Electrophysiological Effects of the Anti-Cancer Drug Lapatinib on Cardiac Repolarization

Abstract

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 microm. In contrast, at concentrations up to 3 microm, lapatinib did not significantly reduce the I(Na), I(K1) or I(Ca) amplitudes; at 3 microm, it did slightly inhibit the I(Ks) amplitude (by 19.4 +/- 4.7%; p < 0.05). At 5 microm, 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).