ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway
| Autor: | Hao Yan, Xiaochun Yang, Qiaojun He, Jiangxia Du, Xueqin Chen, Bo Yang, Peihua Luo |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male medicine.drug_class DNA damage Cell Survival Apoptosis Toxicology Proto-Oncogene Mas Tyrosine-kinase inhibitor Receptor tyrosine kinase Cell Line 03 medical and health sciences 0302 clinical medicine Crizotinib medicine ROS1 Anaplastic lymphoma kinase Humans Protein Kinase Inhibitors Pharmacology biology Dose-Response Relationship Drug Chemistry 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Hepatocyte biology.protein Cancer research Hepatocytes Reactive Oxygen Species medicine.drug DNA Damage |
| Zdroj: | Toxicology and applied pharmacology. 383 |
| ISSN: | 1096-0333 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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