Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

[Rich66]

Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

The Pink Sheet Daily. 2009 Apr 28, S Haley

Among the therapies showcased at the recent American Association for Cancer Research meeting in Denver were a growing number aimed at attacking cancer from a new or at least a different angle, through the specialized tumor cells known as cancer stem cells.
Cancer stem cells, the very aggressive cancer cells believed responsible for tumor metastases, are not stem cells in the way embryonic stem cells have captured the scientific imagination, but they are a very small, defined population of cancer cells than can go forth and generate a new tumor. And there's a good chance that if their migration in the body can be stopped, cancers can be made more susceptible to chemotherapy and tumors eliminated entirely, with no nasty surprises years down the road.
When a tumor cell divides it creates one new cancer stem cell, which goes into a resting state, and progeny cells, which become the mass of the tumor. It is these resting cells that are thought to be responsible for not only metastasis but also chemoresistance. They have a very low proliferation rate - so antiproliferatives don't reach them entirely - they overexpress paths that carry drugs out of the cell, and they have more detoxifying enzymes than other tumor cells, Patrick A. Baeuerle, chief scientific officer at Micromet, a company working in the space, explained at the firm's R&D day April 24.
In fact, Baeuerle said, "there is good evidence" that chemotherapy actually enriches the environment for cancer stem cells. When the other cancer cells are eliminated, there are more stem cells to "very rapidly repopulate the tumor."
Micromet harnessing immune system with BiTE antibodies
Micromet's BiTE antibody MT110 can successfully direct the immune system's T-cells to eliminate human colorectal cancer stem cells in cell culture and in animal models, the company reported at AACR.
At the R&D day, Baeuerle explained the significance of MT110's efficacy "in a dish and in a mouse." Eradicating 100 percent of the cells is important because as few as 100 stem cells left in the body after treatment can give rise to a new tumor later on, he said. In both the Petri dish and mouse model, MT100 yielded complete inhibition - meaning there was no further colonization in culture and no tumor growth in the animals.
Using its bispecific T-cell engager (BiTE) technology, the biotech engineered an antibody able to tether resting T-cells to tumor cells, then deliver a cytotoxic payload. MT110 is specific for epithelial cell adhesion molecule (Ep-CAM), a target antigen highly expressed on the surface of cancer stem cells from a variety of tumor types. The biologic is in a Phase I dose-escalating clinical trial in patients with lung or gastrointestinal cancer.
Geron going after telomerase inhibition with imetelstat
Another company working in the cancer stem cell space, Geron, gave five presentations at AACR involving its telomerase inhibitor imetelstat (GRN 163L). It is being studied against cancer stem cells from non-small cell lung, breast, pancreatic, prostate and pediatric neural tumors. Imetelstat is a short chain oligonucleotide with a high affinity and specificity to the telomerase site, thus inhibiting enzyme activity.
Imetelstat currently is in six clinical dose-ranging/safety trials. The drug is being tried in combination with standard of care carboplatin and paclitaxel in a Phase I/II trial testing it against non-small cell lung cancer.
Preclinical data shared at AACR showed that continued treatment of NSCLC cell lines with imetelstat induced progressive decreases in telomere length, resulting in cell death. Treatment over several months resulted in "a dramatic decrease" in colonies in culture, investigators said. In addition, they noted "marked" changes in the number of genes associated with stem cell proliferation. Together, the results mean imetelstat will have to be administered over a sustained period and that the cancer stem cells responsible for NSCLC proliferation were indeed targeted by the drug, investigators said.
Geron also presented preclinical data against four human prostate cancer cell lines, in which tumors express high levels of telomerase activity, suggesting clinical trials could produce a positive result in that cancer. Telomerase is absent or expressed occasionally and only at low levels in normal adult tissue. In another presentation of research, in pediatric neural tumors, including neuroblastoma, preclinical data show telomerase is only active in the tumor's stem cells and that treatment resulted in inhibition of telomerase, loss of replicative potential, and cell aging. In addition, cells pre-treated with imetelstat appeared more susceptible to radiation.
Geron, in Menlo Park, Calif., is best known as the stalwart company that continued its research with human embryonic stem cells during the Bush administration ban on federally funded investigations in that area, a complication that hindered the ability of university researchers to participate in studies of Geron candidates.
In January, FDA lifted a clinical hold on Geron's regenerative stem cell therapy OPC1, allowing Geron to proceed with human trials in spinal cord injury.
Biotechs not alone: big pharma pursuing cancer stem cells, too
Big pharmas also have been edging into the cancer stem cell space, as the increasing emphasis on oncology portfolios increases demand for novel approaches.
In 2007 Sanofi-Aventis formed a collaboration with Chinese researchers at the Tianjin Institute of Hematology and Blood Diseases Hospital. That same year, GlaxoSmithKline and Redwood City, Calif.-based OncoMed formed a back-end loaded relationship worth up to $1.4 billion for the biotech if the cancer stem cell bet pays off. Then in 2008, Roche paid $190 million in cash to take over Canadian antibody company Arius Research and gain control of its cancer stem cell program.
That leaves plenty of big pharma firms focused on oncology that could be interested in the programs from Micromet and Geron.

