Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib-Induced QT Interval Prolongation.

Juan Zhang,Jie Qiao,Miaoling Li,Lin Wu,Zhiyi Li,Fang Li,Xiaoli Gao,Dan Luo,Shao Liang

doi:10.1155/2021/3520034

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.

Highlights

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor, which originates from thyroid parafollicular cells (C cells) [1]
Our study demonstrated that ginsenoside Rg3 can reverse vandetanib-induced QT interval prolongation by targeting on the human ether-a-go-go-related gene (hERG) K+ channel
Vandetanib is regarded as a class of tyrosine kinase inhibitors (TKIs), which has been used for the treatment of thyroid cancer in clinic with a good therapeutic effect

Summary

Introduction

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor, which originates from thyroid parafollicular cells (C cells) [1]. With the development of targeted drugs, a variety of multitarget small-molecular tyrosine kinase inhibitors have been reported to be effective against unresectable locally advanced MTC, including vandetanib, cabozantinib, lenvatinib, anlotinib, sulfatinib, and axitinib. Vandetanib is a once-daily oral (300 mg/day) small molecular kinase inhibitor, by targeting on vascular endothelial growth factor receptor (VEGFR), rearranged during transfection (RET), epidermal growth factor receptor EGFR [2,3,4], and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene (v-kit) [5]. Vandetanib was demonstrated to be the most preferred drug for MTC treatment with regard to progression-free survival [6, 7]. In 2011, the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved vandetanib for the treatment of progressive, symptomatic, inoperable locally

Objectives

Results

Conclusion