ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway
ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway
复制标题
ROS 依赖性 DNA 损伤通过细胞凋亡途径导致克唑替尼诱导的肝毒性
DOI：
10.1016/j.taap.2019.114768
复制
发表时间：
2019
影响因子：
3.8
通讯作者：
Peihua Luo
中科院分区：
文献类型：
--
作者：
Hao Yan;Jiangxia Du;Xueqin Chen;Bo Yang;Qiaojun He;Xiaochun Yang;Peihua Luo
克唑替尼是一种口服小分子酪氨酸激酶抑制剂，靶向间变性淋巴瘤激酶（ALK）、ROS原癌基因1、受体酪氨酸激酶（ROS1）和MET原癌基因、受体酪氨酸激酶（MET）。不幸的是，肝毒性严重限制了其临床应用，其原因仍不得而知。在本研究中，我们检测了克唑替尼对人肝细胞系HL-7702和人原代肝细胞的作用，结果显示克唑替尼治疗引起肝细胞损伤，提示克唑替尼通过引起肝细胞死亡引起肝损伤，与临床病例一致。在机制上，克唑替尼通过凋亡途径诱导肝细胞死亡，并观察到cleaved PARP （c-PARP）是一种信号蛋白。此外，线粒体膜电位（MMP）降低有助于克唑替尼诱导的肝细胞凋亡，并伴有肝细胞DNA损伤和活性氧（ROS）的产生。重要的是，克唑替尼诱导的肝细胞凋亡不依赖于其靶点ALK、ROS1和MET。综上所述，我们的数据表明，克唑替尼通过不依赖于ALK、ROS1和MET的凋亡途径，通过肝细胞死亡诱导肝损伤。我们还发现MMP减少、DNA损伤和ROS生成参与了这一过程。
Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) and MET proto-oncogene, receptor tyrosine kinase (MET). Unfortunately, hepatotoxicity is a serious limitation in its clinical application, and the reason remains largely unknown. In this study, we tested the effect of crizotinib in human hepatocyte cell line HL-7702 and human primary hepatocytes, and the results showed that crizotinib treatment caused hepatocyte damage, suggesting that crizotinib induced liver injury by causing hepatocyte death, consistent with the clinical cases. Mechanistically, crizotinib induced hepatocyte death via the apoptotic pathway, and cleaved PARP (c-PARP) was observed as a signaling protein. Moreover, mitochondrial membrane potential (MMP) decrease contributed to crizotinib-induced hepatocyte apoptosis accompanied by hepatocyte DNA damage and reactive oxygen species (ROS) generation. Importantly, crizotinib induced hepatocyte apoptosis independent of its targets, ALK, ROS1 and MET. In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process.