Researchers target telomeres to attack tumors

5. May 2009 19:09Hoping to develop more effective long-term attacks on cancer, researchers at the Indiana University School of Medicine are conducting the first human tests of a breast cancer drug regimen that includes a compound meant to force cancer cells to grow old and die.

The early stage clinical tests are an attempt to block a mechanism cancer cells use to avoid the aging process that affects most normal cells. If successful, the new therapy could enhance the effects of other cancer treatments.
"This is really a completely different way of trying to tackle the problem that hasn't been tested in the clinic before," said Kathy Miller, M.D., associate professor of medicine and Sheila D. Ward Scholar at the IU School of Medicine and medical oncologist at the Indiana University Melvin and Bren Simon Cancer Center.
The clinical test is a good example of how positive results in basic science experiments can push a promising compound from the laboratory to the bedside - a process known as "translational research."
The new approach is based on research into telomeres, the caps that protect the ends of the 46 chromosomes in each cell that contain our genetic information. The telomeres, which some compare to the tips of shoelaces, help prevent genomic instability. Each time a cell divides, the telomeres shorten. When they become too short, losing their protective ability, it's a signal to the cell to die, or to go into a state of permanently arrested growth called senescence.
Telomeres in cancer cells generally are shorter than those in normal cells. That offers a tempting target, except that cancer cells know a trick. Cancer cells produce an enzyme called telomerase, which provides maintenance services on the telomeres, preventing them from reaching the critically short stage that would set off the cell death signal.
So, researchers have figured, if you could block cancer cells from producing telomerase, you could make them easier to kill. But how to do that? Several approaches seemed possible, including one that Brittney-Shea Herbert, Ph.D., then a post-doctoral researcher, was working on 10 years ago at the University of Texas Southwest in Dallas. Her approach: Find a special type of chemical compound, called an oligonucleotide, that would block access to telomerase and prevent it from doing its job. She began working with a new compound, with the chemical name GRN163L, that had been developed by Geron Corp. of Menlo Park, Calif.
Dr. Herbert has continued to work with GRN163L - now called imetelstat sodium - in the laboratory since coming in 2003 to the IU School of Medicine, where she is an assistant professor of medical and molecular genetics. She has published work showing that imetelstat disrupts telomere maintenance, in the process suppressing both tumor growth and metastasis - the appearance of tumors in other tissues. Another study found that telomere damage in breast cancer cells treated with the compound caused the cells to be more susceptible to radiation treatment. Furthermore, she has shown that imetelstat can restore the sensitivity of Herceptin-resistant breast cancer cell lines in the laboratory.
"What's interesting about GRN163L is that it can get into almost any cancer cell type, including drug resistant cancer cells. That's been a problem: A lot of agents cannot be taken up into drug resistant cells. This telomerase inhibitor can be taken up in any cell type - you can target those cells. So that's why we hope this will be great for reducing recurrence and metastasis," said Dr. Herbert.
Such results have made imetelstat an attractive compound to test in conjunction with other anti-cancer drugs, which is what brought Drs. Miller and Herbert together. They are testing imetelstat with the drugs Taxol and Avastin, initially to determine the appropriate dose of imetelstat, test whether the three drugs are safe to give in combination, and to determine whether there are side effects that must be dealt with.
Assuming the first phase goes well a second phase of testing will begin more formal evaluation of how well the combination therapy works.
Dr. Miller's research has shown that Taxol and Avastin are more effective in combination than Taxol alone, shrinking tumors in about twice as many women and providing such benefits more than twice as long. The therapy doesn't cure metastatic disease, though. Eventually the tumors become resistant to the drugs and other treatments are necessary.
If, as expected, imetelstat doesn't raise side effects issues, and "if it makes the cells more sensitive to the effects of the Taxol and Avastin, and allows the benefits of that therapy to continue for a much longer period of time, that would be a big benefit for those ladies with metastatic disease. It would also then give us the support for looking at this agent even earlier in the course of disease," said Dr. Miller.
Dr. Herbert's research indicated that imetelstat can reduce metastatic spread of cancer, though it's not yet clear what the mechanism is. But, as Dr. Miller points out, for patients that will be a distinction with little difference.
"Whether it actually prevents the cells from spreading or they spread but can't grow to make clinically apparent tumors we don't know, but I can tell you my patients don't care," she said.
http://www.iupui.edu


