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

J Pharmacol Exp Ther. 2012 Apr;341(1):183-95. doi: 10.1124/jpet.111.189589. Epub 2011 Dec 30.

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 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Autophagy / drug effects*
  • Autophagy / physiology
  • 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
  • Resveratrol
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors*
  • Ribosomal Protein S6 Kinases, 70-kDa / physiology*
  • Stilbenes / pharmacology*

Substances

  • Stilbenes
  • Doxorubicin
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Resveratrol