Metformin in cancer: translational challenges
- 1Division of Signalling Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2M9
2Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9
3Division of Clinical Epidemiology, Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 1284-600 University Avenue, Toronto, Ontario, Canada M5G 1X5
- (Correspondence should be addressed to P J Goodwin; Email: pgoodwin{at}mtsinai.on.ca)
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Figure 1
Evidence supporting the use of metformin in the treatment of cancer. The potential use of metformin in the prevention and treatment of cancer is based on emerging evidence from a number of research fields. Metabolic factors such as obesity and hyperinsulinaemia are associated with cancer risk while epidemiological studies have demonstrated a reduced incidence of cancer in diabetic patients receiving metformin. Moreover, preclinical studies have provided evidence of the anti-cancer effects of metformin and defined its mechanism of action.
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Figure 2
Mechanism of action of metformin in cancer. The anti-cancer activity of metformin is associated with direct and indirect effects of the drug. The direct insulin-independent effects of metformin are mediated by activation of AMPK and a reduction in mTOR signalling and protein synthesis in cancer cells. The tumour suppressors LKB1 and TSC2 are important in mediating the effects of metformin on AMPK and mTOR respectively; however, metformin may also inhibit mTOR independently of LKB1, AMPK and TSC2. The indirect insulin-dependent effects of metformin are mediated by its ability to activate AMPK and inhibit gluconeogenesis in the liver and stimulate glucose uptake in muscle. The resulting reduction in circulating insulin alleviates activation of PI3K/AKT/mTOR signalling in cancer cells. The cell membrane transporter OCT1 is required for metformin uptake in tissue and therefore may play a key role in efficacy.
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Figure 3
Concentrations of metformin used in clinical and preclinical studies. The anti-cancer effects of metformin have been tested over a wide range of doses. Clinical and epidemiological studies have utilised metformin at standard doses of up to 2250 mg/day. Conversely, preclinical studies often involve extremely high, non-physiological concentrations of metformin that are in excess of the therapeutic levels achieved in human patients.
- © 2012 Society for Endocrinology
