Antagonistic effect of N‐ethylmaleimide on arsenic‐mediated oxidative stress‐induced poly(ADP‐ribosyl)ation and cytotoxicity

Abstract

Long-term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As O ) in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H O )-induced PARylation was suppressed by As O exposure in different human cancer cells. Moreover, As O treatment promoted H O -induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide (NEM), an organic compound derived from maleic acid, could reverse As O -mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione with l-buthionine-sulfoximine blocked the antagonistic effect of NEM on As O , thereby continuing As O -mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against As O -mediated DNA damage in a glutathione-dependent manner. Copyright © 2016 John Wiley & Sons, Ltd.