AIM:To explore the efficacy of PCI-24781,a broadspectrum,hydroxamic acid-derived histone deacetylase inhibitor,in the treatment of gastric cancer(GC).METHODS:With or without treatment of PCI-24781and/or cis-diamminedi...AIM:To explore the efficacy of PCI-24781,a broadspectrum,hydroxamic acid-derived histone deacetylase inhibitor,in the treatment of gastric cancer(GC).METHODS:With or without treatment of PCI-24781and/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 typeⅠ 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.展开更多
基金Supported by National Natural Science Foundation of China,No.30973395,No.81172337,No.31271444 and No.81201726Municipal Medicine Science and Technology Foundation of Guangzhou,No.201102A212012+1 种基金Science and Technology Development Program of Guangdong,No.2012B031800115Science Novel Program of Guangdong Education Department,No.A2003165
文摘AIM:To explore the efficacy of PCI-24781,a broadspectrum,hydroxamic acid-derived histone deacetylase inhibitor,in the treatment of gastric cancer(GC).METHODS:With or without treatment of PCI-24781and/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 typeⅠ 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.
