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

Vilma A. Sardão; Paulo J. Oliveira; Jon Holy; Catarina R. Oliveira; Kendall B. Wallace

doi:10.1007/s00280-009-0932-x

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

Vilma A. Sardão
, Paulo J. Oliveira
, Jon Holy
, Catarina R. Oliveira
, Kendall B. Wallace

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

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.

Original language	English (US)
Pages (from-to)	811-827
Number of pages	17
Journal	Cancer chemotherapy and pharmacology
Volume	64
Issue number	4
DOIs	https://doi.org/10.1007/s00280-009-0932-x
State	Published - Sep 2009

Bibliographical note

Funding Information:
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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Bax
Cardiomyopathy
Doxorubicin
H9c2 myoblast
Oxidative stress
P53

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10.1007/s00280-009-0932-x

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title = "Doxorubicin-induced mitochondrial dysfunction is secondary to nuclear p53 activation in H9c2 cardiomyoblasts",

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.",

keywords = "Bax, Cardiomyopathy, Doxorubicin, H9c2 myoblast, Oxidative stress, P53",

author = "Sard{\~a}o, \{Vilma A.\} and Oliveira, \{Paulo J.\} and Jon Holy and Oliveira, \{Catarina R.\} and Wallace, \{Kendall B.\}",

note = "Funding Information: Acknowledgments This work was supported by NIH grant HL 58016 and FCT SAU-OSM-64084-2006. Vilma A. Sard{\~a}o 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.",

year = "2009",

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doi = "10.1007/s00280-009-0932-x",

language = "English (US)",

volume = "64",

pages = "811--827",

journal = "Cancer chemotherapy and pharmacology",

issn = "0344-5704",

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T1 - Doxorubicin-induced mitochondrial dysfunction is secondary to nuclear p53 activation in H9c2 cardiomyoblasts

AU - Sardão, Vilma A.

AU - Oliveira, Paulo J.

AU - Holy, Jon

AU - Oliveira, Catarina R.

AU - Wallace, Kendall B.

N1 - Funding Information: 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.

PY - 2009/9

Y1 - 2009/9

N2 - 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.

AB - 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.

KW - Bax

KW - Cardiomyopathy

KW - Doxorubicin

KW - H9c2 myoblast

KW - Oxidative stress

KW - P53

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

Abstract

Bibliographical note

UN SDGs

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