Doxorubicin-mediated reactive oxygen species generation opens ryanodine receptors, resulting in an increase in intracellular Ca2+ that reciprocally induces further ROS production and apoptosis in rat cardiomyocytes.
Doxorubicin-induced cardiotoxicity involves a reciprocal modulation where DOX-generated ROS opens ryanodine receptors to increase intracellular Ca2+, which further promotes ROS production and apoptosis.
valor p: p=<0.001
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.
Kim et al. (Sun,) conducted a other in Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Control (vehicle) or Doxorubicin + Ca2+ channel blockers/antioxidants was evaluated on Intracellular Ca2+ concentration ([Ca2+]i) and ROS generation (p=<0.001). Doxorubicin-mediated reactive oxygen species generation opens ryanodine receptors, resulting in an increase in intracellular Ca2+ that reciprocally induces further ROS production and apoptosis in rat cardiomyocytes.