Characterization of cytotoxicity induced by arsenic trioxide (a potent anti-APL drug) in rat cardiac myocytes.
Arsenic, a known environmental toxicant, is ubiquitously present in the environment. Arsenic trioxide (ATO), an anti-acute promyelocytic leukemia (APL) drug, is associated with cardiac toxicity. It is reported to induce cardiac arrhythmia via altering various ion channels involved in the repolarization phase of cardiac action potential. The exact molecular mechanism of cardiovascular adverse effect due to ATO exposure has not been fully elucidated except for alteration on ion channels. To evaluate the cytotoxic effect of ATO on cardiac myocytes, primary culture of myocytes was treated with different doses (30, 60 and 90 microM) of ATO for various periods (24, 48 and 72 h). Cardiac toxicity was assessed by monitoring cell viability, mitochondrial and deoxyribonucleic acid (DNA) integrity, reactive oxygen species (ROS) generation, calcium overload and apoptosis. ATO exposure caused alteration in mitochondrial integrity, generation of ROS, calcium overload and apoptosis in cardiac cells in dose- and duration-dependent manner. There was no DNA fragmentation. Hence our results show that ATO causes apoptosis in cardiomyocytes by generation of ROS and the induction of calcium overload.
Raghu
K G
KG
Pharmacology Division, Central Drug Research Institute, Lucknow, Uttar Pradesh 226001, India. raghukgopal@rediffmail.com
Cherian
Ozhathil Lijo
OL
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010087:Oxides / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D000077237:Arsenic Trioxide; D002118:Calcium