Arsenic trioxide-induced apoptosis in H9c2 cardiomyocytes: implications in cardiotoxicity.
Arsenic trioxide (As(2)O(3)) achieved dramatic remissions in patients with acute promyelocytic leukaemia. Clinical reports have shown that treatment was associated with cardiotoxicity. We investigated the toxic mechanisms of As(2)O(3) in H9c2 cardiomyocytes. Clinically relevant concentrations of As(2)O(3) (2-10 microM) reduced the viability of H9c2 cells in a concentration-dependent manner. The decreased cell viability was because As(2)O(3) induced cell apoptosis (cell shrinkage, nuclear alterations and caspase-3 activation), or even necrosis at higher concentrations. Inhibition of caspase-3 with a specific inhibitor, Ac-DEVD-CHO, suppressed apoptosis induced by As(2)O(3). In addition, reactive oxygen species formation and cellular Ca(2+) overload were observed in H9c2 cells exposed to As(2)O(3), which was partly inhibited by vitamin E and verapamil. These results suggest that As(2)O(3)-induced cardiotoxicity is mediated, at least in part, by activation of caspase-3 pathway, which may be triggered by reactive oxygen species formation and intracellular Ca(2+) overload.
Zhao
Xiaoyan
X
Department of Pharmacology, Harbin Medical University, Harbin, China.
Feng
Tieming
T
Chen
He
H
Shan
Hongli
H
Zhang
Yong
Y
Lu
Yanjie
Y
Yang
Baofeng
B
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000009:adverse effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D001152:Arsenicals; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010087:Oxides; D017382:Reactive Oxygen Species; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D014810:Vitamin E; D014700:Verapamil; D053148:Caspase 3; D000077237:Arsenic Trioxide