phosphorylated HER2 at both auto- and Src- phosphorylation sites), AKT/mTOR signaling, Cyclin D1 and E2F1 with G1 arrest in HER2 overexpressing breast cancer cells. We sought to determine if metformin would enhance trastuzumab associated cytotoxicity and modulate acquired resistance in vitro.
Methods: We used trastuzumab sensitive (SKBR3, BT474) and resistant cell lines (BT-474/HR20, SKBR3/P2, MCF-7/713 and MCF-7/HER2Δ16) to study the effects of metformin, metformin + trastuzumab and trastuzumab alone. Assays included MTS for proliferation, clonogenicity studies, Western blots, and pull down experiments with Western blots.
Results: Trastuzumab sensitive breast cancer cells were less sensitive to metformin alone, compared to trastuzumab resistant HER2 subtype breast cancer cell lines. Trastuzumab sensitive cells showed enhanced growth and clonogenicity inhibition when treated by both metformin and trastuzumab. At the molecular level, these bi-treated cells showed decreases in HER2/pHER2, erbB3/perbB3, and inactivation of AKT and MAPk signaling. Metformin as low as 20mM increased the efficacy of trastuzumab. All HER2 resistant cell lines showed higher levels of IGF1R and HER2/IGF1R complexes, as compared to sensitive parental lines. In these resistant lines Metformin decreased cell proliferation and clonogenicity, HER2/IGF1R complexes (identified through pull down experiments) and protein expression of HER2/pHER2, erbB3/perbB3, IGF1R/pIGF1R as well as downstream signaling via Akt and IGF1 pathways. Metformin overcame trastuzumab resistance as demonstrated by growth and clonogenicity assays.
Conclusions: HER2 amplified trastuzumab resistant breast cancer cells showed greater sensitivity to metformin than sensitive parental lines. Metformin reversed trastuzumab resistance and decreased HER2:IGF1R complexes, HER2/pHER2 and IGF1R expression, whereas sensitive parental lines showed no complex formation. These preclinical data suggest a combination of metformin and trastuzumab may have clinical benefit, improving the efficacy and reducing the emergence of or reversing trastuzumab resistance in HER2 positive breast cancer patients.
Herceptin graciously provided by Genentech

Thursday, December 10, 2009 5:30 PM

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

http://genesdev.cshlp.org/content/23/5/537.full#sec-1

http://genesdev.cshlp.org/content/23....full.pdf+html

Tumor suppressors and cell metabolism: a recipe for cancer growth.

Abstract

Growing tumors face two major metabolic challenges—how to meet the bioenergetic and biosynthetic demands of increased cell proliferation, and how to survive environmental fluctuations in external nutrient and oxygen availability when tumor growth outpaces the delivery capabilities of the existing vasculature. Cancer cells display dramatically altered metabolic circuitry that appears to directly result from the oncogenic mutations selected during the tumorigenic process. An emerging theme in cancer biology is that many of the genes that can initiate tumorigenesis are intricately linked to metabolic regulation. In turn, it appears that a number of well-established tumor suppressors play critical roles in suppressing growth and/or proliferation when intracellular supplies of essential metabolites become reduced. In this review, we consider the potential role of tumor suppressors as metabolic regulators.


