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Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells
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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Korean Society of Applied Pharmacology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254647/ https://www.ncbi.nlm.nih.gov/pubmed/30173503 http://dx.doi.org/10.4062/biomolther.2018.061 |
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author | Park, Jong Kook Seo, Jung Seon Lee, Suk Kyeong Chan, Kenneth K Kuh, Hyo-Jeong |
author_facet | Park, Jong Kook Seo, Jung Seon Lee, Suk Kyeong Chan, Kenneth K Kuh, Hyo-Jeong |
author_sort | Park, Jong Kook |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6254647 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Korean Society of Applied Pharmacology |
record_format | MEDLINE/PubMed |
spelling | pubmed-62546472018-11-27 Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells Park, Jong Kook Seo, Jung Seon Lee, Suk Kyeong Chan, Kenneth K Kuh, Hyo-Jeong Biomol Ther (Seoul) Original Article 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. The Korean Society of Applied Pharmacology 2018-11 2018-09-03 /pmc/articles/PMC6254647/ /pubmed/30173503 http://dx.doi.org/10.4062/biomolther.2018.061 Text en Copyright ©2018, The Korean Society of Applied Pharmacology http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Park, Jong Kook Seo, Jung Seon Lee, Suk Kyeong Chan, Kenneth K Kuh, Hyo-Jeong Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells |
title | Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells |
title_full | Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells |
title_fullStr | Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells |
title_full_unstemmed | Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells |
title_short | Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells |
title_sort | combinatorial antitumor activity of oxaliplatin with epigenetic modifying agents, 5-aza-cdr and fk228, in human gastric cancer cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254647/ https://www.ncbi.nlm.nih.gov/pubmed/30173503 http://dx.doi.org/10.4062/biomolther.2018.061 |
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