Journal Article

Electrophysiological mechanisms of vandetanib-induced cardiotoxicity: Comparison of action potentials in rabbit Purkinje fibers and pluripotent stem cell-derived cardiomyocytes

Kim, Ki-Suk, Lee, Hyang-Ae, Chae, Jong-Hak, Hyun, Sung-Ae, Byun, Byungjin

2018

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Action potential / Action Potentials - drug effects / Alanine / Animal models / Animals / Arrhythmia / Biology and Life Sciences / Cardiac arrhythmia / Cardiomyocytes / Cardiotoxicity / Cardiotoxicity - physiopathology / Cardiotoxins - chemistry / Cardiotoxins - toxicity / Cardiovascular diseases / Complications and side effects / Depolarization / Docking / Drugs / Electrophysiological Phenomena / Electrophysiology / Engineering and Technology / Enzyme inhibitors / ERG1 Potassium Channel - chemistry / ERG1 Potassium Channel - genetics / ERG1 Potassium Channel - metabolism / Female / Fibers / Growth factors / Health aspects / Heart diseases / HEK293 Cells / Human influences / Humans / In Vitro Techniques / Induced Pluripotent Stem Cells - cytology / Induced Pluripotent Stem Cells - drug effects / Induced Pluripotent Stem Cells - physiology / Ion channels / KCNQ1 Potassium Channel - genetics / KCNQ1 Potassium Channel - metabolism / KCNQ1 protein / Kinases / Laboratory animals / Medical screening / Medicine and Health Sciences / Models, Molecular / Mutagenesis / Myocytes, Cardiac - cytology / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - physiology / NAV1.5 Voltage-Gated Sodium Channel - genetics / NAV1.5 Voltage-Gated Sodium Channel - metabolism / Oncology / Patch-Clamp Techniques / Pharmacology / Physical Sciences / Piperidines - chemistry / Piperidines - toxicity / Pluripotency / Potassium channels / Potassium channels (delayed-rectifying) / Potassium channels (inwardly-rectifying) / Potassium channels (voltage-gated) / Potassium Channels, Inwardly Rectifying - genetics / Potassium Channels, Inwardly Rectifying - metabolism / Potassium Channels, Voltage-Gated - genetics / Potassium Channels, Voltage-Gated - metabolism / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - toxicity / Purkinje fibers / Purkinje Fibers - drug effects / Purkinje Fibers - physiopathology / Quinazolines - chemistry / Quinazolines - toxicity / Rabbits / Rectifiers / Research and Analysis Methods / Risk factors / Stem cells / Toxicology / Vandetanib