The mechanism of rh-endostatin-induced cardiotoxicity and its protection by dihydromyricetin[in vivo/in vitro, C57BL/6 mice, AC16 and hiPSC-CMs]. (15th March 2023)

• Record Type: Journal Article
• Authors: Guan, Xiaoran; Li, Wuquan; Wang, Yong; Zhao, Qun; Yu, Xinru; Jiang, Jing; Bian, Weihua; Xu, Cong; Sun, Yeying; Zhang, Chunxiang
• Is Part Of: Toxicology letters. Volume 377(2023)
• Page Start: 29
• Page End: 37
• Publication Date: 2023-03-15
• Subjects: NSCLC non-small-cell lung cancer -- hiPSC-CMs human-induced pluripotent stem cell-derived cardiomyocytes -- DHM dihydromyricetin -- VEGF vascular endothelial growth factor -- NLRP3 NLR family pyrin domain containing 3 -- SIRT3 sirtuin 3; Recombinant human endostatin -- Cardiotoxicity -- Mitochondrial dysfunction -- Mechanism; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2023.01.012
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Recombinant human endostatin (rh-endostatin) is an anti-angiogenic drug, which is used for the treatment of advanced non-small-cell lung cancer (NSCLC) and other cancers. However, its side effects, especially the cardiotoxicity with unclear mechanisms limit its wide application in clinical practice. In this study, human cardiomyocyte cell line AC16 and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with different doses of rh-endostatin were used to analyze its effect on cardiac cell toxicity. The results revealed that rh-endostatin dose-dependently enhanced cardiomyocyte apoptosis through Apaf-1 apoptotic factor and apoptosis-related proteins such as p53. rh-endostatin-induced changes of mitochondrial function and mitophagy were involved in rh-endostatin-mediated cardiac cell toxicity. Rh-endostatin-induced cardiotoxicity was further verified in vivo in mice. Interestingly, Rh-endostatin-induced cardiotoxicity was inhibited by dihydromyricetin (DHM) both in cultured cells in vitro and in mouse hearts in vivo. The study provides new inside into rh-endostatin-induced cardiotoxicity and identified a novel potential medication DHM to overcome the serious adverse effect. Highlights: Rh-endostatin enhanced cardiomyocyte apoptosis through Apaf-1 apoptotic factor and apoptosis-related proteins such as p53. Mitochondrial function and mitophagy were involved in rh-endostatin-mediated cardiac cell toxicity. Rh-endostatin-induced cardiotoxicity was inhibited by dihydromyricetin (DHM) both in vitro and in vivo.