Biomol Ther  
Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells
Jong Kook Park1, Jung Seon Seo2, Suk Kyeong Lee2, Kenneth K Chan3 and Hyo-Jeong Kuh2,4,5,*
1Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chuncheon 24252,
2Department of Biomedicine & Health Science, Graduate School, The Catholic University of Korea, Seoul 06591, Republic of Korea
3Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
4Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591,
5Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
E-mail: hkuh@catholic.ac.kr
Tel: +82-2-2258-7511, Fax: +82-2-592-2428
Received: April 13, 2018; Revised: July 13, 2018; Accepted: July 31, 2018; Published online: September 3, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Epigenetic silencing is considered to be a major mechanism for loss of activity in tumor suppressors. Reversal of epigenetic silencing by using inhibitors of DNA methyltransferase (DNMT) or histone deacetylases (HDACs) such as 5-Aza-CdR and FK228 has shown to enhance cytotoxic activities of several anticancer agents. This study aims to assess the combinatorial effects of gene-silencing reversal agents (5-Aza-CdR and FK228) and oxaliplatin in gastric cancer cells, i.e., Epstein-Barr virus (EBV)-negative SNU-638 and EBV-positive SNU-719 cells. The doublet combinatorial treatment of 5-Aza-CdR and FK228 exhibited synergistic effects in both cell lines, and this was further corroborated by Zta expression induction in SNU-719 cells. Three drug combinations as 5-Aza-CdR/FK228 followed by oxaliplatin, however, resulted in antagonistic effects in both cell lines. Simultaneous treatment with FK228 and oxaliplatin induced synergistic and additive effects in SNU-638 and SNU-719 cells, respectively. Three drug combinations as 5-Aza-CdR prior to FK228/oxaliplatin, however, again resulted in antagonistic effects in both cell lines. This work demonstrated that efficacy of doublet synergistic combination using DNMT or HDACs inhibitors can be compromised by adding the third drug in pre- or post-treatment approach in gastric cancer cells. This implies that the development of clinical trial protocols for triplet combinations using gene-silencing reversal agents should be carefully evaluated in light of their potential antagonistic effects.
Keywords: Combinatorial index, EBV, Zta, Synergism, Antagonism


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