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06-03-2009, 02:13 PM
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#1
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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Metformin: May 'Revolutionize' Cancer Therapies: Unexpected T-cell Breakthr
(synergizes with chemo, potential chemo dose reducer, w/2DG, anti-CSC, gene modifying, anti glycolysis yet more, aromatase inhib, effective acrosss tissue type differences, HexokinaseII, Cyclin D1 inhibitior, anti-inflammation/Il-8, immune enhancing, VEGF inhib, mTOR, AKT, AMPk, w/MNTX, monotherapy potential in triple neg, tripled neoadj response)
Metformin in Breast Cancer: Time for Action
http://jco.ascopubs.org/cgi/reprint/27/20/3271
3 page PDF
By inhibiting transcription of key gluconeogenesis genes in the liver and increasing glucose uptake in skeletal muscle, metformin reduces levels of circulating glucose, increases insulin sensitivity, and reduces the hyperinsulinemia associated with insulin resistance, 5 all of which are factors associated with breast cancer prognosis.
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[PowerPoint Slide for Teaching]
| Fig 1. Mechanism of metformin action. IR, insulin receptor; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; Akt, v-akt murine thymoma viral oncogene homolog; Erk, extracellular signal-regulated kinase; TSC2, tuberous sclerosis complex tumor suppressor gene 2; mTOR, mammalian target of rapamycin; BC, breast cancer cell. |
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.
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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06-03-2009, 02:23 PM
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#2
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Senior Member
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More on metformin
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.
Adapted from materials provided by Johns Hopkins Medical Institutions, via EurekAlert!, a service of AAAS.
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06-03-2009, 02:40 PM
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#3
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Link to carbs and blood sugar??
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06-04-2009, 04:02 PM
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#4
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Senior Member
Join Date: Mar 2006
Posts: 1,843
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Good find Rich - thank you for posting - very interesting at a number of levels, particularly the connection between diabetes impaired fat metabolism and immune function.
More thought required (-:
RB
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06-05-2009, 10:35 AM
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#5
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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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
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06-05-2009, 12:08 PM
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#6
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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- REFERENCE: Toleration of Metformin in non-diabetic patients.
- 1: Arch Physiol Biochem. 2009 May;115(2):86-96.
- Obesity related hyperinsulinaemia and hyperglycaemia and cancer development.
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
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]
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07-18-2009, 03:20 PM
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#7
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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- 1: Clin Transl Oncol. 2009 Jul;11(7):455-9.Links
- 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)).
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.
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]
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07-18-2009, 06:47 PM
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#8
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Senior Member
Join Date: Sep 2005
Location: Alaska
Posts: 2,018
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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
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07-18-2009, 07:03 PM
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#9
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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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.
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09-14-2009, 10:18 PM
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#10
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
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.
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09-15-2009, 03:04 PM
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#11
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
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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.
- 1: Cancer Res. 2009 Sep 14. [Epub ahead of print] Links
- Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission.
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].
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09-27-2009, 12:02 PM
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#12
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Senior Member
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Location: South East Wisconsin
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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]
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10-02-2009, 11:58 PM
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#13
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Senior Member
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Location: South East Wisconsin
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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]
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10-02-2009, 11:59 PM
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#14
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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.
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: ‘
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10-03-2009, 12:30 AM
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#15
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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
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11-02-2009, 01:57 AM
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#16
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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]
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11-11-2009, 02:10 AM
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#17
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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
Mahvash Zakikhani1, Ryan Dowling2, I. George Fantus3, Nahum Sonenberg2 and Michael Pollak1 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.
Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth 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 gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment. (Cancer Res 2006; 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]
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11-14-2009, 07:12 PM
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#18
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Senior Member
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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:
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]
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11-14-2009, 07:14 PM
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#19
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Senior Member
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Location: South East Wisconsin
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea
Metformin, insulin, breast cancer and more…
Lev M Berstein *
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.
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11-14-2009, 10:33 PM
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#20
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Senior Member
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Location: South East Wisconsin
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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:
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.
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
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