Abstract P3115: The Protective Effect Of Canagliflozin Against Carfilzomib-induced Endothelial Toxicity

• Published in: Circulation research 2022-08, Vol.131 (Suppl_1), p.AP3115-AP3115
• Main Authors: Dabour, Mohamed S, Abdelgawad, Ibrahim, Grant, Marianne, Zordoky, Beshay
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P3115

IntroductionThe anti-cancer agent carfilzomib (CFZ) is associated with serious cardiovascular side effects. There is anecdotal clinical evidence that endothelial dysfunction contributes to CFZ-induced cardiovascular complications; however, the toxic effects of CFZ have not been reported in endothelial cells (ECs). The anti-diabetic Sodium glucose cotransporter 2 (SGLT2) inhibitors have newly emerged as cardio-protective agents in heart failure, myocardial infarction, stroke, and diabetic cardiomyopathy. The objectives of the current work are to characterize the toxic effects of CFZ in two human-derived endothelial cell lines, human umbilical vein endothelial cells (HUVECs) and EA.hy926, determine the molecular signaling changes associated with these toxic effects, and investigate the protective effects of SGLT2 inhibitors (Empagliflozin, Dapagliflozin, Canagliflozin) on CFZ-induced endothelial toxicity. MethodsBoth ECs were treated with clinically relevant concentrations of CFZ (0.05, 0.1, 0.2, 0.5, and 1 μM) for 24 hours. EA.hy926 cells were treated with 0.5 μM CFZ with or without SGLT2 inhibitor (0.1, 1, 10, 50, 100 μM). Cell viability was determined by the MTT assay and protein expressions of apoptotic markers, mitogen-activated protein kinases (MAPKs), and the p70S6K pathway were determined by western blotting. ResultsCFZ reduces cell viability and induces apoptotic cell death in the two cell lines in a concentration-dependent manner. CFZ-induced apoptosis is also associated with activation of the p38 and JNK MAPK pathways and a remarkable inhibition of the p70S6K pathway. In EA.hy926, Canagliflozin prevents reduction in cell viability caused by CFZ, while empagliflozin and dapagliflozin have not shown any protective effects in vitro. Mechanistically, canagliflozin abrogates CFZ-induced endothelial cell apoptosis, and prevents CFZ-induced JNK activation. ConclusionThis is the first study to report the endothelial toxicity of CFZ. CFZ induces endothelial cell apoptosis which may contribute to CFZ-induced cardiovascular complications and canagliflozin protects against CFZ endothelial toxicity. Future research is warranted to identify the protective effects of SGLT2 inhibitors against CFZ in vivo.