Metformin and cancer: Between the bioenergetic disturbances and the antifolate activity.
For decades, metformin has been the first-line drug for the treatment of type II diabetes mellitus, and it thus is the most widely prescribed antihyperglycemic drug. Retrospective studies associate the use of metformin with a reduction in cancer incidence and cancer-related death. However, despite extensive research about the molecular effects of metformin in cancer cells, its mode of action remains controversial. In this review, we summarize the current molecular evidence in an effort to elucidate metformin's mode of action against cancer cells. Some authors describe that metformin acts directly on mitochondria, inhibiting complex I and restricting the cell's ability to cope with energetic stress. Furthermore, as the drug interrupts the tricarboxylic acid cycle, metformin-induced alteration of mitochondrial function leads to a compensatory increase in lactate and glycolytic ATP. It has also been reported that cell cycle arrest, autophagy, apoptosis and cell death induction is mediated by the activation of AMPK and Redd1 proteins, thus inhibiting the mTOR pathway. Additionally, unbiased metabolomics studies have provided strong evidence to support that metformin alters the methionine and folate cycles, with a concomitant decrease in nucleotide synthesis. Indeed, purines such as thymidine or hypoxanthine restore the proliferation of tumor cells treated with metformin in vitro. Consequently, some authors prefer to refer to metformin as an "antimetabolite drug" rather than a "mitochondrial toxin". Finally, we also review the current controversy concerning the relationship between the experimental conditions of in vitro-reported effects and the plasma concentrations achieved by chronic treatment with metformin.
Unidad de Farmacología y Farmacogenética, ICOD, Facultad de Odontología, Universidad de Chile, Santiago, Chile.
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Jara
Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile. Electronic address: rodrigo.lopez@uach.cl.
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López-Muñoz
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D008687:Metformin / Q000494:pharmacology*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control*
D000963:Antimetabolites; D005493:Folic Acid Antagonists; D007004:Hypoglycemic Agents; D008687:Metformin
Cancer; Chemotherapy; Complex I; Folate cycle; Metformin; Mitochondria; Nucleotides