期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 177, 期 1, 页码 12-20出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2008.09.012
关键词
Anthracyclines; Oxidative stress; Heart; Cell death; Chemotherapy
资金
- dell'Universita e ella Ricerca Scientifica (MIUR-PRIN)
- FIRST
Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of doxorubicin (DOX) as an anti-tumoral drug, but the mechanism of DOX-mediated apoptosis remains unclear. We examined the interplay between oxidative stress and cell death in cardiac-derived H9c2 myocytes exposed to DOX doses in the range of the plasma levels found in patients undergoing chemotherapy. A low DOX concentration (0.25 mu M) induced apoptosis, whereas the cells treated with the high dose of 2 mu M also showed necrosis. The production of reactive oxygen species (ROS) and induction of oxidative stress markets was increased in the cells treated with 2 mu M DOX but not in those treated with the low dose. Surprisingly, heme oxygenase (HO-1) expression was clown-modulated in the cells exposed to 0.25 mu M DOX, and its Bach I transcriptional repressor was induced. In line with the role of HO-1 as an anti-apoptotic protein, inhibiting HO-1 activity with SnPPIX was sufficient to induce apoptosis and increased DOX-mediated apoptosis, whereas hemin-induced HO-1 activation prevented DOX-mediated apoptotic cell death. In brief, our findings do not Support the hypothesis that oxidative stress plays a role in the apoptotic cell death occurring in cardiomyocytes exposed to low concentrations of DOX. but suggest that DOX may facilitate the apoptosis of cardiomyocytes by inhibiting the anti-apoptotic HO-1. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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