Hum Pathol.. [Epub ahead of print]
Reduction of CD44(+)/CD24(-) breast cancer cells by conventional cytotoxic chemotherapy.

Aulmann S, Waldburger N, Penzel R, Andrulis M, Schirmacher P, Sinn HP.
Institute of Pathology, Heidelberg University, 69120 Heidelberg, Germany.
Breast cancer cells with the CD44(+)/CD24(-) phenotype have been associated with stem cell properties. To analyze effects of cytotoxic chemotherapy on these cells, we examined a series of 50 breast carcinomas before and after neoadjuvant chemotherapy with epirubicin/cyclophosphamide using double immunofluorescence. Before treatment, an average of 4.4% of the tumor cells displayed a CD44(+)/CD24(-) phenotype. However, after chemotherapy, the frequency of CD44(+)/CD24(-) cells dropped to 2% (P = .008). To test this unexpected finding, we analyzed a second collective of 16 patients that preoperatively had received either 4 cycles of doxorubicin/pemetrexed, followed by 4 cycles of docetaxel or 4 cycles of doxorubicin/cyclophosphamide, followed by 4 cycles of docetaxel with similar results (8.7% CD44(+)/CD24(-) cells on average before and 1.1% after chemotherapy). In addition, no association was observed between the frequency of CD44(+)/CD24(-) cells and the response to chemotherapy or patient survival. However, patients with tumors containing high numbers of CD44(+)/CD24(-) cells more frequently developed bone metastases in the course of disease. In conclusion, our findings challenge the proposed role of CD44(+)/CD24(-) cells as cancer stem cells in tumor resistance to chemotherapy as they apparently are not selected by conventional cytotoxic agents.

PMID: 20004947 [PubMed - as supplied by publisher]





Int J Cancer. 2009 Nov 11. [Epub ahead of print]
The effects of telomerase inhibition on Prostate tumor-initiating cells.

Marian CO, Wright WE, Shay JW.
University of Texas Southwestern Medical Center, Department of Cell Biology, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9039.
Prostate cancer is the most lethal malignancy in men and the patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. Most cancer therapies target the bulk tumor cells, but may leave intact a small population of tumor-initiating cells (TICs), which are believed to be responsible for the subsequent relapse and metastasis. Using specific surface markers (CD44, integrin alpha(2)beta(1) and CD133), Hoechst 33342 dye exclusion, and holoclone formation, we isolated TICs from a panel of prostate cancer cell lines (DU145, C4-2 and LNCaP). We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. These findings suggest that telomerase inhibition therapy may be able to efficiently target the prostate TICs in addition to the bulk tumor cells, providing new opportunities for combination therapies. (c) 2009 UICC.

PMID: 19908230 [PubMed - as supplied by publisher]


Experimental drug (Imetalstat) shows promise against brain, prostate cancers
http://news.xinhuanet.com/english/20...t_12749320.htm

The drug's actions, observed in isolated human cells in one trial and in rodents in the other, are especially encouraging because they attacked not only the bulk of the tumor cells but also the rare cancer stem cells that are believed to be responsible for most of a cancer's growth, said Jerry Shay, professor of cell biology and a senior co-author of both papers.

In the glioblastoma study, performed in mice, the drug also crossed from the bloodstream into the brain, which is especially important because many drugs are not able to cross the blood-brain barrier. "Because it attacks a mechanism that's active in most cancers, it might prove to be widely useful, especially when combined with other therapies," said Shay.
Shay and his colleagues study telomeres, bits of DNA that help control how many times a cell divides. Telomeres are protective "caps" of DNA on the ends of chromosomes, the structures that contain the body's genes. As long as telomeres are longer than a certain minimum length, a cell can keep dividing. But telomeres shorten with each cell division, so a cell stops dividing once thetelomeres are whittled down to that minimum.
In cancer cells, however, an enzyme called telomerase keeps rebuilding the telomeres, so the cell never receives the cue to stop dividing. In essence, they become immortal, dividing endlessly.
The drug used in these studies (imetelstat or GRN163L) blocks telomerase. It is already in clinical trials as a potential treatment for breast and lung cancer, as well as for chronic lymphocytic leukemia.

