| Title | Sub-lethal doses of an anti-erbB2 antibody leads to death by apoptosis in cardiomyocytes sensitized by low pro-senescent doses of epirubicin: the protective role of dexrazoxane. | | Author(s) | Spallarossa P, Altieri P, Pronzato P, Aloi C, Ghigliotti G, Barsotti A, Brunelli C | | Institution | 1 Research Center of Cardiovascular Biology, Division of Cardiology, University of Genova; | | Source | J Pharmacol Exp Ther 2009 Oct 19. | | 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 sub-apoptotic doses of anthracyclines. After having identified pro-senescent and pro-apoptotic doses of epirubicin and B10, an anti-erbB2 monoclonal antibody, we investigated the effects of the sequential treatment with pro-senescent doses of both drugs on H9c2 cells and neonatal rat cardiomyocytes pre-treated with or without the cardioprotective agent dexrazoxane. Cells were analyzed by senescence-associated beta galactosidase, ssDNA, annexin/propidium double staining, F-actin and mitochondrial transmembrane potential. ErbB2 expression levels, AKT activation, and the effects of the inhibition of NAD(P)H oxidase and PI3K were also assessed. Data demonstrate that 1) the toxic effects of epirubicin mainly occur through NAD(P)H oxidase activation; 2) the erbB2 over-expression 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 pro-senescent dose of epirubicin, 4) dexrazoxane promotes survival pathways, as demonstrated by the activation of Akt and the PI3K-dependent erbB2 over-expression, 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19841470 |
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