Metformin for Cancer

October 26, 2008 http://cancerx.wordpress.com/2008/10...in-for-cancer/


Metformin’s many physiologic actions include suppressing liver’s own sugar production (”hepatic gluconeogenesis”), increasing insulin sensitivity, enhancing body sugar utilization and decreasing absorption of sugar from the intestines. Overall, we can summarily say that Metformin improves overall sugar metabolism (I have long supported reducing carbohydrate consumption as an adjunct in controlling cancer, perhaps to my colleagues’ consternation if not ridicule. Sugar and cancer is a very important theme, though usually under appreciated by conventional oncologists despite the strength of corollary data. But alas, the topic would be a whole separate blog)
Given so many modern illnesses (eg hyperlipidemia, obesity, diabetes etc) resulting from deranged carbohydrate metabolism, it is not hard to imagine that Metformin may have a role to play in the treatment of conditions resulting from defective insulin signalling (incl. polycystic ovary syndrome [PCOS], infertility, non-alcoholic fatty liver disease (NAFLD) or steato hepatitis, metabolic syndrome X, etc), and these could all be considered “off-label” uses for Metformin as a drug .
A higher incidence of cancer in patients with diabetes has been observed for a century, so much so that Dr Anna Barker, deputy director at the National Cancer Institute estimated that the obesity and diabetes pandemic will cause an additional 30-40% increase in incidence of total solid tumour cancers over the next 10 years – notably in breast, prostate, and colorectal cancer (Financial Times, Oct 1st, 2008). So it makes common sense that an anti-diabetic medicine may somehow inhibit cancer. More recently, despite many mainstream oncologists curiously still denying a role of sugar and diet for cancer control, science has reviewed an emerging key role for insulin and sugar metabolism or insulin signalling in determining cancer risk, tumor growth or cancer progression (See recent review “Insulin, Insulin-like growth factors, Insulin resistance and neoplasia” by Pollack MN of McGill University in Am J Clin Nutri 2007 Sep;86(3):s820-2 for an overview), then it is no surprise that Metformin has off-label application potential in cancer treatment, as do drugs from another class of anti-diabetic agents, the PPAR agonists [discussion to be posted in this blog soon].
And there is a bit of evidence for this:-
a) In Vitro (cellular evidence):
Active against breast cancer (Zakikhani M,Cancer Res. 2006 Nov 1;66(21):10269-73), ovarian cancer (Gotlieb WH et al. Gynecol Oncol. 2008 Aug;110(2):246-50), prostate cancer (Ben Sahra I, et al.Oncogene. 2008 Jun 5;27(25):3576-86), glioma brain cancer (Isakovic A, Cell Mol Life Sci. 2007 May;64(10):1290-302).
Observed mechanisms of action of Metformin against various cancers seems mainly to be related to apoptosis and includes decrease in cyclin D1, AMPK activation leading to inhibition of mTOR and a reduction in translation initiation, selective toxicity to p53-deficient cells, and induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation.
b) In Vivo (animal evidence):
Prevention of pancreas cancer in hamsters (Schneider MB, Gastroenterology. 2001 Apr;120(5):1263-70)
Metformin inhibits development of breast cancer in mice (Anisimov VN, : Bull Exp Biol Med. 2005 Jun;139(6):721-3)
Metformin suppresses intestinal polyp growth in mice (Tomimoto et al. 2008)
Metformin attenuates growth of lung cancer in mice (Algire C. et al, Endocr Relat Cancer. 2008 Sep;15(3):833-9)
Metformin inhibits prostate cancer (Ben Sahra I, et al.Oncogene. 2008 Jun 5;27(25):3576-86)
c) Clinical (human evidence):
Dr. Dario Alessi’s research (U. of Dundee) involving data from patient records over ten years, have shown that patients on metformin showed anywhere between a 30-40% protection against all forms of cancer. While this and lowered instance of breast cancer in women with diabetes treated with Metformin has been known for a while, but recent work presented this year demonstrating Metformin’s role in increasing the response rates of breast cancer patients with diabetes is very exciting:
“Using the M. D. Anderson Breast Medical Oncology database, Drs. Gonzalez-Angulo, Jiralerspong and their team at MD Anderson identified 2,529 women with early-stage breast cancer who received chemotherapy. Of the patients, 68 were diabetic but not taking metaformin and 87 were diabetic and taking the drug. The researchers found that the pathologic complete response rates in the breast cancer patients taking Metformin was 24 percent, three times higher than the rates in patients not taking the drug”
When interviewed, Dr. Gonzalez-Angulo thinks that the result maybe from decreased insulin levels as insulin is a known potent growth factor for cancer. The MD Anderson doctors are planning a trial of Metformin in metastatic breast cancer patients who are obese (and who may thus have insulin resistance and high circulating insulin levels).
My take
Such a benign drug as Metformin can be safely given as an off-label adjunctive treatment in cancer patients, especially breast, ovarian, colorectal, prostate, pancreas and perhaps in glioma patients who have Type 2 diabetes, exhibit metabolic syndrome X, who have elevated circulating insulin levels, or are obese, or even simply those who cannot or do not adhere to a low carb low fat diet.




Future Oncol. 2010 Aug;6(8):1313-23.
Modern approach to metabolic rehabilitation of cancer patients: biguanides (phenformin and metformin) and beyond.

Berstein LM.
N.N.Petrov Research Institute of Oncology, Pesochny-2, Leningradskaja 68, St Petersburg 197758, Russia. levmb@endocrin.spb.ru.


TEXT

Abstract

Comparing the experience accumulated for more than 40 years in the Laboratory of Endocrinology of Petrov Institute of Oncology (St Petersburg, Russia) with similar approaches practiced elsewhere, evidence supports the reasonability of metabolic rehabilitation of patients suffering from breast cancer or other hormone-dependent malignancies. The primary objective of such approaches is to improve treatment results by ameliorating hormonal-metabolic disturbances, including excess body fat, glucose intolerance, insulin resistance and manifestations of endocrine-genotoxic switchings, and modify tissue and cellular targets or mechanisms related or nondirectly related to the aforementioned disturbances. The relevant measures may be categorized as pharmacological (antidiabetic biguanides exemplified with metformin being most popular but not exclusive) and nonpharmacological (rational nutrition, moderate physical activity and so forth) and used separately or in different combinations.

PMID: 20799876 [PubMed - in process]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Is it the time for metformin to take place in adjuvant treatment of Her-2 positive breast cancer? Teaching new tricks to old dogs.

