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.
Highlights
Metformin is a biguanide widely used in the treatment of type II diabetes [1]
As complex I is an important source of reactive oxygen species (ROS) [24], we studied the influence of metformin on levels of ROS in cells treated with H2O2, which acts as an exogenous source of ROS, or paraquat, which stimulates the endogenous production of ROS by complex I [25]
Given that several effects of metformin in glucose metabolism and diabetes can be explained by activation of the AMP kinase (AMPK) [16, 17, 19], we used AMPKaþ/þ and AMPKaÀ/À mouse embryonic fibroblasts (MEF) to evaluate the role of metformin-induced AMPK activation on the observed effects (Fig. 1A)
Summary
Metformin is a biguanide widely used in the treatment of type II diabetes [1]. While details of its mechanism of action remain an active area of research, there is prior evidence that its primary effect is in mitochondria, where it interferes with respiratory complex I and reduces ATP production [2], leading to the activation of AMP kinase In type II diabetes, metformin action in the liver results in inhibition of gluconeogenesis, reducing blood glucose concentration [4, 5], and secondarily reducing the elevated insulin levels characteristic of this condition. 11–13) suggests that type II diabetics receiving metformin have substantially lower. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/). Algire: Department of Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
