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Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib-Induced QT Interval Prolongation
Juan Zhang1, Dan Luo1, Fang Li1
1Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
Abstract:
Inhibition of human ether-a-go-go-related gene (hERG) potassium channel is responsible for acquired long QT syndromes, which leads to life-threatening cardiac arrhythmia. A multikinase inhibitor, vandetanib, prolongs the progression-free survival time in advanced medullary thyroid cancer. However, vandetanib has been reported to induce significant QT interval prolongation, which limits its clinical application. Some studies have showed that ginsenoside Rg3 decelerated hERG K(+) channel tail current deactivation. Therefore, in this study, we aim to confirm whether ginsenoside Rg3 targeting hERG K(+) channel could be used to reverse the vandetanib-induced QT interval prolongation. Electrocardiogram (ECG) and monophasic action potential (MAP) were recorded using electrophysiology signal sampling and analysis system in Langendorff-perfused rabbit hearts. The current clamp mode of the patch-clamp technique was used to record transmembrane action potential. The whole-cell patch-clamp technique was used to record the hERG K+ current. In Langendorff-perfused hearts, vandetanib prolonged the QT interval in a concentration-dependent manner with an IC50 of 1.96 μmol/L. In human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), vandetanib significantly prolonged the action potential duration at 50%, 70%, and 90% repolarization (APD50, APD70, and APD90). In stable transfected human hERG gene HEK293 cells, vandetanib caused concentrate-dependent inhibition in the step and tail currents of hERG. As expected, ginsenoside Rg3 relieved vandetanib-induced QT interval prolongation in Langendorff-perfused heart and reversed vandetanib-induced APD prolongation in hiPSC-CMs. Furthermore, ginsenoside Rg3 alleviated vandetanib-induced hERG current inhibition and accelerated the process of the channel activation. Ginsenoside Rg3 may be a promising cardioprotective agent against vandetanib-induced QT interval prolongation through targeting hERG channel. These novel findings highlight the therapeutic potential of ginsenoside to prevent vandetanib-induced cardiac arrhythmia.
Insights
Ginsenoside Rg3 may protect against vandetanib-induced heart problems by targeting the hERG channel. This study confirms ginsenoside Rg3 can reverse vandetanib
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Inhibition of the human ether-a-go-go-related gene (hERG) potassium channel causes acquired long QT syndromes and life-threatening cardiac arrhythmias.
- Vandetanib, a multikinase inhibitor, prolongs progression-free survival in advanced medullary thyroid cancer but can induce significant QT interval prolongation, limiting its clinical use.
- Ginsenoside Rg3 has been shown to decelerate hERG K(+) channel tail current deactivation.
Purpose of the Study:
- To investigate whether ginsenoside Rg3, by targeting the hERG K(+) channel, can reverse vandetanib-induced QT interval prolongation.
- To evaluate the cardioprotective potential of ginsenoside Rg3 against vandetanib-induced cardiac side effects.
Main Methods:
- Electrophysiology: ECG and monophasic action potential (MAP) recordings in Langendorff-perfused rabbit hearts.
- Patch-clamp technique (current clamp and whole-cell) to record transmembrane action potentials and hERG K(+) currents in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 cells.
- Concentration-dependent assessment of vandetanib's effects on QT interval and hERG currents, and ginsenoside Rg3's reversal effects.
Main Results:
- Vandetanib prolonged the QT interval in a concentration-dependent manner (IC50 = 1.96 μmol/L) and significantly prolonged action potential duration (APD50, APD70, APD90) in hiPSC-CMs.
- Vandetanib caused concentration-dependent inhibition of hERG channel step and tail currents.
- Ginsenoside Rg3 relieved vandetanib-induced QT interval prolongation in hearts and reversed APD prolongation in hiPSC-CMs.
- Ginsenoside Rg3 alleviated vandetanib-induced hERG current inhibition and accelerated hERG channel activation.
Conclusions:
- Ginsenoside Rg3 effectively reverses vandetanib-induced QT interval prolongation and action potential duration prolongation.
- Ginsenoside Rg3 mitigates vandetanib's inhibitory effects on hERG currents and enhances channel activation.
- Ginsenoside Rg3 demonstrates potential as a cardioprotective agent against vandetanib-induced cardiotoxicity via hERG channel modulation.
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