Yurekli BS, Karaca B, Cetinkalp S, Uslu R.
Division of Endocrinology and Metabolism, Ege University School of Medicine, 35100 Izmir, Turkey. bsareryurekli@yahoo.com
Breast cancer is the most common malignancy diagnosed among women. According to the new molecular subclassification, basal like and Her-2 positive breast cancers have the worst outcome and these are the ones in which chemotherapy is a must as a part of adjuvant treatment. New treatment options that could be used as an adjuvant maintenance treatment are still being investigated. Insulin hormone is one of the reasons of breast cancer recurrence and death in breast cancer survivors. Targeting insulin as a therapeutic modality in breast cancer could be an option in the adjuvant treatment of breast cancer. It seems that insulin may signal to activate a cascade of proliferative and anti-apoptotic events in the cancer cell. Metformin, an oral anti-diabetic known for 50 years, may also have direct effects on cancer cells. Metformin causes Her-2 suppression via the inhibition of mTOR in breast cancer cells. Thus, we believe that the time has arrived both to target insulin reduction and to alter Her-2 oncogene based molecular pathogenetic steps in breast cancer by using metformin as an adjuvant therapy in breast cancer patients.



Cell Cycle. 2010 Jan 22;9(1). [Epub ahead of print]
Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo.

Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA.
N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
Population studies have shown that treatment with the antidiabetic biguanide metformin significantly reduced cancer risk. In our animal studies, metformin delayed the onset of mammary adenocarcinoma (MAC) in transgenic HER-2/neu mice but not the onset of spontaneous mammary tumors in female SHR mice. Pineal hormone also inhibits mammary carcinoma development in HER2/neu transgenic mice as well as in female SHR mice. Here we demonstrated that a combination of metformin and melatonin significantly inhibits growth of transplanted tumors in mice. Metformin (0.5 mg/ml in drinking water) increased mean life span by 8% and MAC latency by 13.2% (p < 0.05) in HER2/neu mice. The treatment with melatonin alone (2 mg/L in drinking water during the night time) or combined treatment with metformin (0.5 mg/ ml in drinking water during the day time) + melatonin (2 mg/L in drinking water during the night time) did not influence mammary carcinogenesis in the mice. The treatment metformin alone inhibited the growth of transplantable HER2 mammary carcinoma in FVB/N male mice by 46% at the 45(th) day after transplantation (p < 0.001). The combined treatment with metformin + melatonin significantly suppressed Ehrlich tumor growth (by 40%, p < 0.001). These results suggest that metformin may be useful in prevention and treatment of breast cancer.

PMID: 20016287 [PubMed - as supplied by publisher]




Indian J Cancer. 2009 Oct-Dec;46(4):274-87. Chemotherapy in adult soft tissue sarcoma.

Jain A, Sajeevan KV, Babu KG, Lakshmaiah KC.
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India. ankitjaindm@gmail.com
Soft tissue sarcomas (STSs) are rare and histologically diverse neoplasms. Recent results of various meta-analyses and development of newer drugs have changed the medical management of soft tissue sarcoma. This review gives an outline of chemotherapy and the newer targeted therapies for the same. We have carried out an extensive search in PubMed, Medline for almost all relevant articles concerning chemotherapy of soft tissue sarcoma. The available data from the literature is mainly composed of the most recent reviews, meta-analyses, phase II, and randomized phase III trials published in various peer reviewed journals and various international conferences. The role of neoadjuvant and adjuvant chemotherapy has been found to be controversial. The recent meta-analysis for adjuvant therapy in STSs has shown an increase in the overall survival with combination of ifosfamide and adriamycin. In locally advanced and metastatic STSs, single agent adriamycin remains the basic standard of medication. The combination of ifosfamide and adriamycin may also be used for rapid symptom relief and in patients planned for curative resection for metastases. Newer combinations of docetaxel and gemcitabine appear promising in selected subgroups, especially in leiomyosarcoma and malignant fibrous histiocytoma. Some recent developments include the European Union’s approval of trabectedin for advanced STSs patients who had progressed on adriamycin and ifosfamide therapy. The future of mTOR inhibitors, insulin like growth factor receptor inhibitors and anti-angiogenic drugs appear quite promising. Newer methodologies such as, Bayesian adaptive randomization and inclusion of newer end points like progression-free rate, time of progression rate, and tumor growth rate will improve the results of sarcoma trials. At the end of each section we have also presented recommendations from FNx01European Society of Medical Oncology and FNx08National Comprehensive Cancer Network guidelines v.1.2009 for better correlation with the present literature.




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Curr Oncol Rep. 2009 Nov;11(6):446-53.
Critical signaling pathways in bone sarcoma: candidates for therapeutic interventions.

