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. Cancer Prev Res; 5(4); 536-43. Ó2012 AACR.

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

“…S2). Because metformin has also been reported to be associated with cellular oxidative stress (Algire et al., 2012; Pernicova & Korbonits, 2014), we then examined the transcript levels of 11 antioxidant genes associated with oxidative stress (Li et al., 2015; Rhee, Woo, Kil & Bae, 2012; Turpaev, 2002) after 6 hr of metformin treatment. Of these genes, GPX7 and HO‐1 (HMOX1) were the most strongly upregulated (Figure 2a), suggesting the potential involvement of these two genes in regulating aging and/or homeostasis in HDFs.…”

“…Metformin has been reported to reduce oxidative stress and thus DNA damage (Algire et al., 2012). Our results show that chronic metformin treatment upregulates an ER‐localized peroxidase, GPx7, which safeguards worms and human cells from premature aging.…”

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…It is likely, but not proven, that these all are ultimately attributable to the primary site of action in the mitochondria. One example of potential relevance to cancer prevention concerns evidence that metformin not only reduces ATP production as a complex I inhibition, but also reduces reactive oxygen species (ROS) production, consistent with the fact that complex I is an important source of ROS ( 68 ). This action, in an in vitro model, is suffi cient to reduce DNA damage and mutation rate, and if confi rmed in vivo , could account for reduced cancer incidence observed in certain pharmacoepidemiologic studies.…”

Les nouvelles promesses de la metformine

“…La metformine participe à la réponse aux dommages à l'ADN par une activation sélective de la protéine ATM (ataxia telangiectasia mutated), mais également en bloquant la production d'espèces réactives de l'oxygène induite par la transformation par l'oncogène Ras [38]. Par ailleurs, la metformine contribue à la prévention du développe-ment tumoral par le contrôle de l'ontogenèse des cellules souches cancéreuses en ciblant la transition épithélio-mésenchymateuse et la différenciation de ces cellules [39,40].…”