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 As2O3exposure in different human cancer cells. Moreover, As2O3treatment 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.
Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan, People's Republic of China.|Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, People's Republic of China.
Alexander Sheng-Shin
AS
Wang
Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan, People's Republic of China.
Yu-Ting
YT
Chou
Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, People's Republic of China.
Yeong-Shiau
YS
Pu
D000931:Antidotes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000037:antagonists & inhibitors*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D005033:Ethylmaleimide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000074747:Poly ADP Ribosylation / Q000187:drug effects*
D000931:Antidotes; D001152:Arsenicals; D010087:Oxides; D019328:Buthionine Sulfoximine; D005033:Ethylmaleimide; D000077237:Arsenic Trioxide
DNA damage; N-ethylmaleimide; PARP; arsenic; poly(ADP-ribosyl)ation