Assessment of anti-cancer drug induced cardiotoxicity in human induced pluripotent stem cell (hiPSC) derived cardiomyocytes using a multiparametric approach

Cardiotoxicity is a major cause of attrition during (pre)clinical anticancer drug development [1] and a growing concern with the increasing survival of cancer patients [2]. Many anti-cancer drugs inhibit kinases that are critical for both cancer cell growth and cardiac homeostasis, thereby leading to the destruction of cancer cells, but also to cardiac dysfunction. The main cause of failure in early cardiotoxicity screening is the lack of relevant disease models and assay technologies that can mimic the complex conditions of the human cardiovascular system and subsequently detect cardiac side effects.We developed a combination of novel cardiotoxicity assays based on our hiPSC-derived cardiomyocytes (Pluricyte? Cardiomyocytes) to determine cardiotoxicity of (novel) pharmaceuticals. In addition to assays that can detect pro-arrhythmic effects (e.g. multi-electrode array assays), we developed functional assays to study other types of cardiotoxic effects, such as kinase activity assays and detection of alterations in contractility. For a set of oncology drugs (doxorubicin and the tyrosine kinase inhibitors sunitinib, imatinib, lapatinib and nilotinib) we investigated cardiotoxic effects in Pluricyte? Cardiomyocytes through a range of biochemistry- and electrophysiology-based assays. Treatment of the cardiomyocytes with these drugs led to the expected alterations in beating patterns, as well as in contractility and viability of the cells, supporting the use of hiPSC-derived cardiomyocytes to assess toxic effects of cardio-active compounds in preclinical research. Our multiparameter platform, which combines hiPSC-derived cardiomyocytes with biochemistry- and electrophysiology-based assays, enables early cardiotoxicity screening with the potential to greatly reduce the use of animal experiments in preclinical development.<br><br>[1] Khan et al., British Journal of Pharmacology, 2013<br>[2] Sheppard et al., Frontiers in Pharmacology, 2013<br><br><b>Disclosure</b>: The authors are employees of Pluriomics B.V., a biotech company which commercialized hiPSC-derived cardiomyocytes and assays with these cells