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ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2019 Nov 15; Vol. 383, pp. 114768. Date of Electronic Publication: 2019 Oct 19. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2019. Published by Elsevier Inc.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0333
- Volume :
- 383
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 31639374
- Full Text :
- https://doi.org/10.1016/j.taap.2019.114768