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Metformin

Metformin

The active ingredient in a drug used to treat diabetes mellitus (a condition in which the body cannot control the level of sugar in the blood). It is also being studied in the treatment of cancer. It decreases the amount of glucose (a type of sugar) released into the bloodstream from the liver and increases the body’s use of the glucose. Metformin is a type of antidiabetic agent. Also called Glucophage.
National Cancer Institute


CAUTION

  1. Metformin may contain a cancer-forming nitrosamine, NDMA, and also seems to make BRAF mutation cancer more aggressive when used on its own.
  2. This drug has a black box warning.

This is the most serious warning from the Food and Drug Administration (FDA). A black box warning alerts doctors and patients about drug effects that may be dangerous.

Lactic acidosis is a rare but serious side effect of this drug. In this condition, lactic acid builds up in your blood. This is a medical emergency that requires treatment in the hospital. Lactic acidosis is fatal in about half of people who develop it. You should stop taking this drug and call your doctor right away or go to the emergency room if you have symptoms of lactic acidosis.

Symptoms include weakness, unusual muscle pain, trouble breathing, unusual sleepiness, and stomach pains. They also include nausea or vomiting, dizziness or lightheadedness, and slow or irregular heart rate.

 


This 2020 study recruited 2400 patients with gastric cancer undergoing gastrectomy…Among them, 651 had type II Diabetes and 1749 patients did not have Diabetes. The study showed that the use of Metformin significantly reduces the risk of tumour recurrence and confers cancer-specific survival benefits in patients with stage III Gastric Cancer and Diabetes after surgery.

This meta-analysis looked at 18 studies (8 on lung cancer risk and 10 on lung cancer survival) were included. Metformin treatment was associated with decreased lung cancer incidence and increased lung cancer survival.
Conclusions: Our findings demonstrate that metformin is significantly associated with a decreased risk and increased survival in lung cancer.

This study reviewed the records of 460 consecutive patients with pathologically proved stage I-III breast cancer. These patients received adjuvant chemotherapy during the period from January 2008 to December 2008. Patients were compared by groups that consisted of 25 diabetic patients taking metformin, 14 diabetic patients not taking metformin, and 400 nondiabetic patients.

Regarding overall survival, diabetic breast cancer patients treated with metformin as antidiabetic agent had longer mean overall survival time (59.71 months) than diabetic patients not treated with metformin (41.79 months) and nondiabetic patients (52.0 months).

Furthermore, nondiabetic breast cancer patients had longer mean overall survival time (52.0 months) than diabetic patients not taking metformin (41.79 months) and the difference was statistically significant.

Conclusion: There is an association between metformin use and better survival outcome in diabetic breast cancer patients who received metformin during adjuvant chemotherapy.

This 2020 Meta-Analysis of 12 studies involving 35,346 Pancreatic Cancer patients found significant differences in overall survival between Pancreatic Cancer patients who were treated with metformin and underwent pancreatectomy and those who underwent pancreatectomy without metformin use. Conclusions: Metformin use is related to a better survival benefit for Pancreatic Cancer patients who underwent pancreatectomy, which would be a potential drug for the treatment of Pancreatic Cancer.

Metformin as a promising anti-cancer agent is supported by extensive epidemiologic, preclinical and clinical data, says this study.

In human cancer cells of different origin, metformin has been shown to induce cell cycle arrest, growth inhibition and apoptosis…As demonstrated in a number of recent studies,
metformin is able to selectively target Cancer Stem Cells in different types of human cancers, including breast , pancreatic and thyroid cancer. In particular, metformin has been shown to selectively kill Cancer Stem Cells in four genetically different types of human breast cancer, according to this study

This 2016 Review published in Annals of Oncology looked at data from observational studies comprising 24,178 participants. In those with early-stage colorectal cancer, metformin use was associated with a significant benefit in all outcomes.

For men with early-stage prostate cancer, metformin was associated with significant, or borderline significant, benefits in all outcomes. The data suggest that prostate cancer patients treated with radical radiotherapy may benefit more from metformin. In breast and urothelial cancer, no significant benefits were identified.

This study says: The combination of Metformin and caffeic acid to suppress cervical carcinoma cells by two independent mechanisms may provide a promising approach to cancer treatment.

This study notes: Preclinical evidence suggests that metformin appears to inhibit the proliferation and growth of certain types of cancer. Results of numerous clinical studies, although inconclusive, indicate that metformin use, and possibly cumulative duration of therapy and cumulative dose, is associated not only with decreased incidence of cancer in diabetic population, but also with the better outcome in cancer patients.

 
In this study, the first to examine the effect of metformin on survival rates for breast cancer patients, researchers examined clinical outcomes for 1,215 patients who were diagnosed and underwent surgical treatment for breast cancer between 1997 and 2013. Ninety-seven patients examined reported using metformin before their diagnosis, and 97 reported use of the drug after diagnosis.

Results of the study showed that patients who used metformin before being diagnosed with breast cancer were more than twice as likely to die than patients who never used the drug, while patients who began using metformin after their cancer diagnosis were almost 50 percent more likely to survive than non-users.

