Experimental Study on Cardiotoxicity of Tumor Targeting Drugs Based on iPS Technology
HAN Dong1, MIAO Jiaxin1,2, MA Yan1,2, ZHANG Yang1,2, CAO Feng1
Increasing attention has been paid to the cardiovascular side effects of TKIs (tyrosine kinase inhibitors). Human induced pluripotent stem cells can differentiate into various types of somatic cells in vitro and have a rich resource, which provides an ideal choice for early drug toxicity evaluation. In this study, the cardiotoxicity of sunitinib was observed in sunitinib-exposed hiPSC-CMs (human induced pluripotents stem cell-derived cardiomyocytes). Cultured in vitro and chemically induced, hiPSC-CMs were divided into control group, 5.6 μmol/L sunitinib (IC50 concentration, determined by CCK8 method) intervention group for 24 h and 48 h group. The expression of HIF-1α, the state of hypoxia and the change of mitochondrial membrane potential were evaluated by immunofluorescence; the structural changes of mitochondria were observed by transmission electron microscope; mitochondrial membrane potential and cell apoptosis were examined by flow cytometry. The results showed that sunitinib induced significant mitochondrial structure damage, mitochondrial membrane potential dissipation, apparent hypoxia, and elevated HIF-1α expression, which was paralleled with overt apoptosis and necrosis. In summary, sunitinib can cause mitochondrial structural damage, hypoxia, apoptosis and necrosis, as well as hyperactivation of HIF-1α in hiPSC-CMs.
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