Why the study?
Many small molecule kinase inhibitors used to treat cancer are associated with cardiotoxicity, making prevention of their clinical failure a priority for preclinical drug discovery.
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In vitro measurement of ATP concentrations and apoptosis in human stem cell-derived cardiomyocytes can provide important insights into the mechanisms of cardiotoxicity of small molecule kinase inhibitors.
Many small molecule kinase inhibitors (SMKIs) used to fight cancer have been associated with cardiotoxicity in the clinic. Therefore, preventing their failure in clinical development is a priority for preclinical discovery. Our study focused on the integration and concurrent measurement of ATP, apoptosis dynamics and functional cardiac indexes in human stem cell-derived cardiomyocytes (hSC-CMs) to provide further insights into molecular determinants of compromised cardiac function. Ten out of the fourteen tested SMKIs resulted in a biologically relevant decrease in either beating rate or base impedance (cell number index), illustrating cardiotoxicity as one of the major safety liabilities of SMKIs, in particular of those involved in the PI3K–AKT pathway. Pearson's correlation analysis indicated a good correlation between the different read-outs of functional importance. Therefore, measurement of ATP concentrations and apoptosis in vitro could provide important insight into mechanisms of cardiotoxicity. Detailed investigation of the cellular signals facilitated multi-parameter evaluation allowing integrative assessment of cardiomyocyte behavior. The resulting correlation can be used as a tool to highlight changes in cardiac function and potentially to categorize drugs based on their mechanisms of action.
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Ziegler et al. (2021) studied this question.
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