BCR-ABL tyrosine kinase inhibitors (TKIs) have contributed to the improvement of the survival of patients with chronic myelogenous leukemia (CML). Growing evidence suggests that cancer therapy-related cardiac dysfunction has become important as the most undesirable side effect of chemotherapy. For example, one of BCR-ABL TKIs, nilotinib, has been reported to have a risk of QT prolongation associated with Torsades des Pointes and cardiac failure. We have previously reported that nilotinib causes QT prolongation and early afterdepolarization (EAD) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). In this study, we evaluated the effect of BCR-ABL TKIs on contractility using hiPSC-CMs.
We used iCell Cardiomyocyte 2.0 (Cellular Dynamics International). To assess the chronic cardiotoxicity of the several BCR-ABL TKIs including nilotinib, we analyzed the contractility velocity recorded by motion vector analysis (SI8000, Sony).
We found that treatment with BCR-ABL TKIs decreased beating rate in hiPSC-CMs in a concentration-dependent manner. In addition, nilotinib and other BCR-ABL TKIs decreased the relaxation velocities.
These results suggest that BCR-ABL TKIs affect contractility in hiPSC-CMs. We are planning to analyze the adverse drug event reporting database using BCR-ABL TKIs to conform the in vitro data.