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Research ArticleCardiovascular

Resveratrol Attenuates Doxorubicin-Induced Cardiomyocyte Death via Inhibition of p70 S6 Kinase 1-Mediated Autophagy

Xianmin Xu, Kai Chen, Satoru Kobayashi, Derek Timm and Qiangrong Liang
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 183-195; DOI: https://doi.org/10.1124/jpet.111.189589
Xianmin Xu
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Kai Chen
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Satoru Kobayashi
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Derek Timm
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Qiangrong Liang
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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.

Footnotes

  • This work was supported by the National Institutes of Health National Center for Research Resources [Grant 2P20-RR-017662-06A1]; the Juvenile Diabetes Research Foundation [Grant 1-2007-741]; and a Career Development Grant from the American Diabetes Association [Grant 1-09-CD-09].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.189589.

  • ABBREVIATIONS:

    DOX
    doxorubicin
    NRC
    neonatal rat ventricular cardiomyocyte
    mTOR
    mammalian target of rapamycin
    AMPK
    AMP-activated protein kinase
    DMEM
    Dulbecco's modified Eagle's medium
    RV
    resveratrol
    3-MA
    3-methyladenine
    BFA
    bafilomycin A1
    PARP
    poly(ADP-ribose) polymerase
    c-PARP
    cleaved PARP
    siRNA
    small interfering RNA
    siCON
    control siRNA
    siS6K1
    siRNA against S6K1
    PI
    propidium iodide
    ANOVA
    analysis of variance
    shRNA
    short hairpin RNA
    shBCN1
    shRNA directed against autophagy gene BCN1
    shCON
    control shRNA
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    AV
    atophagic vacuole
    GFP
    green fluorescent protein
    S6K1
    p70 S6 kinase 1
    LC3
    microtubule-associated protein light chain 3
    Atg
    autophagy-related
    BCN1
    beclin 1
    MOPS
    4-morpholinepropanesulfonic acid
    c-Casp3
    cleaved caspase 3
    Adβgal
    adenovirus expressing β-galactosidase
    AdBCN1
    adenovirus expressing BCN1
    MOI
    multiplicity of infection
    PCR
    polymerase chain reaction
    ERK
    extracellular signal-regulated kinase
    MBP
    myelin basic protein
    CON
    control
    IP
    immunoprecipitation
    IB
    immunoblot
    PE
    phenylephrine
    n.s.
    not significant.

  • Received October 27, 2011.
  • Accepted December 29, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleCardiovascular

Resveratrol Inhibits Doxorubicin Cardiotoxicity

Xianmin Xu, Kai Chen, Satoru Kobayashi, Derek Timm and Qiangrong Liang
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 183-195; DOI: https://doi.org/10.1124/jpet.111.189589

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Research ArticleCardiovascular

Resveratrol Inhibits Doxorubicin Cardiotoxicity

Xianmin Xu, Kai Chen, Satoru Kobayashi, Derek Timm and Qiangrong Liang
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 183-195; DOI: https://doi.org/10.1124/jpet.111.189589
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