The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Antitumor profiles and cardiac electrophysiological effects of aurora kinase inhibitor ZM447439

  • Lee, Hyang-Ae (R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Kwon, Miso (R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Kim, Hyeon-A (R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology) ;
  • Kim, Ki-Suk (R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
  • Received : 2019.07.07
  • Accepted : 2019.08.08
  • Published : 2019.09.01
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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 $IC_{50}$ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect $I_{Na}$, $I_{Ks}$ or $I_{K1}$, but decreased $I_{hERG}$ in a dose-dependent manner ($IC_{50}$: $6.53{\mu}M$). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to $3{\mu}M$, but it at $10{\mu}M$ 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.

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References

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