Differential inhibitory actions by lapatinib or sorafenib known as multi-targeted tyrosine kinase inhibitors on different types of ionic currents in heart cells

Abstract

Lapatinib (LAP) and sorafenib (SOR) are multi-targeted small molecules which belong to a family of tyrosine kinase inhibitors (TKIs) They have been recently approved for the treatment of a variety of malignant cancers They are recognized to influence the signaling pathway of tumor cell proliferation and to inhibit cell surface kinases thus decreasing the angiogenesis However some TKIs have been notably reported to cause a significant prolongation of electrocardiographic QTc interval The prolongation of QTc intervals may cause the tosade de pointes tachyarrhythmia which may result in syncope or sudden death Previous studies have shown that changes in the amplitude and kinetics of the slowly activating delayed-rectifier K+ current IK(S) and erg-mediated K+ current IK(erg) can potentially alter the QT interval duration Therefore in this study we wanted to evaluate the possible effects of LAP or SOR on ionic currents including IK(S) IK(erg) inwardly rectifying K+ current IK(IR) voltage-gated Na+ current (INa) in heart-derived H9C2 cells and in neonatal rat ventricular cardiomyocytes by using the patch-clamp technique Findings from these results have shown that the presence of LAP or SOR was able to suppress IK(S) amplitude as well as to alter the IK(S) activation and deactivation time courses The presence of LAP can also shift the activation curve of IK(S) towards more depolarized potentials with no significant change in gating charge of the curve Therefore the presence of LAP or SOR can directly suppress the amplitudes of IK(S) IK(erg) IK(IR) and INa with different potency observed in heart cells Addition of LAP or SOR can also cause the prolongation of action potential duration The targets for these ion channels in heart cells tend to be direct and could be of clinical relevance for this group of drugs if similar findings occur in vivo

Date of Award	2019
Original language	English
Supervisor	Sheng-Nan Wu (Supervisor)