title: 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).
authors.affiliation: Department of Pharmacological Research, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea.
authors.forename: Hyang-Ae
authors.initials: HA
authors.lastname: Lee
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Kim
authors.forename: Sung-Ae
authors.initials: SA
authors.lastname: Hyun
authors.forename: Sung-Gurl
authors.initials: SG
authors.lastname: Park
authors.forename: Ki-Suk
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D000077341:Lapatinib; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects* / Q000503:physiopathology; D011799:Quinazolines / Q000494:pharmacology*; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; C489622:KCNE1 protein, human; C489457:KCNJ2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011799:Quinazolines; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; D015222:Sodium Channels; D000077341:Lapatinib