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

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World Journal of Gastroenterology 2020年第6期26卷 598-613页

作者： Ramchandra Vigay Amnekar Shafqat Ali Khan Mudasir Rashid Bharat Khade Rahul Thorat poonam gera Shailesh V Shrikhande Duane T Smoot Hassan Ashktorab Sanjay Gupta Epigenetics and Chromatin Biology Group Gupta LaboratoryCancer Research InstituteAdvanced Centre for Treatment Research and Education in CancerTata Memorial CentreKhargharNavi MumbaiMaharashtra 410210India Homi Bhabha National Institute Training School ComplexAnushakti NagarMumbaiMaharashtra 400085India Department of Developmental Biology School of MedicineWashington University in St.LouisSaint LouisMO 63130United States Animal House Facility Cancer Research InstituteAdvanced Centre for Treatment Research and Education in CancerTata Memorial CentreKhargharNavi MumbaiMaharashtra 410210India Biorepository Lab Advanced Centre for Treatment Research and Education in CancerTata Memorial CentreKhargharNavi MumbaiMaharashtra 410210India Gastrointestinal and Hepato-Pancreato-Biliary Service Department of Surgical OncologyTata Memorial HospitalParelMumbai 400012India Department of Medicine Meharry Medical CenterNashvilleTN 37208United States Department of Medicine and Cancer Center College of MedicineHoward UniversityWashington DCWA 20060United States

BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic ***,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 *** study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug *** The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and *** potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell *** In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric *** data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle ***-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 *** Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient ***,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.

关键词： Chemotherapy Combinatorial index Gastric cancer Histone acetylation Histone deacetylase inhibitor Patient stratification

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