期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 332, 期 1, 页码 87-96出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.109.159525
关键词
-
资金
- University of Genova (cofinanziamento di Ateneo)
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 beta-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据