Geryk-Hall M, Hughes DP.
Department of Pediatrics Research, Unit 853, Children’s Cancer Hospital, The University of Texas, M. D. Anderson Cancer Center, PO Box 301402, Houston, TX 77030, USA.
Bone sarcomas cause disproportionate morbidity and mortality and desperately need new therapies as there has been little improvement in outcomes in 20 years. Identification of critical signaling pathways, including type 1 insulin-like growth factor receptor (IGF-1R) for Ewing sarcoma and possibly osteosarcoma, and the ERBB and the Wnt signaling pathways for osteosarcoma, have emerged as receptors mediating vital signals for bone sarcoma. Akt, mammalian target of rapamycin (mTOR), phosphoinositide 3-kinases, mitogen-activated protein kinase kinase, extracellular signal-regulated kinases, and Ras pathway play key roles in at least some tumors, and inhibition of mTOR in particular will likely lead to improved survival, although clinical trials are still underway. The Notch pathway and ezrin are essential for osteosarcoma metastasis, and Fas downregulation is necessary for survival of metastases in lungs. As little is known about chondrosarcoma signaling, more preclinical work is needed. By defining vital signaling pathways in bone sarcomas, small molecule inhibitors can be applied rationally, leading to longer survival and reducing morbidity and late effects from intensive chemotherapy.



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Cancer. 2009 Nov 15;115(22):5243-50.
Correlation between clinical outcome and growth factor pathway expression in osteogenic sarcoma.

Abdeen A, Chou AJ, Healey JH, Khanna C, Osborne TS, Hewitt SM, Kim M, Wang D, Moody K, Gorlick R.
Department of Orthopaedic Surgery, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York.
BACKGROUND:: Multiple cell-signaling ligands and receptors-including vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), endothelial growth factor (EGF), v-akt murine thymoma viral oncogene homolog (AKT), platelet-derived growth factor (PDGF), mitogen-activated protein kinase (MAPK), and 70-kilodalton (kD) protein S6 kinase (p70S6 kinase)-reportedly are variably expressed in osteogenic sarcoma. Expression of these proteins may have future implications for prognostication and targeted therapy. The objective of the current study was to determine the relation between clinical outcome and the expression of these proteins. METHODS:: A paraffin-embedded microarray of 48 human osteogenic sarcoma tissue specimens was stained with the antibodies against VEGF, IGF, EGF, AKT, PDGF, MAPK, and p70S6 kinase. Staining for each protein included the total protein and, when applicable, the phosphorylated version of the protein. Immunohistochemical staining was then correlated with patient survival (overall survival [OS] and event-free survival [EFS]), histologic response to chemotherapy, and serum markers.
RESULTS:: There was a negative correlation between VEGF receptor 3 (VEGF-R3) and both OS and EFS. VEGF-B was correlated with a poor histologic response to chemotherapy. Serum markers were not correlated with any specific proteins. When using a P value of .05, multiple correlations were observed between proteins of various pathways.
CONCLUSIONS: The current results suggested that the VEGF pathway is a critical signaling pathway in osteogenic sarcoma. These data have identified specific proteins within these pathways toward which future investigations should be directed to further clarify their prognostic potential. Cancer 2009. Published 2009 by the American Cancer Society.

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Curr Drug Targets. 2009 Oct;10(10):923-36.
Clinical development of inhibitors of the insulin-like growth factor receptor in oncology.

Gualberto A, Pollak M.
Pfizer Oncology, 50 Pequot Ave. MS6025-A3266, New London, CT 06320, USA. antonio.gualberto@pfizer.com
The insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumor cell survival and resistance to therapy. Ancillary evidence that targeting the IGF-IR may be useful in the treatment of cancer has been accumulating for almost two decades. Today, more than two dozen compounds have been developed and clinical trials are underway for at least 12 of those. The ability to pharmacologically control the IGF-IR pathway holds not only promising therapeutic implications but also the possibility to gather a better understanding of the role of the IGF axis in tumor initiation and progression. This review focuses on the preclinical rationale for targeting the IGF-IR and other components of the IGF-I system, early clinical results observed to date, biomarker approaches employed and the lessons from these early results for future study design. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence of receptor targeting. Instances of single-agent activity during phase I evaluations have been well documented and a recently reported randomized phase II study indicates that co-administration of an anti-IGF-IR antibody with chemotherapy improves objective response rate and progression-free survival in non-small cell lung cancer patients. These early results support ongoing research across a broad range of cancer indications.

PMID: 19663769 [PubMed - in process]


J Clin Endocrinol Metab. 2009 Oct;94(10):3931-8. Epub 2009 Jul 21.
Growth hormone excess promotes breast cancer chemoresistance.

Zatelli MC, Minoia M, Molè D, Cason V, Tagliati F, Margutti A, Bondanelli M, Ambrosio MR, degli Uberti E.
Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, 44100 Ferrara, Italy.
CONTEXT: GH and IGF-I are known to promote breast carcinogenesis. Even if breast cancer (BC) incidence is not increased in female acromegalic patients, mortality is greater as compared with general population. OBJECTIVE: The objective of the study was to evaluate whether GH/IGF-I excess might influence BC response to chemotherapy. DESIGN: We evaluated GH and IGF-I effects on cell proliferation of a BC cell line, MCF7 cells, in the presence of doxorubicin (Doxo), frequently used in BC chemotherapy, and the possible mechanisms involved.
RESULTS: GH and IGF-I induce MCF7 cell growth in serum-free conditions and protect the cells from the cytotoxic effects of Doxo. GH effects are direct and not mediated by IGF-I because they are apparent also in the presence of an IGF-I receptor blocking antibody and disappear in the presence of the GH antagonist pegvisomant. The expression of the MDR1 gene, involved in resistance to chemotherapeutic drugs, was not induced by GH. In addition, c-fos transduction was reduced by Doxo, which prevented GH stimulatory effects. Pegvisomant inhibited basal and GH-induced c-fos promoter transcriptional activity. Autocrine GH action is ruled out by the lack of endogenous GH expression in this MCF7 cell strain.
CONCLUSIONS: These data indicate that GH can directly induce resistance to chemotherapeutic drugs with a mechanism that might involve GH-induced early gene transcription and support the hypothesis that GH excess can hamper BC treatment, possibly resulting in an increased mortality.



