Original Article
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World J Gastroenterol. Aug 7, 2014; 20(29): 10094-10107
Published online Aug 7, 2014. doi: 10.3748/wjg.v20.i29.10094
RAD51 potentiates synergistic effects of chemotherapy with PCI-24781 and cis-diamminedichloroplatinum on gastric cancer
Wei-Ling He, Yu-Huang Li, Wei-Jian Hou, Zun-Fu Ke, Xin-Lin Chen, Li-Ya Lu, Shi-Rong Cai, Wu Song, Chang-Hua Zhang, Yu-Long He
Wei-Ling He, Shi-Rong Cai, Wu Song, Chang-Hua Zhang, Yu-Long He, Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
Yu-Huang Li, Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, United States
Wei-Jian Hou, Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
Zun-Fu Ke, Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
Xin-Lin Chen, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou 510006, Guangdong, China
Li-Ya Lu, Public Health, Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8RZ, United Kingdom
Author contributions: He WL and Li YH designed research; He WL, Hou WJ and Zhang CH performed research; Ke ZF, Cai SR and He YL contributed new reagents or analytic tools; Hou WJ, Chen XL and Song W analyzed data; He WL, Li YH and Lu LY wrote the paper; He WL, Li YH and Hou WJ contributed equally to this work.
Supported by National Natural Science Foundation of China, No. 30973395, No. 81172337, No. 31271444 and No. 81201726; Municipal Medicine Science and Technology Foundation of Guangzhou, No. 201102A212012; Science and Technology Development Program of Guangdong, No. 2012B031800115; and Science Novel Program of Guangdong Education Department, No. A2003165
Correspondence to: Yu-Long He, Professor, Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Binjiang Rd, Guangzhou 510080, Guangdong Province, China. hylsums@hotmail.com
Telephone: +86-20-87755766 Fax: +86-20-87331059
Received: December 28, 2013
Revised: January 20, 2014
Accepted: March 6, 2014
Published online: August 7, 2014
Abstract

AIM: To explore the efficacy of PCI-24781, a broad-spectrum, hydroxamic acid-derived histone deacetylase inhibitor, in the treatment of gastric cancer (GC).

METHODS: With or without treatment of PCI-24781 and/or cis-diamminedichloroplatinum (CDDP), GC cell lines were subjected to functional analysis, including cell growth, apoptosis and clonogenic assays. Chromatin immunoprecipitation and luciferase reporter assays were used to determine the interacting molecules and the activity of the enzyme. An in vivo study was carried out in GC xenograft mice. Cell culture-based assays were represented as mean ± SD. ANOVA tests were used to assess differences across groups. All pairwise comparisons between tumor weights among treatment groups were made using the Tukey-Kramer method for multiple comparison adjustment to control experimental-wise type I error rates. Significance was set at P < 0.05.

RESULTS: PCI-24781 significantly reduced the growth of the GC cells, enhanced cell apoptosis and suppressed clonogenicity, and these effects synergized with the effects of CDDP. PCI-24781 modulated the cell cycle and significantly reduced the expression of RAD51, which is related to homologous recombination. Depletion of RAD51 augmented the biological functions of PCI-24781, CDDP and the combination treatment, whereas overexpressing RAD51 had the opposite effects. Increased binding of the transcription suppressor E2F4 on the RAD51 promoter appeared to play a major role in these processes. Furthermore, significant suppression of tumor growth and weight in vivo was obtained following PCI-24781 treatment, which synergized with the anticancer effect of CDDP.

CONCLUSION: These data suggest that RAD51 potentiates the synergistic effects of chemotherapy with PCI-24781 and CDDP on GC.

Keywords: Chemotherapy, Combination, Gastric cancer, Histone deacetylase inhibitor, Homologous recombination

Core tip: This is the first study to show that PCI-24781 synergizes with the chemotherapeutic effect of cis-diamminedichloroplatinum in gastric cancer in vivo and in vitro, and PCI-24781-induced RAD51 repression may be one of the mechanisms. PCI-24781 could be a potential drug and novel therapeutic strategy for the treatment of gastric cancer.