Diabetes patients treated with metformin?the drug that has been used to treat diabetes for more than six decades?have been reported to have their risk of cancer reduced by around 40% compared with other diabetics. During the Annual meeting of the EASD, the European Association for the Study of Diabetes (September 22 – 24, Stockhom, Sweden), Professor Michael Pollak, McGill University, Montreal, Canada, showed that evidence suggesting that the commonly-used antidiabetic drug may be used to treat or prevent common cancers such as those of the colon, lung, breast, or prostate, is increasing.

“It is unclear if metformin provides a chemopreventative effect that prevents development of cancer, inhibits the growth of established cancers, or both,” says Pollak “It also remains to be established if the recent observations concerning the beneficial effects of metformin have relevance to people without diabetes, that is whether non-diabetics would also have their cancer risk reduced by metformin.”

Pollak says laboratory models provide independent impressive evidence for activity of metformin (and other drugs in the biguanide family) in both cancer treatment and chemoprevention. But investigations regarding mechanisms have revealed considerable complexity, and have identified important gaps in knowledge (such as the optimal dosage) that Pollak says should be addressed to ensure optimal design of clinical trials “Future work may define important new indications of biguanides for the prevention and/or treatment of many common cancers. This represents a particularly interesting and active area of research at the interface between diabetes and cancer,” he says.

Metformin works in T2DM mainly in the liver, where it leads to activation of AMP-activated protein kinase (AMPK), which results in reduced glucose secretion by the liver, thus lowering glucose levels. But Pollak says it is a fundamental action action of metformin?reducing the production of the energy molecule adenosine triphosphate (ATP) in cells?that could be key to its role in cancer prevention, in three ways. First, this leads not only to reduced glucose levels, but also to reduced insulin levels: this may inhibit the subset of cancers which are growth stimulated by insulin (such as those above)

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Second, if cancer cells or epithelial cells at risk for transformation are exposed to a sufficiently high concentration of biguanides such as metformin, and if they have intact regulatory signaling pathways, then they are growth inhibited because they try to cope with the decreased energy supply due to the effect of metformin on cellular energy production. Finally, cancer cells are sometimes defective in energy-sensing capability. In this situation, they do not recognize that metformin is reducing their energy supply, attempt to continue to proliferate rapidly, and this leads to an “energy depletion crisis” that is fatal to the cell.

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“The evidence from population surveys suggesting reduced cancer rates among diabetics taking metformin compared to other diabetics, together with laboratory studies that provide independent evidence for an inhibitory effect of metformin and similar compounds on cancer growth, has created much interest in the research community and to new collaborations between oncologists and diabetologists,” concludes Pollak. “Some early clinical trials have started and many are being planned. The off-patent status of metformin has limited private sector interest in investing in this area, but there are possibilities that new metformin derivatives will be developed.”

Pollak M, Metformin and Other Biguanides in Oncology: Advancing the Research Agenda. Cancer Prev Res (Phila). 2010 Sep;3(9):1060-5. Epub 2010 Sep 1.

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