1: Eur J Gynaecol Oncol. 2001;22(5):347-9.Links

Herbal complex suppresses telomerase activity in chemo-endocrine resistant cancer cell lines.

Lian Z, Fujimoto J, Yokoyama Y, Niwa K, Tamaya T.
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu City, Japan.
A herbal complex consisting of Hoelen, Angelicae radix, Scutellariae radix and Glycyrrhizae radix suppressed cell viability and telomerase activity in hormone-refractory and chemo-resistant cancer cell lines, namely poorly differentiated uterine endometrial cancer cell line AN3 CA, adriamycin-resistant breast cancer cell line MCF7/ADR and cisplatin-resistant ovarian cancer cell line A2780. Furthermore, the herbal complex suppressed the expression of the full length of human telomerase reverse transcriptase (hTERT), which is related to telomerase activity. This indicates that the herbal complex can suppress the tumor growth of chemoendocrine resistant cancers, at least in part via suppression of telomerase activity associated with down-regulated hTERT.
PMID: 11766737

Surprise!

Herbal mix has patent: http://www.freepatentsonline.com/7527812.html

What? Is this bad? Excercise activates and reduces shortening of Telomerase? http://www.fightaging.org/archives/2...-telomeres.php




Blocking inflammation receptor kills breast cancer stem cells, study finds
1/4/2010
http://www.physorg.com/news181851567.html

Scientists at the University of Michigan Comprehensive Cancer Center have uncovered an important link between inflammation and breast cancer stem cells that suggests a new way to target cells that are resistant to current treatments.

"Developing treatments to effectively target the cancer stem cell population is essential for improving outcomes. This work suggests a new strategy to target cancer stem cells that can be readily translated into the clinic," says senior study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center. Wicha was part of the team that first identified stem cells in breast cancer.

Results of the current study appear online Jan. 4 in the Journal of Clinical Investigation and will appear in the journal's February print issue.
CXCR1 is a receptor for Interleukin-8, or IL-8, a protein produced during chronic inflammation and tissue injury. When tumors are exposed to chemotherapy, the dying cells produce IL-8, which stimulates cancer stem cells to replicate. Addition of the drug repertaxin to chemotherapy specifically targets and kills breast cancer stem cells by blocking CXCR1.
Mice treated with repertaxin or the combination of repertaxin and chemotherapy had dramatically fewer cancer stem cells than those treated with chemotherapy alone. In addition, repertaxin-treated mice developed significantly fewer metastases than mice treated with chemotherapy alone.
"These studies suggest that important links between inflammation, tissue damage and breast cancer may be mediated by cancer stem cells. Furthermore, anti-inflammatory drugs such as repertaxin may provide a means of blocking these interactions, thereby targeting breast cancer stem cells," Wicha says.
Repertaxin has been tested in early phase clinical trials to prevent rejection after organ transplantation. In these studies, side effects seem to be minimal. There are no reports of using repertaxin to treat cancer.

More information: Journal of Clinical Investigation, Vol. 120, No. 2, February 2010; doi:10.1172/JCI39397



Other available Interleukin-8 inhibitors:

Thymiquone from Nigella Sativa or black cumin
(used in Indian spice Charnushka)

Wikipedia
Thymoquinone is a phytochemical compound found in the plant Nigella sativa. It has antioxidant effects and has been shown to protect against heart, liver and kidney damage in animal studies, as well as having possible anti-cancer effects.^{[1][2][3][4][5][6][7]} It also has analgesic^[8] and anticonvulsant effects in animal models.^[9] It is an angiogenesis inhibitor.

