Resveratrol attenuates doxorubicin-induced cardiomyocyte death via inhibition of p70 S6 kinase 1-mediated autophagy

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 341; no. 1; pp. 183 - 195
• Main Authors: Xu, Xianmin, Chen, Kai, Kobayashi, Satoru, Timm, Derek, Liang, Qiangrong
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.04.2012
• Subjects: Animals; Animals, Newborn; Autophagy - drug effects; Autophagy - physiology; Cardiovascular; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Doxorubicin - antagonists & inhibitors; Doxorubicin - pharmacology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 70-kDa - physiology; Stilbenes - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.111.189589

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 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, up-regulation of autophagy by beclin 1 overexpression not only exacerbated DOX cardiotoxicity but also abolished the protective effects of resveratrol. Intriguingly, p70 S6 kinase 1 (S6K1) was activated by DOX, which was prevented by resveratrol. Knocking down S6K1 with small interfering RNA 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 indicate that the protective effect of resveratrol against DOX cardiotoxicity largely depends on its ability to suppress DOX-induced autophagy via the inhibition of S6K1.