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Doxorubicin-induced mitochondrial dysfunction is secondary to nuclear p53 activation in H9c2 cardiomyoblasts

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Abstract

Purpose

Doxorubicin (DOX) is a widely prescribed chemotherapeutic. The hypothesis for the present study is that DOX-induced myocyte apoptosis involves mitochondrial dysfunction that is a consequence of nuclear DOX effects.

Methods

H9c2 myoblasts were incubated with 0, 0.5 and 1 μM DOX and nuclear and mitochondrial alterations were determined.

Results

Doxorubicin accumulation in the nucleus was detected after 3 h treatment, followed by an increase in p53 and a decrease in mitochondrial membrane potential. Apoptotic markers, such as caspase activation and chromatin condensation were detected after 24 h of DOX treatment. Bax and p53 translocation to mitochondria as well as the formation of Bax clusters in the cytosol were observed. Importantly, pifithrin-alpha, a p53 inhibitor, protected against DOX-induced mitochondrial depolarization, caspase activation and cell death.

Conclusion

Mitochondrial dysfunction in H9c2 myoblasts treated with DOX is a consequence of nuclear p53 activation rather than a direct effect of the drug on mitochondria.

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Acknowledgments

This work was supported by NIH grant HL 58016 and FCT SAU-OSM-64084-2006. Vilma A. Sardão is supported by grants from the Portuguese Foundation for Science and Technology, SFRH/BD/10251/2002 and SFRH/BPD/31549/2006. We acknowledge Ana Filipa Branco for excellent technical assistance. We also acknowledge Dr. Marc Fariss (University of Colorado, Denver) for providing vitamin E-succinate.

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Authors and Affiliations

  1. Department of Zoology, Center for Neurosciences and Cellular Biology, University of Coimbra, 3004-517, Coimbra, Portugal

    Vilma A. Sardão & Paulo J. Oliveira

  2. Department of Anatomy, Microbiology and Pathology, University of Minnesota Medical School, Duluth, USA

    Jon Holy

  3. Department of Biochemistry, Center for Neurosciences and Cellular Biology, Medical School, University of Coimbra, Coimbra, Portugal

    Catarina R. Oliveira

  4. Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, USA

    Kendall B. Wallace

Authors
  1. Vilma A. Sardão
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  2. Paulo J. Oliveira
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  4. Catarina R. Oliveira
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Correspondence to Vilma A. Sardão.

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Sardão, V.A., Oliveira, P.J., Holy, J. et al. Doxorubicin-induced mitochondrial dysfunction is secondary to nuclear p53 activation in H9c2 cardiomyoblasts. Cancer Chemother Pharmacol 64, 811–827 (2009). https://doi.org/10.1007/s00280-009-0932-x

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  • DOI: https://doi.org/10.1007/s00280-009-0932-x

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