Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes

• Published in: Experimental & molecular medicine 2006, 38(5), , pp.535-545
• Main Authors: Kim, Seon-Young, Kim, Sang-Jin, Kim, Byoung-Joo, Rah, So-Young, Chung, Sung Mo, Im, Mie-Jae, Kim, Uh-Hyun
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antioxidants - pharmacology; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Caspase 3 - metabolism; Cells, Cultured; Doxorubicin - pharmacology; Enzyme Activation - drug effects; Female; Male; Myocytes, Cardiac - drug effects; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - chemical synthesis; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic Reticulum - drug effects; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/emm.2006.63

Doxorubicin (DOX) is one of the most potent anticancer drugs and induces acute cardiac arrhythmias and chronic cumulative cardiomyopathy. Though DOX-induced cardiotoxicity is known to be caused mainly by ROS generation, a disturbance of Ca2+ homeostasis is also implicated one of the cardiotoxic mechanisms. In this study, a molecular basis of DOX-induced modulation of intracellular Ca2+ concentration ([Ca2+]i) was investigated. Treatment of adult rat cardiomyocytes with DOX increased [Ca2+]i irrespectively of extracellular Ca2+, indicating DOX-mediated Ca2+ release from intracellular Ca2+ stores. The DOX-induced Ca2+ increase was slowly processed and sustained. The Ca2+ increase was inhibited by pretreatment with a sarcoplasmic reticulum (SR) Ca2+ channel blocker, ryanodine or dantrolene, and an antioxidant, alpha-lipoic acid or alpha-tocopherol. DOX-induced ROS generation was observed immediately after DOX treatment and increased in a time-dependent manner. The ROS production was significantly reduced by the pretreatment of the SR Ca2+ channel blockers and the antioxidants. Moreover, DOX-mediated activation of caspase-3 was significantly inhibited by the Ca2+ channel blockers and a-lipoic acid but not a-tocopherol. In addition, cotreatment of ryanodine with alpha-lipoic acid resulted in further inhibition of the casapse-3 activity. These results demonstrate that DOX-mediated ROS opens ryanodine receptor, resulting in an increase in [Ca2+]i and that the increased [Ca2+]i induces ROS production. These observations also suggest that DOX/ROS-induced increase of [Ca2+]i plays a critical role in damage of cardiomyocytes.