For Glioblastoma patients, this study found that a combination of high-dose Metformin and Temozolomide showed the highest cancer cell death activity.

This study concluded: Metformin is the first-line drug for the treatment of T2DM [Type 2 Diabetes]. Epidemiological and basic studies have demonstrated that it may also inhibit the growth of a variety of tumor cells, and an increasing number of ongoing clinical trials on the antitumor activity of metformin are being processed for the treatment of cancer.


Mass. General study reveals how diabetes drug metformin prevents, suppresses cancer growth

Source: Massachusetts General Hospital
Ancient genetic pathway could provide targets for fighting cancers, supporting healthy aging

Considerable evidence has indicated that the drug metformin, used for more than 50 years to treat type 2 diabetes, also can prevent or slow the growth of certain cancers; but the mechanism behind its anticancer effects has been unknown. Now a team of Massachusetts General Hospital (MGH) investigators has identified a pathway that appears to underlie metformin’s ability both to block the growth of human cancer cells and to extend the lifespan of the C.elegans roundworm, implying that this single genetic pathway plays an important role in a wide range of organisms.

“We found that metformin reduces the traffic of molecules into and out of the nucleus – the ‘information center’ of the cell,” says Alexander Soukas, MD, PhD, of the MGH Center for Human Genetic Research, senior author of the study in the Dec. 15 issue of Cell. “Reduced nuclear traffic translates into the ability of the drug to block cancer growth and, remarkably, is also responsible for metformin’s ability to extend lifespan. By shedding new light on metformin’s health-promoting effects, these results offer new potential ways that we can think about treating cancer and increasing healthy aging.”

Metformin’s ability to lower blood glucose in patients with type 2 diabetes appears to result from the drug’s effects on the liver – reducing the organ’s ability to produce glucose for release into the bloodstream. Evidence has supported the belief that this is the result of metformin’s ability to block the activity of mitochondria, structures that serve as the powerhouse of the cell. But while that explanation appears to be fairly straightforward, Soukas explains, more recent information suggests the mechanism is more complex.

Several studies have suggested that individuals taking metformin have a reduced risk of developing certain cancers and of dying from cancers that do develop. Current clinical trials are testing the impact of metformin on cancers of the breast, prostate and pancreas; and several research groups are working to identify its molecular targets. Soukas’s team had observed that, just as it blocks the growth of cancer cells, metformin slows growth in C.elegans, suggesting that the roundworm could serve as a model for investigating the drug’s effects on cancer.

Their experiments found that metformin’s action against cancer relies on two elements of a single genetic pathway – the nuclear pore complex, which allows the passage of molecules into and out of the nucleus, and an enzyme called ACAD10. Basically, metformin’s suppression of mitochondrial activity reduces cellular energy, restricting the traffic of molecules through the nuclear pore. This shuts off an important cellular growth molecule called mTORC1, resulting in activation of ACAD10, which both slows the growth and extends the lifespan of C.elegans.

In human melanoma and pancreatic cancer cells, the investigators confirmed that application of drugs in the metformin family induced ACAD10 expression, an effect that depended on the function of the nuclear pore complex. Without the complete signaling pathway – from mitochondrial suppression, through nuclear pore restriction to ACAD10 expression – cancer cells were no longer sensitive to the effects of metformin-like drugs.

“Amazingly, this pathway operates identically, whether in the worm or in human cancer cells,” says Soukas, who is an assistant professor of Medicine at Harvard Medical School. “Our experiments showed two very important things: if we force the nuclear pore to remain open or if we permanently shut down ACAD10, metformin can no longer block the growth of cancer cells. That suggests that the nuclear pore and ACAD10 may be manipulated in specific circumstances to prevent or even treat certain cancers.”

The essential contribution of ACAD10 to metformin’s anticancer action is intriguing, Soukas adds, because the only published study on ACAD10 function tied a variant in the gene to the increased risk of type 2 diabetes in Pima Indians, suggesting that ACAD10 also has a role in the drug’s antidiabetes action. “What ACAD10 does is a great mystery that we are greatly interested in solving,” he says. “Determining exactly how ACAD10 slows cell growth will provide additional insights into novel therapeutic targets for cancer and possibly ways to manipulate the pathway to promote healthy aging.”

Lianfeng Wu, PhD, of the MGH Center for Human Genetic Research (CHGR) is lead author of the Cell paper. Additional co-authors are Ben Zhou, PhD, Christopher Webster, PhD, Michael Kacergis, MS, and Michael Talkowski, PhD, MGH CHGR; Noriko Oshiro-Rapley, PhD, Fan Mou, PhD, and Christopher Carr, PhD, MGH Department of Molecular Biology; Man Li, PhD and Bin Zheng, PhD, MGH Cutaneous Biology Research Center; and Joao Paulo, PhD and Steven Gygi, PhD, Harvard Medical School. Support for this study includes National Institutes of Health grants R03DK098436, K08DK087941, R01DK072041, and R01CA166717, a Broad Institute SPARC Grant, and the Ellison Medical Foundation New Scholar in Aging Award.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of “America’s Best Hospitals.”

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