期刊
CIRCULATION RESEARCH
卷 109, 期 12, 页码 1401-U157出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.255695
关键词
zebrafish; kinase inhibitors; cancer; cardiotoxicity; ERK
资金
- Thomas Jefferson University
- National Heart, Lung, and Blood Institute [HL061688, HL091799]
Rationale: Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. Sorafenib is a KI of concern because it inhibits growth factor receptors and Raf-1/B-Raf, kinases that are upstream of extracellular signal-regulated kinases (ERKs) and signal cardiomyocyte survival in the setting of stress. Objectives: To explore the potential use of zebrafish as a preclinical model to predict cardiotoxicity and to determine whether sorafenib has associated cardiotoxicity, and, if so, define the mechanisms. Methods and Results: We find that the zebrafish model is readily able to discriminate a KI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib). Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, a reduction in total myocyte number per heart, contractile dysfunction, and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirus-mediated gene transfer of constitutively active MEK1, which restores ERK activity even in the presence of sorafenib. Whereas growth factor induced activation of ERKs requires Raf, alpha-adrenergic agonist-induced activation of ERKs does not require it. Consequently, activation of alpha-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of alpha-adrenergic signaling with the receptor antagonist prazosin worsens sorafenib-induced cardiomyopathy in zebrafish. Conclusions: Zebrafish may he a valuable preclinical tool to predict cardiotoxicity. The alpha-adrenergic signaling pathway is an important modulator of sorafenib cardiotoxicity in vitro and in vivo and appears to act through a here-to-fore unrecognized signaling pathway downstream of alpha-adrenergic activation that bypasses Raf to activate ERKs. (Circ Res. 2011;109:1401-1409.)
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