(1) Department of Radiation Oncology, Kimmel Cancer Center and Jefferson Medical College of Thomas Jefferson, Philadelphia PA
(2) Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA
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Epidemiological studies have shown a correlation between insulin resistance, a marker of impaired glucose metabolism and metabolic syndrome, and malignancy development. Insulin resistance leads to a hyperinsulinemic state, which is thought to promote carcinogenesis via the direct effect of insulin on the insulin like growth factor 1 (IGF-1), an increase in IGF-1 synthesis, modulation of sex hormone availability, and finally through the resultant elevated glucose levels that promote inflammation and aid glycolysis in cancer cells. In addition to an increased incidence of cancer induction, insulin resistance has also been correlated with worse prognosis in cancer patients undergoing active treatment. Metformin is an oral agent that is widely used in the treatment of diabetes as it has been shown to sensitize cells to the effects of insulin. Several epidemiologic studies show a potential protective effect of metformin in diabetic patients. Preclinical studies have shown a direct inhibitory effect of metformin on cancer cell lines both in vitro and in vivo. This is thought to be mediated through multiple mechanisms, including effects on cellular metabolism via the AMP-activated protein kinase (AMPK) pathway, effects on cell cycle progression, and decreased cellular oxygen consumption. Though the data is conflicting, several retrospective studies suggest an antitumor benefit of metformin in cancer patients undergoing active treatment. Several prospective studies examining the role of metformin as an adjunctive antineoplastic agent are currently ongoing. This review serves to explore the current role of metformin in cancer treatment and prevention of cancer, and to hypothesize that, in part, the effects of metformin may come from modulation of the metabolic environment of tumour cells.
Cancer cells and their inherent molecular pathways appear to be greatly influenced by the metabolic environment. Metformin modulates pathways their pathways directly, whle indirectly affecting them through its effect on the metabolic environment. Clinical trials will tell us how effective it in at preventing and treating cancer. In the meantime, metformin remains a promising cancer treatment that links the roots of cancer as both a metabolic and genetic disease.