Oncogene. 2009 Aug 27;28(34):3009-21. Epub 2009 Jul 6.
Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions.

Gualberto A, Pollak M.
Clinical Department, Pfizer Oncology, New London, CT, USA.
Preclinical evidence that targeting the insulin-like growth factor receptor (IGF-IR) is effective in cancer treatment has been accumulating for almost two decades. Efforts to develop drugs began in the late 1990s, and initial data from clinical trials were reported in 2006. The biological rationale for IGF-IR targeting has potential relevance to many tumor types, and early results have justified expanded programs to evaluate IGF-IR-targeting agents in many areas of clinical need. More than two dozen drug candidates have been developed and clinical trials are underway for at least 12 of these. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence that the receptor can be successfully targeted. It is premature to draw conclusions regarding efficacy, but well-documented instances of single-agent activity were noted during phase I evaluations, and recent evidence from a phase II study suggests that co-administration of an anti-IGF-IR antibody with chemotherapy for non-small-cell lung cancer improves objective response rate and progression-free survival. With more than 70 trials involving a variety of drug candidates underway, the IGF-IR is becoming one of the most intensively investigated molecular targets in oncology. Early results justify the continuation of ongoing research across a broad range of cancer indications.



Med Hypotheses. 2009 Oct;73(4):606-7. Epub 2009 Jun 27.

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

http://www.oncologystat.com/news-and..._Study_US.html

Metformin Use Protective Against Cancer Mortality in Prospective Study Elsevier Global Medical News.
2009 Nov 25, D Napoli

Metformin may be protective against cancer-related mortality in type 2 diabetes, according to data from a prospective study of over 1,300 patients in the Netherlands. The finding - the first to come from a prospective study - could "further strengthen the position of metformin as preferred initial treatment in patients with type 2 diabetes mellitus," wrote the study authors in an article published online on Nov. 16 ahead of print in Diabetes Care (doi:10.2337/dc09-1380). The authors, led by Dr. Gijs W. Landman of the Isala Clinics in Zwolle, the Netherlands, looked at 1,353 patients who were enrolled in the Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study. That study, begun in 1998, aimed to assess patients under the care of diabetes specialist nurses in addition to general practitioners. A total of 289 patients in the ZODIAC study used metformin at baseline; 1,064 did not. The average age of all patients was about 68 years, and slightly more than half were women. Among metformin users, the average duration of disease was 4.9 years, compared with 7.1 years in the nonuser group, a non-significant difference. The nonuser group did have significantly lower HbA1c levels, lower body mass index levels, and lower estimated glomerular filtration rates (eGFR), as well as significantly higher rates of use of insulin and sulfonylurea. After a mean follow-up of 9.6 years, there were a total of 122 cancer deaths in the entire cohort. According to the authors, the standardized mortality rate for cancer mortality among all patients was 1.47 (95% CI 1.22-1.76). However, adjusted for 13 variables including smoking, age, sex, diabetes duration and pertinent lab values, metformin patients' hazard ratio fell to 0.43, compared with nonusers (95% CI 0.23-0.80). Furthermore, "The hazard [ratio] for cancer mortality decreased by 42% for every one gram increase in the metformin dosage," wrote the authors. The research study had some limitations. According to the authors, "patients with a very short life expectancy (including patients with active cancer) or insufficient cognitive abilities were excluded" from the original ZODIAC study. In addition, there are no data about nonfatal cancer incidence, nor about cancer history. The authors also pointed out that metformin was a relatively new drug at the ZODIAC study's baseline. "Patients who were taking metformin at the beginning of this study (in 1998) might also be different from patients taking metformin at this moment," they wrote. "If there is an association between cancer mortality and metformin use, a long-term follow-up is needed, because cancer takes a long time to develop and it takes time before patients die from cancer," they added. According to Dr. Landman, the study authors - all from the Netherlands - had no personal disclosures to report, nor did the study receive any outside funding or support.


Metformin and Letrozole seem compatible at some level in non-cancer setting:

Hum Reprod. 2006 Jun;21(6):1432-5. Epub 2006 Feb 14.
Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.

