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Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer

BACKGROUND: The prognosis of gastric cancer continues to remain poor, and epigenetic drugs like histone deacetylase inhibitors (HDACi) have been envisaged as potential therapeutic agents. Nevertheless, clinical trials are facing issues with toxicity and efficacy against solid tumors, which may be pa...

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Autores principales: Amnekar, Ramchandra Vigay, Khan, Shafqat Ali, Rashid, Mudasir, Khade, Bharat, Thorat, Rahul, Gera, Poonam, Shrikhande, Shailesh V, Smoot, Duane T, Ashktorab, Hassan, Gupta, Sanjay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Baishideng Publishing Group Inc 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029347/
https://www.ncbi.nlm.nih.gov/pubmed/32103870
http://dx.doi.org/10.3748/wjg.v26.i6.598
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author Amnekar, Ramchandra Vigay
Khan, Shafqat Ali
Rashid, Mudasir
Khade, Bharat
Thorat, Rahul
Gera, Poonam
Shrikhande, Shailesh V
Smoot, Duane T
Ashktorab, Hassan
Gupta, Sanjay
author_facet Amnekar, Ramchandra Vigay
Khan, Shafqat Ali
Rashid, Mudasir
Khade, Bharat
Thorat, Rahul
Gera, Poonam
Shrikhande, Shailesh V
Smoot, Duane T
Ashktorab, Hassan
Gupta, Sanjay
author_sort Amnekar, Ramchandra Vigay
collection PubMed
description BACKGROUND: The prognosis of gastric cancer continues to remain poor, and epigenetic drugs like histone deacetylase inhibitors (HDACi) have been envisaged as potential therapeutic agents. Nevertheless, clinical trials are facing issues with toxicity and efficacy against solid tumors, which may be partly due to the lack of patient stratification for effective treatments. AIM: To study the need of patient stratification before HDACi treatment, and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer. METHODS: The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues. The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays, chromatin remodeling and cell death. RESULTS: In the present study, the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypo-acetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer. The data highlights for the first time that pre-treatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation, chromatin relaxation and cell cycle arrest. Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes, including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin, exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines. CONCLUSION: Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification. Furthermore, HDACi therapy in pre-treatment regimes is more effective with chemotherapy drugs, and may aid in predicting individual patient prognosis.
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spelling pubmed-70293472020-02-26 Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer Amnekar, Ramchandra Vigay Khan, Shafqat Ali Rashid, Mudasir Khade, Bharat Thorat, Rahul Gera, Poonam Shrikhande, Shailesh V Smoot, Duane T Ashktorab, Hassan Gupta, Sanjay World J Gastroenterol Basic Study BACKGROUND: The prognosis of gastric cancer continues to remain poor, and epigenetic drugs like histone deacetylase inhibitors (HDACi) have been envisaged as potential therapeutic agents. Nevertheless, clinical trials are facing issues with toxicity and efficacy against solid tumors, which may be partly due to the lack of patient stratification for effective treatments. AIM: To study the need of patient stratification before HDACi treatment, and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer. METHODS: The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues. The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays, chromatin remodeling and cell death. RESULTS: In the present study, the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypo-acetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer. The data highlights for the first time that pre-treatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation, chromatin relaxation and cell cycle arrest. Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes, including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin, exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines. CONCLUSION: Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification. Furthermore, HDACi therapy in pre-treatment regimes is more effective with chemotherapy drugs, and may aid in predicting individual patient prognosis. Baishideng Publishing Group Inc 2020-02-14 2020-02-14 /pmc/articles/PMC7029347/ /pubmed/32103870 http://dx.doi.org/10.3748/wjg.v26.i6.598 Text en ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved. http://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
spellingShingle Basic Study
Amnekar, Ramchandra Vigay
Khan, Shafqat Ali
Rashid, Mudasir
Khade, Bharat
Thorat, Rahul
Gera, Poonam
Shrikhande, Shailesh V
Smoot, Duane T
Ashktorab, Hassan
Gupta, Sanjay
Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer
title Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer
title_full Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer
title_fullStr Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer
title_full_unstemmed Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer
title_short Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer
title_sort histone deacetylase inhibitor pre-treatment enhances the efficacy of dna-interacting chemotherapeutic drugs in gastric cancer
topic Basic Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029347/
https://www.ncbi.nlm.nih.gov/pubmed/32103870
http://dx.doi.org/10.3748/wjg.v26.i6.598
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