1. ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway.
- Author
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Yan H, Du J, Chen X, Yang B, He Q, Yang X, and Luo P
- Subjects
- Adult, Apoptosis physiology, Cell Line, Cell Survival drug effects, Cell Survival physiology, DNA Damage physiology, Dose-Response Relationship, Drug, Hepatocytes pathology, Humans, Male, Protein Kinase Inhibitors toxicity, Proto-Oncogene Mas, Apoptosis drug effects, Crizotinib toxicity, DNA Damage drug effects, Hepatocytes drug effects, Hepatocytes metabolism, Reactive Oxygen Species metabolism
- Abstract
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., (Copyright © 2019. Published by Elsevier Inc.)
- Published
- 2019
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