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Lapatinib is one of several tyrosine kinase inhibitors used against solid tumour cancers such as breast and lung cancer. Although lapatinib is associated with a risk of QT prolongation, the effects of the drug on cellular cardiac electrical properties and on action potential duration (APD) have not been studied. To evaluate the potential effects of lapatinib on cardiac repolarization, we investigated its electrophysiological effects using a whole-cell patch-clamp technique in transiently transfected HEK293 cells expressing human ether-à-go-go (hERG; to examine the rapidly activating delayed rectifier K + current, I Kr ), KCNQ1 ⁄ KCNE1 (to examine the slowly activating delayed rectifier K + current, I Ks ), KCNJ2 (to examine the inwardly rectifying K + current, I K1 ), or SCN5A (to examine the inward Na + current, I Na ) and in rat cardiac myocytes (to examine the inward Ca 2+ current, I Ca ). We also examined its effects on the APD at 90% (APD 90 ) in isolated rabbit Purkinje fibres. In ion channel studies, lapatinib inhibited the hERG current in a concentration-dependent manner, with a half-maximum inhibition concentration (IC 50 ) of 0.8 € 0.09 lM. In contrast, at concentrations up to 3 lM, lapatinib did not significantly reduce the I Na , I K1 or I Ca amplitudes; at 3 lM, it did slightly inhibit the I Ks amplitude (by 19.4 € 4.7%; p < 0.05). At 5 lM, lapatinib induced prolongation of APD 90 by 16.1% (p < 0.05). These results suggest that the APD 90 -prolonging effect of lapatinib on rabbit Purkinje fibres is primarily a result of inhibition of the hERG current and I Ks , but not I Na , I K1 or I Ca .

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.