Sloan Kettering description and links
http://www.mskcc.org/mskcc/html/69141.cfm

Nigella sativa web

More background and Oil and capsules available here:
http://www.kitchendoctor.com/herbs/black_cumin.php



Herbal extract inhibits pancreatic cancer development
LINK ABSTRACT
April 20th, 2009
Dr. Arafat said that Nigella sativa seeds and oil, used in traditional medicine by many Middle Eastern and Asian countries, helps treat a broad array of diseases, including some immune and inflammatory disorders.
Previous studies have also shown it to have anti-cancer effects on prostate and colon cancers.
Based upon their previously published findings that thymoquinone inhibits histone deacetylases (HDACs), Dr. Arafat and her colleagues compared the anti-inflammatory properties of thymoquinone and trichostatin A, an HDAC inhibitor that has previously shown to ameliorate inflammation-associated cancers.
The researchers used pancreatic ductal adenocarcinoma (PDA) cells, some of which were pretreated with the cytokine TNF-alpha to induce inflammation.
Thymoquinone almost completely abolished the expression of several inflammatory cytokines, including TNF-alpha, interleukin-1beta, interleukin-8, Cox-2 and MCP-1, an effect that was more superior to the effect of trichostatin A.
The herb also inhibited the activation and synthesis of NF-kappaB, a transcription factor that has been implicated in inflammation-associated cancer.
Activation of NF-kappaB has been observed in pancreatic cancer and may be a factor in pancreatic cancer’s resistance to chemotherapeutic agents.
When animal models of pancreatic cancer were treated with thymoquinone, 67 percent of the tumours were significantly shrunken, and the levels of proinflammatory cytokines in the tumours were significantly reduced.

Cancer Res. 2009 Jul 1;69(13):5575-83. Epub 2009 Jun 23.
Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer.

Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S, Sarkar FH, Mohammad RM.
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
Previous studies have shown biological activity of thymoquinone, an active compound extracted from Nigella sativa, in pancreatic cancer cells; however, preclinical animal studies are lacking. Here, we report, for the first time, the chemosensitizing effect of thymoquinone to conventional chemotherapeutic agents both in vitro and in vivo using an orthotopic model of pancreatic cancer. In vitro studies revealed that preexposure of cells with thymoquinone (25 mumol/L) for 48 h followed by gemcitabine or oxaliplatin resulted in 60% to 80% growth inhibition compared with 15% to 25% when gemcitabine or oxaliplatin was used alone. Moreover, we found that thymoquinone could potentiate the killing of pancreatic cancer cells induced by chemotherapeutic agents by down-regulation of nuclear factor-kappaB (NF-kappaB), Bcl-2 family, and NF-kappaB-dependent antiapoptotic genes (X-linked inhibitors of apoptosis, survivin, and cyclooxygenase-2). As shown previously by our laboratory, NF-kappaB gets activated on exposure of pancreatic cancer cells to conventional chemotherapeutic agents; interestingly, thymoquinone was able to down-regulate NF-kappaB in vitro, resulting in chemosensitization. In addition to in vitro results, here we show for the first time, that thymoquinone in combination with gemcitabine and/or oxaliplatin is much more effective as an antitumor agent compared with either agent alone. Most importantly, our data also showed that a specific target, such as NF-kappaB, was inactivated in animal tumors pretreated with thymoquinone followed by gemcitabine and/or oxaliplatin. These results provide strong in vivo molecular evidence in support of our hypothesis that thymoquinone could abrogate gemcitabine- or oxaliplatin-induced activation of NF-kappaB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics.

PMID: 19549912 [PubMed - indexed for MEDLINE]



Parthenolide (feverfew)

http://cat.inist.fr/?aModele=afficheN&cpsidt=18687031

Subcutaneous injection or oral administration of parthenolide showed significant tumor growth inhibition in the xenograft model via decreased production of interleukin-8 (IL-8) or vascular endothelial growth factor (VEGF). Immunohistochemistry and Western blot analysis showed decreased nuclear localization of NF-KB and phosphorylated NF-KB protein and subsequently expression of MMP-9, Bcl-xL and Cox-2 in response to parthenolide treatment.

J Clin Endocrinol Metab. 2007 Aug;92(8):3213-8. Epub 2007 May 15.
Metformin suppresses interleukin (IL)-1beta-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells.

