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

Long‐term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As₂O₃) 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 (H₂O₂)‐induced PARylation was suppressed by As₂O₃ exposure in different human cancer cells. Moreover, As₂O₃ treatment promoted H₂O₂‐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 As₂O₃‐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 As₂O₃, thereby continuing As₂O₃‐mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against As₂O₃‐mediated DNA damage in a glutathione‐dependent manner. Copyright © 2016 John Wiley & Sons, Ltd.