Vaccarin Ameliorates Doxorubicin-Induced Cardiotoxicity via Inhibition of p38 MAPK Mediated Mitochondrial Dysfunction

Doxorubicin is a frequently used chemotherapeutic agent for treating various malignancies. However, it leads to severe cardiotoxic side effects, such as heart failure, and elevates the risk of sudden cardiac death among cancer patients. While oxidative stress has been identified as the primary cause of doxorubicin-induced cardiotoxicity, therapeutic antioxidant approaches have yielded unsatisfactory outcomes. The aim of this study is to explore the therapeutic potential of vaccarin, an active flavonoid glycoside extracted from traditional Chinese herbal agent Semen Vaccariae, in doxorubicin-induced cardiotoxicity. We observed that vaccarin significantly ameliorates doxorubicin-induced heart dysfunction in mouse model and suppresses oxidative stress mediated cell apoptosis via specifically inhibiting the activation of p38 MAPK pathway. In vitro, we observed that vaccarin alleviates doxorubicin-induced mitochondrial membrane depolarization and ROS generation in H9c2 cell, but the p38 MAPK agonist anisomycin reverses these effects. Our findings provide a promising natural antioxidant to protect against DOX-induced cardiotoxicity.