Quercetin Attenuates Doxorubicin Cardiotoxicity By Modulating Bmi-1Expression

Background and objective:Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity.Methods and results:Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2cardiomyocytes and C57BL/6mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment.In H9c2cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53and oxidase (p47and Noxl) and by increased expression of Bcl-2and Bmi-1. Bmi-1siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1and anti-oxidative superoxide dismutase.Conclusion:Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy.