An efficient human stem cells derived cardiotoxicity testing platform for testing oncotherapeutic analogues of quercetin and cinnamic acid.

Abstract

Oncotherapeutics research is progressing at a rapid pace, however, not many drugs complete the successful clinical trial because of severe off-target toxicity to cardiomyocytes which ultimately leads to cardiac dysfunction. It is thus important to emphasize the need for early testing for possible cardiotoxicity of emerging oncotherapeutics. In this study, we assessed a novel stem cell-derived cardiac model for testing for cardiotoxicity of novel oncotherapeutics. We evaluated the cardiotoxic effect of synthesized derivatives of oncotherapeutics, quercetin (QMJ-2, -5, and -6) and cinnamic acid (NMJ-1, -2, and -3) using human Wharton's jelly mesenchymal stem cells-derived cardiomyocytes (WJCM) against known cardiotoxic oncologic drugs, doxorubicin, 5-fluorouracil, cisplatin. QMJ-6, NMJ-2, and NMJ-3 were not cardiotoxic and had minimum cardiac side effects. They did not show any effect on cardiomyocyte viability, caused low LDH release, and intracellular ROS production kept the calcium flux minimal and protected the active mitochondrial status in cardiomyocytes. They persevered cardiac-specific gene expression as well. However, compounds QMJ-2, QMJ-5, and NMJ-1 were cardiotoxic and the concentration needs to be reduced to prevent toxic effects on cardiomyocytes. Significantly, we were able to demonstrate that WJCM is an efficient cardiac testing model to analyze the cardiotoxicity of drugs in a human context.