Mechanism of hepatotoxicity of first-line tyrosine kinase inhibitors: Gefitinib and afatinib
| Autor: | Cai Yang, Pin Wei, Yao Zhang, Ming-Fang He, Ling-Ling Jiang, Shi-Ru Zhang, Chong-Yong Li |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Embryo Nonmammalian Afatinib CHOP Toxicology Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine Gefitinib Epidermal growth factor medicine Animals Protein Kinase Inhibitors neoplasms Zebrafish business.industry General Medicine respiratory tract diseases 030104 developmental biology Gene Expression Regulation Liver Apoptosis Toxicity Cancer research Liver function Chemical and Drug Induced Liver Injury business Tyrosine kinase 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Toxicology Letters. 343:1-10 |
| ISSN: | 0378-4274 |
| DOI: | 10.1016/j.toxlet.2021.02.003 |
| Popis: | Aims Both gefitinib and afatinib are epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in the treatment of non-small cell lung cancer (NSCLC). It has been reported that gefitinib and afatinib could cause hepatotoxicity during the clinic treatment, therefore it is critical to investigate their hepatotoxicity systematically. In this study, zebrafish (Danio rerio) were used as model animals to compare the hepatotoxicity and their toxic mechanism. Main methods The zebrafish transgenic line [Tg (fabp10a: dsRed; ela3l:EGFP) was used in this study. After larvae developed at 3 days post fertilization (dpf), they were put into different concentrations of gefitinib and afatinib. At 6 dpf, the viability, liver area, fluorescence intensity, histopathology, apoptosis, transaminase reflecting liver function, the absorption of yolk sac, and the expression of relative genes were observed and analyzed respectively. Key findings Both gefitinib and afatinib could induce the larvae hepatotoxicity dose-dependently. Based on the liver morphology, histopathology, apoptosis and function assessments, gefitinib showed higher toxicity, causing more serious liver damage. Both gefitinib and afatinib caused abnormal expressions of genes related to endoplasmic reticulum stress (ERS) pathway and apoptosis. For example, jnk, perk, bip, chop, ire1, bid, caspase3 and caspase9 were up-regulated, while xbp1s, grp78, bcl-2/bax, and caspase8 were down-regulated. The hepatotoxicity difference of gefitinib and afatinib might be due to the different expression level of related genes. |
| Databáze: | OpenAIRE |
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