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Research ArticleCARDIOVASCULAR

Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane

Paolo Spallarossa, Paola Altieri, Paolo Pronzato, Concetta Aloi, Giorgio Ghigliotti, Antonio Barsotti and Claudio Brunelli
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 87-96; DOI: https://doi.org/10.1124/jpet.109.159525
Paolo Spallarossa
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Paola Altieri
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Paolo Pronzato
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Concetta Aloi
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Giorgio Ghigliotti
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Antonio Barsotti
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Claudio Brunelli
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Abstract

The cardiotoxic synergism resulting from the sequential treatment with anthracyclines and trastuzumab has been attributed to the trastuzumab-induced loss of the erbB2-related functions that serve as a salvage pathway against the damaging effects of anthracyclines. Cellular senescence is a novel mechanism of cardiotoxicity induced by subapoptotic doses of anthracyclines. After having identified prosenescent and proapoptotic doses of epirubicin and rat MAb c-erbB2/Her-2/neu Ab-9 clone B10 (B10), an anti-erbB2 monoclonal antibody, we investigated the effects of the sequential treatment with prosenescent doses of both drugs on H9c2 cells and neonatal rat cardiomyocytes pretreated with or without the cardioprotective agent dexrazoxane. Cells were analyzed by senescence-associated β-galactosidase, single-stranded DNA, annexin/propidium double staining, F-actin, and mitochondrial transmembrane potential. ErbB2 expression levels, AKT activation, and the effects of the inhibition of nicotinamide adenine dinucleotide phosphate oxidase [NAD(P)H oxidase] and phosphoinositide-3-OH kinase (PI3K) were also assessed. Data demonstrate that 1) the toxic effects of epirubicin mainly occur through NAD(P)H oxidase activation; 2) the erbB2 overexpression induced by epirubicin is a redox-sensitive mechanism largely dependent on NAD(P)H oxidase; 3) the loss of erbB2-related functions caused by B10 determines marginal cellular changes in untreated cells, but causes massive death by apoptosis in cells previously exposed to a prosenescent dose of epirubicin, 4) dexrazoxane promotes survival pathways, as demonstrated by the activation of Akt and the PI3K-dependent erbB2 overexpression; and 5) it also prevents epirubicin-induced senescence and renders epirubicin-treated cells more resistant to treatment with B10. Data underline the importance of NAD(P)H oxidase in epirubicin-induced cardiotoxicity and shed new light on the protective mechanisms of dexrazoxane.

Footnotes

  • This work was supported by the University of Genova (cofinanziamento di Ateneo).

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

    doi:10.1124/jpet.109.159525

  • ABBREVIATIONS:

    SIPS
    stress-induced premature senescence
    B10
    rat MAb c-erbB2/Her-2/neu Ab-9 clone B10
    NAC
    N-acetylcysteine
    NAD(P)H oxidase
    nicotinamide adenine dinucleotide phosphate oxidase
    FITC
    fluorescein isothiocyanate
    DPI
    diphenyleneiodonium
    PBS
    phosphate-buffered saline
    PI3K
    phosphoinositide-3-OH kinase
    LY294002
    2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
    ssDNA
    single-stranded DNA
    AV/PI
    annexinV/propidium iodide
    SA-β-gal
    senescence-associated β-galactosidase staining
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    ct
    control
    Epi
    epirubicin
    Dox
    doxorubicin
    Dex
    dexrazoxane
    ROS
    reactive oxygen species.

    • Received August 7, 2009.
    • Accepted October 16, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleCARDIOVASCULAR

Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane

Paolo Spallarossa, Paola Altieri, Paolo Pronzato, Concetta Aloi, Giorgio Ghigliotti, Antonio Barsotti and Claudio Brunelli
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 87-96; DOI: https://doi.org/10.1124/jpet.109.159525

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Research ArticleCARDIOVASCULAR

Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane

Paolo Spallarossa, Paola Altieri, Paolo Pronzato, Concetta Aloi, Giorgio Ghigliotti, Antonio Barsotti and Claudio Brunelli
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 87-96; DOI: https://doi.org/10.1124/jpet.109.159525
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