Abstract
Vandetanib, a multi-kinase inhibitor used for the treatment of various cancers, has been reported to induce several adverse cardiac effects. However, the underlying mechanisms of vandetanib-induced cardiotoxicity are unclear. This study aimed to investigate the mechanism of vandetanib-induced cardiotoxicity using intracellular electrophysiological recordings on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), rabbit Purkinje fibers, and HEK293 cells transiently expressing human ether-a-go-go-related gene (hERG; the rapidly activating delayed rectifier K+ channel, IKr), KCNQ1/KCNE1 (the slowly activating delayed rectifier K+ current, IKs), KCNJ2 (the inwardly rectifying K+ current, IK1) or SCN5A (the inward Na+ current, INa). Purkinje fiber assays and ion channel studies showed that vandetanib at concentrations of 1 and 3 μM inhibited the hERG currents and prolonged the action potential duration. Alanine scanning and in silico hERG docking studies demonstrated that Y652 and F656 in the hERG S6 domain play critical roles in vandetanib binding. In hiPSC-CMs, vandetanib markedly reduced the maximum rate of depolarization during the AP upstroke. Ion channel studies revealed that hiPSC-CMs were more sensitive to inhibition of the INa by vandetanib than in a heterogeneously expressed HEK293 cell model, consistent with the changes in the AP parameters of hiPSC-CMs. The subclasses of Class I antiarrhythmic drugs inhibited INa currents in a dose-dependent manner in hiPSC-CMs and SCN5A-encoded HEK293 cells. The inhibitory potency of vandetanib for INa was much higher in hiPSC-CMs (IC50: 2.72 μM) than in HEK293 cells (IC50: 36.63 μM). These data suggest that AP and INa assays using hiPSC-CMs are useful electrophysiological models for prediction of drug-induced cardiotoxicity.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Action Potentials / drug effects
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Animals
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Cardiotoxicity / physiopathology*
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Cardiotoxins / chemistry
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Cardiotoxins / toxicity*
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ERG1 Potassium Channel / chemistry
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ERG1 Potassium Channel / genetics
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ERG1 Potassium Channel / metabolism
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Electrophysiological Phenomena
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Female
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HEK293 Cells
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Humans
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In Vitro Techniques
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Induced Pluripotent Stem Cells / cytology
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Induced Pluripotent Stem Cells / drug effects*
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Induced Pluripotent Stem Cells / physiology*
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KCNQ1 Potassium Channel / genetics
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KCNQ1 Potassium Channel / metabolism
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Models, Molecular
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / physiology*
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NAV1.5 Voltage-Gated Sodium Channel / genetics
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NAV1.5 Voltage-Gated Sodium Channel / metabolism
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Patch-Clamp Techniques
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Piperidines / chemistry
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Piperidines / toxicity*
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Potassium Channels, Inwardly Rectifying / genetics
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Potassium Channels, Inwardly Rectifying / metabolism
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Potassium Channels, Voltage-Gated / genetics
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Potassium Channels, Voltage-Gated / metabolism
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / toxicity
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Purkinje Fibers / drug effects*
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Purkinje Fibers / physiopathology*
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Quinazolines / chemistry
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Quinazolines / toxicity*
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Rabbits
Substances
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Cardiotoxins
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ERG1 Potassium Channel
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KCNE1 protein, human
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KCNH2 protein, human
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KCNJ2 protein, human
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KCNQ1 Potassium Channel
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KCNQ1 protein, human
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NAV1.5 Voltage-Gated Sodium Channel
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Piperidines
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Potassium Channels, Inwardly Rectifying
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Potassium Channels, Voltage-Gated
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Protein Kinase Inhibitors
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Quinazolines
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SCN5A protein, human
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vandetanib
Grants and funding
This work was supported by the Technology Innovation Program (10067737, Establishment of Risk management platform with aim to reduce attrition of new drugs and its service) funded By the Ministry of Trade, Industry & Energy (MI, Korea) to KSK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.