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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
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.
Core tip: Our study suggests that pre-treatment with histone deacetylase inhibitors (HDACi) in a pre-clinical model of gastric cancer increases acetylation, opens chromatin and favors synergistic binding of DNA-interacting chemotherapeutic drugs. This enhances the cytotoxic potential of chemotherapeutic drugs at low therapeutic doses, and reduces toxicity. The dose response studies using Fa plots and median curve analysis proposes valproic acid as the most synergistic and effective HDACi in combination with platinum-based drugs. Furthermore, HDAC expression, or activity-based patient stratification prior to HDACi therapy, has been put forth for better clinical outcomes of chemotherapeutic drugs in solid tumors.