Sohrabvand F, Ansari Sh, Bagheri M.
Department of Infertility & IVF, Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran. fsohrabvand@yahoo.com
BACKGROUND: Adding metformin to clomiphene citrate in clomiphene-resistant polycystic ovary syndrome (PCOS) patients increases ovulatory response. However, because of anti-estrogenic effects of clomiphene it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. Letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects. METHODS: Infertile women with PCOS were randomly divided into metformin-letrozole (29 patients) and metformin-clomiphene groups (30 patients). After an initial 6-8 weeks of metformin, they received either letrozole (2.5 mg) or clomiphene (100 mg) from day 3-7 of their menstrual cycle. Estradiol (E2) levels, number of follicles, pregnancy rates and endometrial thickness were measured on the day of HCG administration. RESULTS: Mean total E2 and E2 per mature follicle were significantly higher in clomiphene group without a difference in mean number of mature follicles >18 mm and ovulation rate. Endometrial thickness was significantly higher in letrozole group. The pregnancy rate in letrozole group (10 patients, 34.50%) as compared with clomiphene group (5 patients, 16.67%) did not show significant difference, whereas full-term pregnancies were higher in letrozole group [10 patients (34.50%) versus 3 patients (10%)]. CONCLUSION: In clomiphene-resistant PCOS patients, the combination of letrozole and metformin leads to higher full-term pregnancies.

PMID: 16478764 [PubMed - indexed for MEDLINE]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

J Clin Oncol. 2009 Nov 30. [Epub ahead of print]
Metformin, B12 and Enhanced Breast Cancer Response to Chemotherapy.

1 page PDF suggests Metformin (and chemo) induced B12 reduction is part of benefit.
Interesting mention of Nitrous oxide anaesthesia rapidly reduces B12 and can kill tumor cells: Garcia A, Tisman G.
Department of Medical Oncology, The Whittier Cancer Research Building, Whittier, CA.
PMID: 19949002 [PubMed - as supplied by publisher]


Int J Radiat Biol. 2009 Nov;85(11):963-71.
The anti-oxidant capacity of tumour glycolysis.

Sattler UG, Mueller-Klieser W.
Institute of Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
PURPOSE: In this mini-review data are summarised which provide evidence for the biological and clinical significance of tumour glycolysis and of its relationship to the redox state of cancer cells. RESULTS: Malignant transformation is associated with an overexpression of numerous glycolysis-related genes in the vast majority of human cancers. At the same time, glycolytic activity and glycolysis-linked metabolic milieu are often variable between individual tumours which induces large variations in treatment response and aggressiveness. Currently, there is no genetic or proteomic marker for the prediction of the therapeutic response for individual tumours, but the prognostic value of tumour lactate accumulation for the emergence of metastasis, for patient survival and for radioresistance has been documented in a number of studies. CONCLUSIONS: Transactivation of tumour glycolyis appears to generate a chemically reduced milieu associated with an inhibition of ROS (reactive oxygen species) -mediated fixation of DNA damage and induction of radioresistance. Furthermore, highly glycolytic cells enhance the antioxidant defense via glutathione, and pyruvate can be decarboxylated non-enzymatically upon reducing hydrogen peroxide. The summary of data given here emphasises the importance of further research efforts on the link between carbohydrate metabolism and redox state of cancer cells.

PMID: 19895273 [PubMed - in process]


LINK to full text
LINK to PDF

Abstract
The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great
promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent,
doxorubicin, kills both cancer stem cells and non–stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2months after combinatorial therapy with metformin and doxorubicin is
ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers. [Cancer Res 2009;69(19):7507–11]

To our knowledge, the ability of metformin to selectively kill cancer stem cells and to function synergistically with doxorubicin to block both cancer stem cells and non–stem-transformed cells is unique. In the case of breast cancer, herceptin and tamoxifen are useful drugs for cancer types that, respectively, express the HER2 and ERs, but some forms of breast cancer lack these receptors and resist these treatments. For all of these types of
breast cancer, metformin selectively inhibits cancer stem cell growth and, hence, is likely to function synergistically with chemotherapeutic drugs. In addition, as metformin inhibits transformation of MCF10A-ER-Src cells, it might have a potential use in preventing the development of cancer, as opposed to treating cancer that has already occurred.

...the concentration of metformin needed for the anticancer effects observed here is considerably below that used for the treatment of diabetes. Lastly, the selectivity of metformin and doxorubicin for distinct types of cells in the tumor can explain the striking combinatorial effects on reducing tumor mass and prolonging remission in nude mice, and it provides the rationale for combining metformin with chemotherapy as a new treatment for breast (and possibly other) cancers.





SABC 2009
[1054] Deleterious Effect of Chemotherapy on Measures of Insulin Resistance in Patients with Newly-Diagnosed Invasive Breast Cancer.

