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Antitumor profiles and cardiac electrophysiological effects of aurora kinase inhibitor ZM447439

Korean Journal of Physiology & Pharmacology 2019년 23권 5호 p.393 ~ 402
 ( Le Hyang-Ae ) - Korea Research Institute of Chemical Technology

 ( Kwon Mi-So ) - Korea Research Institute of Chemical Technology
 ( Kim Hyeon-A ) - Korea Research Institute of Chemical Technology
 ( Kim Ki-Suk ) - Korea Research Institute of Chemical Technology

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.

키워드

Aurora kinases inhibitor; Cardiotoxicity; Efficacy testing; ZM447439
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