ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway
Hao Yan1, Jiangxia Du1, Xueqin Chen2
1Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
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.
Insights
Crizotinib causes liver injury by inducing hepatocyte death through apoptosis, independent of its known targets. This process involves mitochondrial dysfunction, DNA damage, and reactive oxygen species generation.
Area of Science:
- Hepatology
- Toxicology
- Molecular Biology
Background:
- Crizotinib, a tyrosine kinase inhibitor, is used to treat certain cancers.
- Hepatotoxicity is a significant clinical limitation of crizotinib, with underlying mechanisms poorly understood.
Purpose of the Study:
- To investigate the mechanisms by which crizotinib induces liver injury.
- To determine if crizotinib-induced hepatotoxicity is related to its targeted kinases (ALK, ROS1, MET).
Main Methods:
- Experiments were conducted using the human hepatocyte cell line HL-7702 and primary human hepatocytes.
- Assessed hepatocyte viability, apoptosis markers (cleaved PARP), mitochondrial membrane potential (MMP), DNA damage, and reactive oxygen species (ROS) generation.
Main Results:
- Crizotinib treatment led to significant hepatocyte damage and death in vitro.
- Hepatocyte death occurred via the apoptotic pathway, evidenced by cleaved PARP.
- Apoptosis was associated with decreased mitochondrial membrane potential, DNA damage, and increased ROS production.
- Crizotinib induced apoptosis independently of its known targets: anaplastic lymphoma kinase (ALK), ROS1, and MET.
Conclusions:
- Crizotinib induces liver injury by promoting hepatocyte apoptosis, a process independent of its direct kinase inhibition.
- Mitochondrial dysfunction, DNA damage, and ROS generation are key contributors to crizotinib-induced hepatotoxicity.
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