The effects of jaspamide on human cardiomyocyte function and cardiac ion channel activity

► In vitro assays were performed to determine if jaspamide is cardiotoxic. ► Jaspamide inhibited Kv1.5 cardiac ion channel activity by 98.5%. ► Jaspamide decreased beat amplitude and increased beat rate in human cardiomyocytes. ► Assay data from the known cardiotoxicant mitoxantrone were compared to jaspamide. ► These results may explain the acute in vivo toxicity (in rat, dog) with jaspamide. Jaspamide (jasplakinolide; NSC-613009) is a cyclodepsipeptide that has antitumor activity. A narrow margin of safety was observed between doses required for efficacy in mouse tumor models and doses that caused severe acute toxicity in rats and dogs. We explored the hypothesis that the observed toxicity was due to cardiotoxicity. Jaspamide was tested in a patch clamp assay to determine its effect on selected cardiac ion channels. Jaspamide (10μM) inhibited Kv1.5 activity by 98.5%. Jaspamide also inhibited other channels including Cav1.2, Cav3.2, and HCN2; however, the Kv11.1 (hERG) channel was minimally affected. Using spontaneously contracting human cardiomyocytes derived from induced pluripotent stem cells, effects on cardiomyocyte contraction and viability were also examined. Jaspamide (30nM to 30μM) decreased cardiomyocyte cell indices and beat amplitude, putative measurements of cell viability and cardiac contractility, respectively. Concentration-dependent increases in rhythmic beating rate were noted at ⩽6h of treatment, followed by dose-dependent decreases after 6 and 72h exposure. The toxic effects of jaspamide were compared with that of the known cardiotoxicant mitoxantrone, and confirmed by multiparameter fluorescence imaging analysis. These results support the hypothesis that the toxicity observed in rats and dogs is due to toxic effects of jaspamide on cardiomyocytes.