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

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.

[Retracted] Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib‐Induced QT Interval Prolongation

“…In this study, we demonstrated that vandetanib prolonged the QT interval in Langendorff perfusion rabbit hearts. Also, vandetanib can prolong the cardiac action potential in rabbit heart and hiPSC-CMs, which are consistent with the results reported in the literature [ 22 ]. Malignant arrhythmias caused by QT interval prolongation pose a serious threat to patient's life safety and then limit their clinical application.…”

Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology

“…However, 24-74% of routinely prescribed drugs have the potential to interact with cytochrome P450 3A4 metabolism, which can result in increased toxicity. Indeed, vandetanib has been shown to bind directly to cardiomyocyte hERG potassium channels in vitro and to inhibit potassium and sodium currents, resulting in attenuated depolarisation and delayed action potentials [75].…”

The resting membrane potential of hSC-CM in a syncytium is more hyperpolarised than that of isolated cells

“…Most reports on the RMP and AP waveform of hSC-CMs and hiPSC-CMs present data from isolated cells that were dissociated from their monolayers or 3D structured cultures 4 to 10 days prior to the measurements [13,[44][45][46][47]. On the other hand, native CMs are mostly recorded immediately after dissociation, as longer culturing of these cells leads to more depolarized RMP values and larger AP waveform variability [48].…”