Comparison of cardiotoxicity induced by alectinib, apatinib, lenvatinib and anlotinib in zebrafish embryos

Abstract

Four tyrosine kinase inhibitors, alectinib, apatinib, lenvatinib and anlotinib, have been shown to be effective in the treatment of clinical tumors, but their cardiac risks have also raised concerns. In this study, zebrafish embryos at 6 h post fertilization (hpf) were exposed to the four drugs at concentrations of 0.05–0.2 mg/L until 72 hpf, and then the development of these embryos was quantified, including heart rate, body length, yolk sac area, pericardial area, distance between venous sinus and balloon arteriosus (SV-BA), separation of cardiac myocytes and endocardium, gene expression, vascular development and oxidative stress. At the same exposure concentrations, alectinib and apatinib had little effect on the cardiac development of zebrafish embryos, while lenvatinib and anlotinib could induce significant cardiotoxicity and developmental toxicity, including shortened of body length, delayed absorption of yolk sac, pericardial edema, prolonged SV-BA distance, separation of cardiomyocytes and endocardial cells, and downregulation of key genes for heart development. Heart rate decreased in all four drug treatment groups. In terms of vascular development, alectinib and apatinib did not inhibit the growth of embryonic intersegmental vessels (ISVs) and retinal vessels, while lenvatinib and anlotinib caused serious vascular toxicity, and the inhibition of anlotinib in vascular development was more obvious. Besides, the level of reactive oxygen species (ROS) in the lenvatinib and anlotinib treatment groups was significantly increased. Our results provide reference for comparing the cardiotoxicity of the four drugs.