Cardiotoxicity of the cancer therapeutic agent imatinib mesylate
Cardiotoxicity of the cancer therapeutic agent imatinib mesylate
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DOI：
10.1038/nm1446
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发表时间：
2006-08-01
期刊：
影响因子：
82.9
通讯作者：
Force, Thomas
中科院分区：
文献类型：
--
作者：
Kerkela, Risto;Grazette, Luanda;Force, Thomas
甲磺酸伊马替尼（格列卫）是一种融合蛋白Bcr-Abl的小分子抑制剂，Bcr-Abl是慢性粒细胞白血病的致病因子。在这里，我们报告了10个人谁发展严重的充血性心力衰竭，而伊马替尼，我们表明，伊马替尼治疗小鼠左心室收缩功能障碍。伊马替尼治疗的人和小鼠的透射电子显微镜照片显示线粒体异常和空泡和肌浆网（内）中膜涡的积累，结果提示毒性肌病。在伊马替尼治疗下，培养的心肌细胞显示内质网（ER）应激反应的激活、线粒体膜电位的崩溃、细胞色素c释放到胞质溶胶中、细胞ATP含量的减少和细胞死亡。逆转录病毒基因转移伊马替尼耐药突变体的c-Abl，缓解ER应激或抑制Jun氨基末端激酶，这是激活的结果，ER应激，在很大程度上拯救伊马替尼诱导的死亡心肌细胞。因此，心脏毒性是伊马替尼抑制c-Abl的非预期副作用。
Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco-(endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.