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Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes
Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LA...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084345/ https://www.ncbi.nlm.nih.gov/pubmed/32121388 http://dx.doi.org/10.3390/ijms21051672 |
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author | Chang, Wei-Ting Liu, Ping-Yen Lee, Kaisen Feng, Yin-Hsun Wu, Sheng-Nan |
author_facet | Chang, Wei-Ting Liu, Ping-Yen Lee, Kaisen Feng, Yin-Hsun Wu, Sheng-Nan |
author_sort | Chang, Wei-Ting |
collection | PubMed |
description | Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na(+) and K(+) currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K(+) current (I(K(S))) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of I(K(S)) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of I(K(S)) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from I(K(S)) deactivation. As rapid repetitive stimuli, the I(K(S)) amplitude decreased; however; the LAP-induced inhibition of I(K(S)) remained effective. LAP or SOR alone also suppressed inwardly rectifying K(+) and voltage-gated Na(+) current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals. |
format | Online Article Text |
id | pubmed-7084345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70843452020-03-24 Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes Chang, Wei-Ting Liu, Ping-Yen Lee, Kaisen Feng, Yin-Hsun Wu, Sheng-Nan Int J Mol Sci Article Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na(+) and K(+) currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K(+) current (I(K(S))) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of I(K(S)) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of I(K(S)) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from I(K(S)) deactivation. As rapid repetitive stimuli, the I(K(S)) amplitude decreased; however; the LAP-induced inhibition of I(K(S)) remained effective. LAP or SOR alone also suppressed inwardly rectifying K(+) and voltage-gated Na(+) current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals. MDPI 2020-02-29 /pmc/articles/PMC7084345/ /pubmed/32121388 http://dx.doi.org/10.3390/ijms21051672 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chang, Wei-Ting Liu, Ping-Yen Lee, Kaisen Feng, Yin-Hsun Wu, Sheng-Nan Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes |
title | Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes |
title_full | Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes |
title_fullStr | Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes |
title_full_unstemmed | Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes |
title_short | Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes |
title_sort | differential inhibitory actions of multitargeted tyrosine kinase inhibitors on different ionic current types in cardiomyocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084345/ https://www.ncbi.nlm.nih.gov/pubmed/32121388 http://dx.doi.org/10.3390/ijms21051672 |
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