RAD51 potentiates synergistic effects of chemotherapy with PCI-24781 and cis-diamminedichloroplatinum on gastric cancer.

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.

• Authors: 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
• Journal: World journal of gastroenterology (World J Gastroenterol) Vol. 20 Issue 29 Pg. 10094-107 (Aug 07 2014) ISSN: 2219-2840 [Electronic] United States
• PMID: 25110436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzofurans
• E2F4 Transcription Factor
• E2F4 protein, human
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• RAD51 protein, human
• Rad51 Recombinase
• abexinostat
• Cisplatin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzofurans (administration & dosage)
• Binding Sites
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (administration & dosage)
• Dose-Response Relationship, Drug
• Drug Synergism
• E2F4 Transcription Factor (metabolism)
• Female
• Histone Deacetylase Inhibitors (administration & dosage)
• Humans
• Hydroxamic Acids (administration & dosage)
• Mice, SCID
• Promoter Regions, Genetic
• Rad51 Recombinase (genetics, metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy, genetics, metabolism, pathology)
• Time Factors
• Transfection
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays