Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes
Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes
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DOI：
10.1016/j.taap.2013.04.027
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发表时间：
2013-10-01
影响因子：
3.8
通讯作者：
Bacus, Sarah
中科院分区：
文献类型：
--
作者：
Doherty, Kimberly R.;Wappel, Robert L.;Bacus, Sarah
酪氨酸激酶抑制剂（TKi）极大地改善了多种癌症类型的治疗和预后。然而，在接受这些药物治疗的一部分患者中出现了意想不到的心脏毒性，这并不是完全由临床前试验预测的，临床前试验的中心是动物毒性研究和人类Ether-a-go-go-Related Gene（hERG）通道的抑制。因此，我们试图确定评估药物治疗对细胞、分子和电生理终点影响的多参数测试组是否可以准确预测心脏毒性。我们研究了4种FDA批准的TIC药物如何影响人心肌细胞的细胞活力、细胞凋亡、活性氧（ROS）产生、代谢状态、阻抗和离子通道功能。在我们的体外试验中，临床上与严重心脏不良事件相关的3种药物（克唑替尼、舒尼替尼、尼洛替尼）均被证明具有心脏毒性，而相对心脏安全的药物厄洛替尼仅显示心脏细胞健康的微小变化。克唑替尼是一种ALK/MET抑制剂，可导致ROS产生增加、半胱天冬酶激活、胆固醇蓄积、心脏细胞搏动频率中断和离子通道阻断。多靶点TKi舒尼替尼显示心肌细胞活力降低、AMPK抑制、脂质蓄积增加、搏动模式中断和hERG阻滞。尼洛替尼是第二代Bcr-Abl抑制剂，导致ROS生成增加、半胱天冬酶激活、hERG阻滞和心律失常性搏动模式。因此，每种药物显示出独特的毒性特征，可能反映了导致心脏毒性的多种机制。这项研究表明，多参数方法可以提供药物诱导的心肌细胞损伤的强大表征，可用于提高早期开发期间的药物安全性。(C)2013 Elsevier Inc. All rights reserved.
Tyrosine kinase inhibitors (TKi) have greatly improved the treatment and prognosis of multiple cancer types. However, unexpected cardiotoxicity has arisen in a subset of patients treated with these agents that was not wholly predicted by pre-clinical testing, which centers around animal toxicity studies and inhibition of the human Ether-a-go-go-Related Gene (hERG) channel. Therefore, we sought to determine whether a multi-parameter test panel assessing the effect of drug treatment on cellular, molecular, and electrophysiological endpoints could accurately predict cardiotoxicity. We examined how 4 FDA-approved TIC agents impacted cell viability, apoptosis, reactive oxygen species (ROS) generation, metabolic status, impedance, and ion channel function in human cardiomyocytes. The 3 drugs clinically associated with severe cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while the relatively cardiac-safe drug erlotinib showed only minor changes in cardiac cell health. Crizotinib, an ALK/MET inhibitor, led to increased ROS production, caspase activation, cholesterol accumulation, disruption in cardiac cell beat rate, and blockage of ion channels. The multi-targeted TKi sunitinib showed decreased cardiomyocyte viability, AMPK inhibition, increased lipid accumulation, disrupted beat pattern, and hERG block. Nilotinib, a second generation Bcr-Abl inhibitor, led to increased ROS generation, caspase activation, hERG block, and an arrhythmic beat pattern. Thus, each drug showed a unique toxicity profile that may reflect the multiple mechanisms leading to cardiotoxicity. This study demonstrates that a multi-parameter approach can provide a robust characterization of drug-induced cardiomyocyte damage that can be leveraged to improve drug safety during early phase development. (C) 2013 Elsevier Inc. All rights reserved.