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Original Article

Korean J Physiol Pharmacol 2019; 23(5): 393-402

Published online September 1, 2019 https://doi.org/10.4196/kjpp.2019.23.5.393

Copyright © The Korean Journal of Physiology & Pharmacology.

Antitumor profiles and cardiac electrophysiological effects of aurora kinase inhibitor ZM447439

Hyang-Ae Lee1, Miso Kwon1,2, Hyeon-A Kim1, and Ki-Suk Kim1,*

1R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon 34114, 2Fertility Center, CHA Bunding Medical Center, CHA University, Seongnam 13496, Korea

Correspondence to:*Ki-Suk Kim, E-mail: idkks@kitox.re.kr

Received: July 7, 2019; Revised: August 8, 2019; Accepted: August 8, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with IC50 in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect INa, IKs or IK1, but decreased IhERG in a dose-dependent manner (IC50: 6.53 µM). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to 3 µM, but it at 10 µM induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.

Keywords: Aurora kinases inhibitor, Cardiotoxicity, Efficacy testing, ZM447439