Makari-Judson G, Katz D, Barham R, Mertens WC Comprehensive Breast Center/Baystate Regional Cancer Program and Tufts University School of Medicine, Springfield, MA

Background: Women treated with early stage breast cancer often gain weight in the two years following diagnosis, with adjuvant chemotherapy, younger age, lower body mass index (BMI) and pretreatment menopausal status being associated factors (Breast J 2007; 13:258). The effect of insulin resistance on treatment-related weight gain, and of treatment on measures of insulin resistance, are unclear.
Purpose: To prospectively study weight gain in women receiving adjuvant therapy for early stage breast cancer and assess changes in body mass index, body composition, and explore the relationship between markers of insulin resistance, cancer therapy, exercise and weight gain.
Methods: Prospective, observational study of non-diabetic women with early-stage breast cancer receiving adjuvant chemotherapy and/or hormonal therapy. Fasting insulin, glucose, and triglycerides, weight, BMI, waist and hip circumference were obtained at baseline before adjuvant therapy, and at 6, and 12 months. Patients completed nutrition and exercise logs using the Nutritionist-Pro program. Insulin resistance was calculated using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Waist/hip ratio (WHR) was used as a surrogate for percent body fat.
Results: Complete data available for 95 patients are reported regarding weight change at 6 months (mean 0.4 kg, 95%CI -0.3, 1.0; p=.23 compared to baseline) and 12 months (0.9 kg, 95%CI 0.4, 1.8, p=.04 compared with baseline). Mean baseline HOMA-IR was 2.3 (95%CI 1.9, 2.7); mean baseline WHR was 0.82 (95%CI 0.81, 0.84). Six-month HOMA-IR tended to increase (by mean 0.34, p=.06) as did glucose/insulin ratio (p=.05). Waist measurement (p=.96) and WHR (p=.52) were unchanged. Chemotherapy-treated patients exhibited adverse changes compared with others (mean change for chemotherapy-treated and no chemotherapy for HOMA-IR: 0.53 vs. -0.64, p=.005; glucose/insulin: -2.1 vs. 2.7, p=.003; waist: 0.37 vs. -1.94 cm, p=.08; WHR: 0.001 vs. -0.024, p=.06). Age, BMI, hormonal therapy, or types of breast surgery were not associated with significant changes. Exercising patients demonstrated lower HOMA-IR and WHR, and greater glucose/insulin ratios at baseline, but exercise (aerobic, strength, or any exercise) was not associated with significant change at 6 and 12 months for any of these variables. While differences disappeared at 12 months despite further weight gain repeated measures analysis of variance confirmed the effect of chemotherapy over time for HOMA-IR (p=.048), glucose/insulin (p=.038) and WHR (p=.050).
Conclusions: These preliminary data suggest that patients completing chemotherapy within 6 months of baseline appear to experience at least short-term changes in metabolism suggestive of insulin resistance. These adverse changes may help explain weight gain associated with adjuvant chemotherapy, and merit further prospective study.

Thursday, December 10, 2009 5:30 PM

Poster Session 1: Social, Behavior, Economic, and Outreach Studies: Survivorship Research (5:30 PM-7:


<table class="MPReader_Profiles_SpringerLink_Content_Prim itiveHeadingControl" cellpadding="0" cellspacing="0"><tbody><tr valign="top"><td> Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy

<table cellpadding="0" cellspacing="0"> <tbody><tr> <td class="labelName">Journal</td><td class="labelValue">Breast Cancer Research and Treatment</td> </tr><tr> <td class="labelName">Publisher</td><td class="labelValue">Springer Netherlands</td> </tr><tr> <td class="labelName">ISSN</td><td class="labelValue">0167-6806 (Print) 1573-7217 (Online)</td> </tr><tr> <td class="labelName">Category</td><td class="labelValue">Preclinical study</td> </tr><tr> <td class="labelName">DOI</td><td class="labelValue">10.1007/s10549-009-0647-z</td> </tr><tr> <td class="labelName">Subject Collection</td><td class="labelValue">Medicine</td> </tr><tr> <td class="labelName">SpringerLink Date</td><td class="labelValue">Monday, November 23, 2009</td> </tr> </tbody></table></td><td rowspan="2" class="MPReader_Profiles_SpringerLink_Content_Prim itiveHeadingControlSecondaryLinks" valign="top"> Add to marked items
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</td> </tr><tr> <td>http://www.springerlink.com/images/onlinefirst.gif</td> </tr> </tbody></table> http://www.springerlink.com/images/common/spacer.gifPDF (598.0 KB)http://www.springerlink.com/images/common/spacer.gifHTMLhttp://www.springerlink.com/images/html.gifSupplemental Material

Preclinical study

Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy
Kathryn N. Phoenix¹, Frank Vumbaca¹, Melissa M. Fox¹, Rebecca Evans¹ and Kevin P. Claffey^{1 http://www.springerlink.com/images/contact.gif}
<table> <tbody> <tr valign="top"> <td>(1) </td> <td>Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3501, USA</td> </tr> </tbody> </table> Received: 9 September 2009 Accepted: 11 November 2009 Published online: 22 November 2009
Abstract
Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events.
Electronic supplementary material The online version of this article (doi:10.1007/s10549-009-0647-z) contains supplementary material, which is available to authorized users.


11/16/09
Targets 09 Episode 3: Listen to David Sabatini, M.D., Ph.D., a member of the Whitehead Institute and associate professor of biology at MIT, speak about his work on dietary restriction and tumor response.
http://media.libsyn.com/media/aacr/A...odcastsEp3.mp3

Some notes:

History of dietary/caloric restriction theory: restriction by 30% thought to reduce incidence and growth amongst all cancers.

