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©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 14, 2020; 26(6): 598-613
Published online Feb 14, 2020. doi: 10.3748/wjg.v26.i6.598
Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer
Ramchandra Vigay Amnekar, Shafqat Ali Khan, Mudasir Rashid, Bharat Khade, Rahul Thorat, Poonam Gera, Shailesh V Shrikhande, Duane T Smoot, Hassan Ashktorab, Sanjay Gupta
Ramchandra Vigay Amnekar, Mudasir Rashid, Bharat Khade, Sanjay Gupta, Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
Ramchandra Vigay Amnekar, Mudasir Rashid, Sanjay Gupta, Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra 400085, India
Shafqat Ali Khan, Department of Developmental Biology, School of Medicine, Washington University in St. Louis, Saint Louis, MO 63130, United States
Rahul Thorat, Animal House Facility, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
Poonam Gera, Biorepository Lab, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra 410210, India
Shailesh V Shrikhande, Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai 400012, India
Duane T Smoot, Department of Medicine, Meharry Medical Center, Nashville, TN 37208, United States
Hassan Ashktorab, Department of Medicine and Cancer Center, College of Medicine, Howard University, Washington DC, WA 20060, United States
Author contributions: Gupta S conceived the idea, designed the experiments, and edited the manuscript; Amnekar RV and Khan SA designed the experiments, performed the experiments, analyzed the data, and wrote the manuscript, they contributed equally to the work; Rashid M performed RT-PCR and TCGA data analysis; Khade B performed histone deacetylase and histone acetyltransferase assay; Thorat R and Khade B performed the animal experiments; Smoot DT and Ashktorab H provided the HFE145 cell line; Gera P performed the histopathology analysis; Shrikhande SV provided the tissue samples and clinical data; The paper was critically read by all the authors and approved for publication.
Supported by TMH-IRG (account number - 466/2012 and 164/2016); LTMT grant for project funding and ACTREC-TMC for funding to Gupta lab; Tumor Tissue Repository-ACTREC; and TTR-TMH-Indian Council Medical Research for providing tissue samples. Amnekar RV and Rashid M were supported by ACTREC fellowships.
Institutional review board statement: The study was reviewed and approved by the Institutional Animal Ethics Committee in Kharghar, Navi Mumbai, India.
Institutional animal care and use committee statement: All institutional and national guidelines for the care and use of laboratory animals were followed.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The ARRIVE guidelines have been adopted. In vivo animal work has been carried out considering the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Sanjay Gupta, PhD, Principal Investigator, Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra 410210, India. sgupta@actrec.gov.in
Received: October 15, 2019
Peer-review started: October 15, 2019
First decision: December 4, 2019
Revised: December 20, 2019
Accepted: January 15, 2020
Article in press: January 15, 2020
Published online: February 14, 2020
ARTICLE HIGHLIGHTS
Research background
Alterations of the epigenome play an important role during the process of gastric carcinogenesis. Therefore, drugs like histone deacetylase inhibitors (HDACi) are being explored for their anti-tumor activity.
Research motivation
Identify alterations in the epigenetic milieu of gastric cancer, and check whether the concomitant usage of HDACi with chemotherapeutic drugs increases the drug’s efficacy.
Research objectives
This study aimed to reveal the most optimal combination of chemotherapeutic drugs, as well as HDACi type, dose and regime (pre, post and concurrent). The biochemical mechanism of action was investigated, and the combination was tested in an in vivo system.
Research methods
This study utilized paired gastric cancer human samples, along with the gastric adenocarcinoma cell line AGS and immortalized normal counterpart HFE145. The efficacy of several chemotherapeutic agents and HDACi was tested in the AGS cell line, and the final combination was tested in an animal model of gastric cancer.
Research results
Gastric cancer patients showed differential HDAC activity and levels. Furthermore, pretreatment of valproic acid followed by cisplatin favors an open chromatin conformation via increased histone acetylation. These changes increase the binding of cisplatin to DNA at lower concentrations. In vivo studies suggest a better response with pretreatment regimes that do not cause toxicity.
Research conclusions
This study described that decreased histone acetylation in human gastric cancer tumor samples may be attributed to differential/elevated histone deacetylase activity and expression. Additionally, pre-treatment with HDACi was the most optimal regime that maximally enhanced the cell killing potential of chemotherapeutic drugs. This was achieved by increased intercalation of the drug in chromatin post-HDACi treatment. The pre-treatment of HDACi valproic acid and cisplatin was able to decrease tumor volume in vivo compared to cisplatin alone.
Research perspectives
This pre-clinical study provides evidence that pre-treatment of HDACi followed by standard chemotherapeutic agents enhances the effectiveness of the drug. Hence, clinical testing of such combinations may be explored for better management of gastric cancer.
