Resveratrol attenuates doxorubicin-induced cardiomyocyte death via inhibition of p70 S6 kinase 1-mediated autophagy.
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.
Cardiovascular Health Research Center, Sanford Research/USD, Sioux Falls, SD, USA.
Xianmin
X
Xu
Kai
K
Chen
Satoru
S
Kobayashi
Derek
D
Timm
Qiangrong
Q
Liang
D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*
D013267:Stilbenes; D004317:Doxorubicin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D000077185:Resveratrol