Current research found disparities in response

divided cancers into responsive/unresponsive

Resistant cancers, when cell analyzed didn't care about insulin growth factors. Responsive cancers followed insulin levels tightly which implicated PI3 kinase pathway, one of the major systems of response to insulin levels.
Looked at the two types of cells and found Pi3 kinase pathways differed, resistant cells had mutated PI3 kinase pathways. Manipulation of pathway could induce resistance or responsiveness showing causation and identified PI3K as pivotal.
Mimetics (metformin?) of caloric restriction could prove helpful. However findings suggest need to identify which tumors will respond.

Despite prevalent thinking that restriction worked on all tumors, closer look at data from the 30's actually does show disparities.

Identification of main pathway/response determination is biggest finding. Simplifies what was thought to be a complex process. Insulin levels drop when you calorically restrict. But here's a (mutated) pathway that lets the cells think there's always insulin.

If caloric restriction important the reverse is implicated. Obesity may be biggest driver of increased cancer. Need to find out role of mutated pathway in obese patients.

Suggests organism/metabolism focus is warranted.

Study demonstrated advancement in mouse models that showed same results of human xenograft models.

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Am J Ther. 2004 May-Jun;11(3):236-7.
Metformin-associated respiratory alkalosis.

Bryant SM, Cumpston K, Lipsky MS, Patel N, Leikin JB.
Division of Medical Toxicology and Hyperbaric Medicine, Department of Emergency Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
We present an 84-year-old man with a history of chronic obstructive pulmonary disease, type 2 diabetes, hypertension, glaucoma, and bladder cancer who presented to the emergency department after the police found him disoriented and confused. Metformin therapy began 3 days before, and he denied any overdose or suicidal ideation. Other daily medications included glipizide, fluticasone, prednisone, aspirin, furosemide, insulin, and potassium supplements. In the emergency department, his vital signs were significant for hypertension (168/90), tachycardia (120 bpm), and Kussmaul respirations at 24 breaths per minute. Oxygen saturation was 99% on room air, and a fingerstick glucose was 307 mg/dL. He was disoriented to time and answered questions slowly. Metformin was discontinued, and by day 3, the patient's vital signs and laboratory test results normalized. He has been asymptomatic at subsequent follow-up visits. Metformin-associated lactic acidosis is a well-known phenomenon. Respiratory alkalosis may be an early adverse event induced by metformin prior to the development of lactic acidosis.

PMID: 15133541 [PubMed - indexed for MEDLINE]

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Updated with audio clip in beginning of thread: LINK

Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
 

Oncogene. 2008 Jun 5;27(25):3576-86. Epub 2008 Jan 21.
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F.
INSERM U568, Nice, France.
Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.




Front Biosci. 2008 May 1;13:3273-87.
The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance.

Casa AJ, Dearth RK, Litzenburger BC, Lee AV, Cui X.
Breast Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract

The insulin-like growth factor (IGF) ligands stimulate cellular proliferation and survival by activating the type I insulin-like growth factor receptor (IGF-IR). As a result, the IGF signaling system is implicated in a number of cancers, including those of the breast, prostate, and lung. In addition to mitogenic and anti-apoptotic roles that may directly influence tumor development, IGF-IR also appears to be a critical determinant of response to numerous cancer therapies. This review describes the role of the IGF-IR pathway in mediating resistance to both general cytotoxic therapies, such as radiation and chemotherapy, and targeted therapies, such as tamoxifen and trastuzumab. It concludes with a description of approaches to target IGF-IR and argues that inhibition of IGF signaling, in conjunction with standard therapies, may enhance the response of cancer cells to multiple modalities.

PMID: 18508432 [PubMed - indexed for MEDLINE]




ACTOPLUS MET combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone hydrochloride, a member of the thiazolidinedione class, and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.


http://www.themoneytimes.com/feature...-10115966.html


A new study suggests that a low-dose combination therapy using [COLOR=#009600 ! important][COLOR=#009600 ! important]GlaxoSmithKline[/COLOR][/COLOR]http://kona.kontera.com/javascript/l...rey_loader.gif
(GSK) Avandia and anti-[COLOR=#009600 ! important][COLOR=#009600 ! important]diabetic [COLOR=#009600 ! important]treatment[/COLOR][/COLOR][/COLOR]http://kona.kontera.com/javascript/l...rey_loader.gif
metformin may help prevent progression to type 2 diabetes by two-thirds in people at risk of the ailment. According to experts, Avandia, also known as [COLOR=#009600 ! important][COLOR=#009600 ! important]rosiglitazone[/COLOR][/COLOR]http://kona.kontera.com/javascript/l...rey_loader.gif
and metformin both lower the development of diabetes in patients with impaired glucose tolerance (IGT).


However, both the drugs work differently. While, Avandia is known to increase insulin sensitivity, metformin reduces liver glucose production.