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.Angiogenesis plays a crucial role in tumor pathogenesis, growth, invasion, and metastasis. With the recent development of anti-angiogenic therapies, vascular-targeted therapy has progressed rapidly. Endostatin is a C-terminal fragment of collagen XVIII with a molecular weight of 20 kDa, which can specifically inhibit the proliferation of neovascular endothelial cells， reduce angiogenesis, and thereby inhibit tumor growth via limiting the nutrient supply to tumors . However, its insolubility and instability, together with the high cost of the endostatin protein synthesis, restrict its clinical applications in tumor therapy.

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Mishita
Jornal co-ordinator
Journal of Heart and Cardiovascular Research