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

Abstract

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 (10 μM) 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 (30 nM to 30 μM) 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 ≤6 h of treatment, followed by dose-dependent decreases after 6 and 72 hours 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.

Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: A tool for cardiac safety assessment

“…1B). This is an appealing feature of the system since it provides an internal built-in quality control for the cells and any compounds that may cause structural damage or other types of toxicity can be readily detected, as it has been shown for some kinase inhibitors and anthracyclines such as doxorubicin Schweikart et al, 2013). At high data acquisition of 500 HZ, the system can readily monitor the spontaneous beating of the hiPSC-CMs (Fig.…”

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

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High-Content Assays for Hepatotoxicity Using Induced Pluripotent Stem Cell–Derived Cells

“…17 iPSC-derived tissue specific cells provide relevant human biology in vitro and are increasingly being studied for their potential to accurately predict drug-induced toxicity. [18][19][20][21] As a result, iPSC-derived cell models are being adopted by the pharmaceutical industry for preclinical toxicity studies. 22,23 To realize the full potential of iPSCderived cell models, it is necessary to develop predictive in vitro assays that can be performed in a high-throughput manner.…”