Takemura Y, Osuga Y, Yoshino O, Hasegawa A, Hirata T, Hirota Y, Nose E, Morimoto C, Harada M, Koga K, Tajima T, Yano T, Taketani Y.
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
CONTEXT: Metformin, a widely used treatment for diabetes that improves insulin sensitivity, also has both antiinflammatory properties and a modulatory effect on ovarian steroid production, two actions that have been suggested to be efficacious in therapy for endometriosis. OBJECTIVE: To determine whether metformin may be effective for the treatment of endometriosis, we evaluated the effects of this agent on inflammatory response, estradiol production, and proliferation of endometriotic stromal cells (ESCs). DESIGN: ESCs derived from ovarian endometriomas were cultured with various concentrations of metformin. MAIN OUTCOME MEASURES: IL-8 production, mRNA expression and aromatase activity, and 5-bromo-2'-deoxyuridine incorporation in ESCs were measured. RESULTS: Metformin dose-dependently suppressed IL-1beta-induced IL-8 production, cAMP-induced mRNA expression and aromatase activity, and 5-bromo-2'-deoxyuridine incorporation in ESCs. CONCLUSION: These results suggest that further investigation into the unique therapeutic potential of metformin as an antiendometriotic drug is warranted.

PMID: 17504902 [PubMed - indexed for MEDLINE]



Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):611-7. Epub 2005 Dec 29.
Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells.

http://www.ncbi.nlm.nih.gov/pubmed/16385087

Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schönbeck U, Libby P.
Donald W. Reynolds Cardiovascular Clinical Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
OBJECTIVE: Metformin may benefit the macrovascular complications of diabetes independently of its conventional hypoglycemic effects. Accumulating evidence suggests that inflammatory processes participate in type 2 diabetes and its atherothrombotic manifestations. Therefore, this study examined the potential action of metformin as an inhibitor of pro-inflammatory responses in human vascular smooth muscle cells (SMCs), macrophages (Mphis), and endothelial cells (ECs). METHODS AND RESULTS: Metformin dose-dependently inhibited IL-1beta-induced release of the pro-inflammatory cytokines IL-6 and IL-8 in ECs, SMCs, and Mphis. Investigation of potential signaling pathways demonstrated that metformin diminished IL-1beta-induced activation and nuclear translocation of nuclear factor-kappa B (NF-kappaB) in SMCs. Furthermore, metformin suppressed IL-1beta-induced activation of the pro-inflammatory phosphokinases Akt, p38, and Erk, but did not affect PI3 kinase (PI3K) activity. To address the significance of the anti-inflammatory effects of a therapeutically relevant plasma concentration of metformin (20 micromol/L), we conducted experiments in ECs treated with high glucose. Pretreatment with metformin also decreased phosphorylation of Akt and protein kinase C (PKC) in ECs under these conditions. CONCLUSIONS: These data suggest that metformin can exert a direct vascular anti-inflammatory effect by inhibiting NF-kappaB through blockade of the PI3K-Akt pathway. The novel anti-inflammatory actions of metformin may explain in part the apparent clinical reduction by metformin of cardiovascular events not fully attributable to its hypoglycemic action.

PMID: 16385087 [PubMed - indexed for MEDLINE]


Diet/weight:
http://jcem.endojournals.org/cgi/con...ull/87/10/4602
Plasma Interleukin-8 Concentrations Are Increased in Obese Subjects and Related to Fat Mass and Tumor Necrosis Factor- System




More background on Interleukin-8:
Cytokine Growth Factor Rev. 2001 Dec;12(4):375-91.
http://www.ncbi.nlm.nih.gov/pubmed/11544106

Interleukin-8 and human cancer biology.

Xie K.
Department of Gastrointestinal Medical Oncology and Cancer Biology, M.D. Anderson Cancer Center, The University of Texas, Box 78, 1515 Holcombe Boulevard, Houston, TX 77030, USA. kepxie@mail.mdanderson.org
The aggressive nature of metastatic human cancer has been shown to be related to numerous abnormalities in growth factors and their receptors. These perturbations confer a tremendous growth advantage to the malignant cells. Interleukin-8 (IL-8), originally discovered as a chemotactic factor for leukocytes, has recently been shown to contribute to human cancer progression through its potential functions as a mitogenic, angiogenic, and motogenic factor. While it is constitutively detected in human cancer tissues and established cell lines, IL-8 expression is regulated by various tumor microenvironment factors, such as hypoxia, acidosis, nitric oxide, and cell density. Understanding the mechanisms of both inducible and constitutive IL-8 expression will be helpful in designing potential therapeutic strategies of targeting IL-8 to control tumor growth and metastasis. In this review, the role and regulation of IL-8 expression in the growth and metastasis of human cancer with a focus on human pancreatic adenocarcinoma will be discussed.

PMID: 11544106 [PubMed - indexed for MEDLINE]