title: Metformin reduces endogenous reactive oxygen species and associated DNA damage.
abstract: Pharmacoepidemiologic studies provide evidence that use of metformin, a drug commonly prescribed for type II diabetes, is associated with a substantial reduction in cancer risk. Experimental models show that metformin inhibits the growth of certain neoplasms by cell autonomous mechanisms such as activation of AMP kinase with secondary inhibition of protein synthesis or by an indirect mechanism involving reduction in gluconeogenesis leading to a decline in insulin levels and reduced proliferation of insulin-responsive cancers. Here, we show that metformin attenuates paraquat-induced elevations in reactive oxygen species (ROS), and related DNA damage and mutations, but has no effect on similar changes induced by H(2)0(2), indicating a reduction in endogenous ROS production. Importantly, metformin also inhibited Ras-induced ROS production and DNA damage. Our results reveal previously unrecognized inhibitory effects of metformin on ROS production and somatic cell mutation, providing a novel mechanism for the reduction in cancer risk reported to be associated with exposure to this drug.
authors.affiliation: Division of Experimental Medicine, McGill University and Segal Cancer Centre of Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Algire
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.forename: Xavier
authors.initials: X
authors.lastname: Deschênes-Simard
authors.forename: Lilian
authors.initials: L
authors.lastname: Amrein
authors.forename: Luca
authors.initials: L
authors.lastname: Petruccelli
authors.forename: Elena
authors.initials: E
authors.lastname: Birman
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D016296:Mutagenesis; D009154:Mutation; D009249:NADP / Q000378:metabolism; D017382:Reactive Oxygen Species
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D017382:Reactive Oxygen Species; D009249:NADP; D004815:Epidermal Growth Factor; D008687:Metformin; D006861:Hydrogen Peroxide; D000263:Adenylate Kinase