心脏毒性
血管生成
药理学
癌症研究
生物
斑马鱼
索拉非尼
酪氨酸激酶
医学
内科学
信号转导
细胞生物学
毒性
生物化学
基因
肝细胞癌
作者
Cui Ma,Zhenghua Wu,Xue Wang,Mengling Huang,Xiaona Wang,Wei Wang,Han Qu,Xijier Qiaolongbatu,Yuefen Lou,Lili Jing,Guorong Fan
标识
DOI:10.1016/j.taap.2022.116162
摘要
Pathological angiogenesis is fundamental to progression of cancerous tumors and blinding eye diseases. Anti-angiogenic receptor tyrosine kinase inhibitors (TKIs) are in broad use for the treatment of these diseases. With more and more TKIs available, it is a challenge to make an optimal choice. It remains unclear whether TKIs demonstrate similar anti-angiogenesis activities in different tissues. Many TKIs have shown varying degrees of toxic effects that should also be considered in clinical use. This study investigates the anti-angiogenic effects of 13 FDA-approved TKIs on the intersegmental vessels (ISVs), subintestinal vessels (SIVs) and retinal vasculature in zebrafish embryos. The results show that vascular endothelial growth factor receptor TKIs (VEGFR-TKIs) exhibit anti-angiogenic abilities similarly on ISVs and SIVs, and their efficacy is consistent with their IC50 values against VEGFR2. In addition, VEGFR-TKIs selectively induces the apoptosis of endothelial cells in immature vessels. Among all TKIs tested, axitinib demonstrates a strong inhibition on retinal neovascularization at a low dose that do not strongly affect ISVs and SIVs, supporting its potential application for retinal diseases. Zebrafish embryos demonstrate cardiotoxicity after VEGFR-TKIs treatment, and ponatinib and sorafenib show a narrow therapeutic window, suggesting that these two drugs may need to be dosed more carefully in patients. We propose that zebrafish is an ideal model for studying in vivo antiangiogenic efficacy and cardiotoxicity of TKIs.
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