Retrospective analyses have indicated that the antidiabetic agent metformin may be associated with a quite substantial reduction in risk of cancers. There is evidence that the anticancer effects of metformin are related to inhibition of the growth of certain cancers via activation of AMP kinase with secondary inhibition of protein synthesis or via an indirect mechanism involving reduction in gluconeogenesis that leads to reduced proliferation of insulin-responsive cancers.
In recent in vitro studies, Algire and colleagues from McGill University in Quebec showed that metformin reduces endogenous reactive oxygen species synthesis and resultant DNA damage and mutations, thus identifying another potential mechanism for this drug’s cancer-preventive activity.1 In studies involving mitochondrial toxins, these investigators first showed that metformin had no effect in attenuating exogenously (H2O2) induced reactive oxygen species and DNA damage, but reduced endogenous (paraquat-induced) reactive oxygen species and subsequent DNA damage and mutation.
Inhibition of Ras-related Damage
To assess whether metformin could prevent these processes when induced by naturally occurring oncogenes, the investigators then introduced Ras into primary human fibroblasts, where it is known to induce production of reactive oxygen species, DNA damage, and cell senescence. Metformin attenuated the substantial increase in reactive oxygen species in the Ras-expressing cells, significantly reduced the number of DNA damage foci, and reduced cell proliferation, without having an effect on Ras signaling.
As stated by the investigators, “While experimental investigation of the antineoplastic activity of metformin has documented growth inhibitory activity for established cancers, review of the epidemiologic data suggests that the dominant effect of metformin … may involve reduction in risk rather than improvement in prognosis, as the magnitude of the reported decline in mortality is similar to the magnitude of the decline in incidence.”
They added “Our finding[s] that sequelae of the … mitochondrial actions of metformin include reduced endogenous reactive oxygen species production, reduced oxidative stress, reduced DNA damage, and reduced mutagenesis in normal somatic cells, or their variants expressing activated oncogenes, provide a novel mechanism to explain reduced cancer incidence associated with metformin therapy, and raise the possibility of novel applications in prevention of cancer and other diseases associated with cellular damage caused by mitochondrial reactive oxygen species production.” ■
1. Algire C, Moiseeva O, Deschenes-Simard X, et al: Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 5:536-543, 2012.