Research contributes to the understanding of metformins anticancer effect

Research contributes to the understanding of metformin's anticancer effect

Tuesday, February 3, 2015. On January 27, 2015, the Proceedings of the National Academy of Sciences published the outcome of research which helps explain the anticancer effects of metformin observed in men and women with diabetes.

In their introduction to the article, Shingo Eikawa of Okayama University Graduate School of Medicine in Okayama, Japan and colleagues observe that insulin-based antidiabetic therapies are associated with an increase in the risk of cancer, while metformin has been associated with a reduction in specific cancer risk. Meta-analyses of epidemiologic studies have uncovered a 30-50% reduction in cancer incidence among diabetics who use metformin in comparison with other drugs; however, its anticancer mechanisms have not been well studied.

Dr Eikawa and associates examined the effect of metformin on immune system cells known as CD8+ tumor-infiltrating lymphocytes. Due to repeated stimulation during chronic infectious disease and cancer, these cells are known to undergo immune exhaustion, which is characterized by a reduction in cytokine production and the cells' eventual elimination by apoptosis (programmed cell death), accompanied by the expression of specific markers.

The researchers describe a series of experiments in which metformin enabled animals to reject solid tumors while CD8+ tumor-infiltrating lymphocytes were increased and protected from exhaustion and apoptosis. This anti-tumor effect was not observed in mice with severe combined immune-deficiency, indicating that, rather than a direct tumor cell destructive effect by metformin, its benefit appears to be immune-mediated.

The authors note that previous animal research identified plasma metformin concentrations similar to those measured in human metformin-treated diabetics as achievable by the oral administration of metformin doses used in the current experiments.

"We showed that established solid tumors are regressed by oral administration of metformin, and that CD8+T cells mediate this effect," they write. "Further experiments will be required to elucidate cellular and molecular mechanism underlying metformin-induced reversion of exhausted CD8+ tumor-infiltrating lymphocytes."

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Higher dose metformin associated with improved survival among colorectal cancer patients

The journal Cancer Epidemiology, Biomarkers & Prevention published an article on June 10, 2013 which reports a benefit for the antidiabetic drug metformin in colorectal cancer survival.

The study involved 3,816 men and women with stage I-III colorectal cancer diagnosed between 2001 and 2006, including 207 diabetics who had been prescribed metformin, 108 diabetics who did not use the drug and 3,501 nondiabetics. The subjects were followed through 2010, during which 196 deaths occurred among those with diabetes and 1,897 occurred among the nondiabetics. Among the diabetic patients, 93 deaths were due to colorectal cancer, and 1,082 nondiabetic deaths were attributable to the disease.

When subjects treated with metformin were compared to diabetics who did not use the drug, a reduction in the risk of death due to colorectal cancer that "approached significance" was observed. However, those whose use of metformin was categorized as high intensity (higher dose), had a 56% lower risk of dying of the disease than diabetics who did not use the drug. Metformin use was additionally associated with a 31% lower adjusted risk of dying from any cause among diabetic subjects over follow-up.

"This study is the first, to the authors' knowledge, to assess the presence of an exposure response effect between increasing metformin use and colorectal cancer outcomes," authors Susan C. Spillane and her colleagues at St James Hospital in Dublin announce. "Significant associations were observed in stratified analyses of high intensity exclusive metformin usage and the results also suggest that metformin exposure may potentially improve survival relative to non-diabetic patients. Additional studies in larger population-based cohorts are required to further explore the influence of varying exposure levels and timing and to determine if any patient subgroups are more likely to benefit from metformin."

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Life Extension Magazine® February 2015 Issue Now Online

On the cover

Reports

The deadly consequences of excess abdominal fat, by Jennifer Wasko

Block the vascular origins of cognitive decline, by Michael Downey

Health risks of inhalation insulin for diabetics, by T. R. Shantha, MD, PhD, FACA

Heal traumatic brain injury with bioidentical hormones, by Michael Downey

Departments

As we see it: Major advance in slowing aging, by William Faloon

Superfoods: Sage, the medicinal herb, by Michael Downey

Author interview: Eating on the Wild Side, by Astrid Derfler Kessler

In the News

Ask the pharmacist: Magnesium deficiency may be caused by prescription pills, by Kimmi Stultz, PharmD, CPH

Journal abstracts: Vinpocetine, brain shrinkage, brain injury and bioidentical hormones, Saccharomyces cerevisiae-derived peptides, and inhaled insulin

Health Concern

Colorectal cancer

Metformin is an oral antidiabetic drug that works by suppressing the production of glucose in the liver and boosting insulin sensitivity in peripheral tissues. Metformin is currently considered the treatment of choice for type 2 diabetes.

As with other malignancies, colorectal cancer risk is increased in diabetics, and there is a growing body of evidence that advanced glycation end products (AGEs), which are a consequence of elevated blood glucose, and insulin-receptor signaling are involved in the initiation and propagation of these common tumors (Yamagishi 2005; Mountjoy 1987).

Moreover, colorectal cancers are among those malignancies most closely associated with obesity. Obese individuals are deficient in the protective hormone adiponectin, which activates tumor-suppressing AMPK. Metformin, by independently activating AMPK, may circumvent this deficiency and help to reduce its impact on colorectal cancer risk (Zakikhani 2008). Naturally, these findings have piqued interest in investigating the potential role of metformin against colorectal cancer.

In 2011, researchers conducted a comprehensive review of observational data on the use of metformin and the risk of colorectal cancer in diabetic patients (Zhang 2011). This review encompassed five studies including nearly 110,000 subjects. Compared to all other antidiabetic treatments, the use of metformin was associated with a 37% lower risk of colorectal cancer.

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1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2013 Dec 18.