PLOS ONERESEARCH ARTICLE

Electrophysiological evaluation of an
anticancer drug gemcitabine on cardiotoxicity
revealing down-regulation and modificationof the activation gating properties in thehuman rapid delayed rectifier potassiumchannela1111111111
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Mengyan Wei1,2☯, Pu Wang1,2☯, Xiufang Zhu1,2☯, Masaki Morishima3, Yangong Liu1,2,Mingqi Zheng1, Gang Liu1, Hiroki Osanai2, Kenshi Yoshimura2, Shinichiro Kume2,
Tatsuki Kurokawa2, Katsushige Ono ID2*
1 Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province,
People’s Republic of China, 2 Department of Pathophysiology, Oita University School of Medicine, Yufu,Oita, Japan, 3 Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University, Nara,Japan☯ These authors contributed equally to this work.
* ono@oita-u.ac.jp

OPEN ACCESS
Citation: Wei M, Wang P, Zhu X, Morishima M, Liu
Y, Zheng M, et al. (2023) Electrophysiologicalevaluation of an anticancer drug gemcitabine on
cardiotoxicity revealing down-regulation andmodification of the activation gating properties in
the human rapid delayed rectifier potassiumchannel. PLoS ONE 18(2): e0280656. https://doi.
org/10.1371/journal.pone.0280656
Editor: Zhe Zhang, Xuzhou Medical University,CHINA
Received: July 5, 2022
Accepted: January 5, 2023
Published: February 2, 2023
Copyright: © 2023 Wei et al. This is an open accessarticle distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction inany medium, provided the original author andsource are credited.
Data Availability Statement: All relevant data arewithin the paper and its Supporting information file(pdf).
Funding: The author(s) received no specificfunding for this work.
Competing interests: The authors have declaredthat no competing interests exist.

Abstract
Gemcitabine is an antineoplastic drug commonly used in the treatment of several types ofcancers including pancreatic cancer and non–small cell lung cancer. Although gemcitabine-induced cardiotoxicity is widely recognized, the exact mechanism of cardiac
dysfunction causing arrhythmias remains unclear. The objective of this study was toelectrophysiologically evaluate the proarrhythmic cardiotoxicity of gemcitabine focusing on
the human rapid delayed rectifier potassium channel, hERG channel. In heterologous
hERG expressing HEK293 cells (hERG-HEK cells), hERG channel current (IhERG) was
reduced by gemcitabine when applied for 24 h but not immediately after the application.
Gemcitabine modified the activation gating properties of the hERG channel toward thehyperpolarization direction, while inactivation, deactivation or reactivation gating properties
were unaffected by gemcitabine. When gemcitabine was applied to hERG-HEK cells incombined with tunicamycin, an inhibitor of N-acetylglucosamine phosphotransferase,
gemcitabine was unable to reduce IhERG or shift the activation properties toward the hyperpolarization direction. While a mannosidase I inhibitor kifunensine alone reduced IhERG
and the reduction was even larger in combined with gemcitabine, kifunensine was without
effect on IhERG when hERG-HEK cells were pretreated with gemcitabine for 24 h. In addition, gemcitabine down-regulated fluorescence intensity for hERG potassium channel protein in rat neonatal cardiomyocyte, although hERG mRNA was unchanged. Our results
suggest the possible mechanism of arrhythmias caused by gemcitabine revealing a downregulation of IhERG through the post-translational glycosylation disruption possibly at thePLOS ONE | https://doi.org/10.1371/journal.pone.0280656 February 2, 2023

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