Tyrosine kinase inhibitors (TKIs) have improved the outcome of patient of chronic myelogenous leukemia (CML). As cancer survival rates have been increasing, cancer therapy-related cardiac dysfunction has been recognized as the most undesirable side effects of chemotherapy. Nilotinib, one of BCR-ABL TKIs, has a risk of QT prolongation on electrocardiogram, and cardiac failure. We have previously reported that nilotinib caused QT prolongation and early afterdepolarization (EAD) using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). However, chronic cardiotoxicity by nilotinib treatment has not been fully understood. In the present study, we evaluated the chronic toxicity of nilotinib using hiPSC-CMs.
We used iCell Cardiomyocyte 2.0 (Cellular Dynamics International) as a hiPSC-CM. To assess whether nilotinib induced chronic cardiotoxicity, we investigated the QT interval with multi-electrode array system (MEA, MED64, Alpha Med Scientific) and contractility assay system with motion vector analysis (MVA, SI8000, Sony).
We found that the long-term treatment with nilotinib caused QT prolongation and decreased contraction velocity in a concentration-dependent manner. These results suggest that hiPSC-CMs can be the useful tool for chronic toxicity assessment. In the near future, we are planning to evaluate other types of BCR-ABL TKIs with hiPSC-CMs.