Abstract
Resveratrol is a plant-derived polyphenol that can attenuate the cardiotoxic effects of doxorubicin (DOX), a powerful antibiotic widely used in cancer chemotherapy. However, the underlying protective mechanisms of resveratrol remain elusive. Here we show that resveratrol inhibited DOX-induced autophagy and cardiomyocyte death, and that autophagy suppression is an important mechanism that mediates the ability of resveratrol to protect against DOX cardiotoxicity. Indeed, resveratrol, 3-methyladenine (3-MA) and a short hairpin RNA directed against autophagy gene beclin 1 (shBCN1) each was able to attenuate DOX-induced autophagy and cardiomyocyte death, but resveratrol did not provide additional protection in the presence of 3-MA or shBCN1. In contrast, upregulation of autophagy by beclin 1 overexpression not only exacerbated DOX cardiotoxicity but also abolished the protective effects of resveratrol. Intriguingly, p70 S6 kinase (S6K1) was activated by DOX, which was prevented by resveratrol. Knocking down S6K1 with siRNA diminished DOX-induced autophagy and cardiotoxicity, but resveratrol failed to exert an additive effect. In addition, S6K1 overexpression impaired the ability of resveratrol to antagonize DOX-induced autophagy and cardiomyocyte death. Taken together, our data indicated that the protective effect of resveratrol against DOX cardiotoxicity is largely dependent on its ability to suppress DOX-induced autophagy via inhibition of S6K1.
- Received October 27, 2011.
- Revision received December 28, 2011.
- Accepted December 29, 2011.
- The American Society for Pharmacology and Experimental Therapeutics