Arsenic trioxide-induced apoptosis in H9c2 cardiomyocytes: Implications in cardiotoxicity

Arsenic trioxide (As₂O₃) 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 As₂O₃ in H9c2 cardiomyocytes. Clinically relevant concentrations of As₂O₃ (2-10 μM) reduced the viability of H9c2 cells in a concentration-dependent manner. The decreased cell viability was because As₂O₃ 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 As₂O₃. In addition, reactive oxygen species formation and cellular Ca²⁺ overload were observed in H9c2 cells exposed to As₂O₃, which was partly inhibited by vitamin E and verapamil. These results suggest that As₂O₃-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 Ca²⁺ overload.