Effect Of Dual-selective Inhibitor Of EZH1/2 UNC1999 Combined With Paclitaxal In Prostate Cancer

Objective: To study the effect of EZH1/2 inhibitor and Docetaxel(DOC)on prostate cancer cells and whether there is synergistic effect.Methods: PC3 cell lines without endogenous androgen receptors and capable of invasion and metastasis were selected as the research object.The EZH1/2 inhibitor UNC1999 was selected to treat PC3 cells alone or in combination with DOC to observe the changes of cell activity,invasion and apoptosis in different treatment groups.Results: CCK-8 test results showed that DMSO group did not change the cell activity,the activity was 95%;The cell activity was 73% after 24 h and 68% after 48 h of 0.05 mol/L DOC stimulation.The cell activity of UNC1999 was 61% after 24 h and59% after 48 h of 15 mol/L.Compared with DMSO group,DOC and UNC1999 had significant inhibitory effect on PC3 cells at 0.05 mol/L and 15 mol/L,respectively(p<0.01),and DOC had time-dependent tolerance,and the cell activity of 48 h cells was significantly lower than that of 24 h cells(p <0.05).The scratch test showed that DOC or UNC1999 could inhibit the migration of PC3 cells compared with the control group(p <0.01).Compared with DOC or UNC1999 alone,the combined treatment group showed greater cell scratch spacing,suggesting further inhibition of PC3 migration(p<0.05).Flow cytometry showed that the precent of apoptosis was 8.86%,17.37%,25.12%and 36.30% in DMSO group,DOC group,UNC1999 group and combined treatment group,respectively.Compared with the solvent group,single drug could promote the apoptosis of PC3 tumor cells(p <0.05).Compared with the DOC group and UNC1999 group,the early apoptosis of PC3 cells in the combined treatment group was more obvious(p <0.05).Western Blot showed that compared with DMSO group,single DOC or UNC1999 promoted Caspase3 expression,and the increase of Caspase3 expression was more obvious in DOC +UNC1999 group.Compared with DMSO group and DOC group,UNC1999 could reduce the expression level of EZH2.Compared with UNC1999 group,the expression of EZH2 in the combined treatment group was further decreased.Compared with the DOC group,combination therapy increased expression of the protein NECTIN4.Conclusion:DOC and UNC1999 could inhibit the activity and migration of PC3 cells,and combined therapy had synergistic effect.DOC and UNC1999 alone can promote the apoptosis of PC3 cells,and DOC +UNC1999 can further promote the apoptosis of tumor cells by upregulating the expression of apoptotic protein Caspase3.DOC combined with UNC1999 could further inhibit the expression of EZH2.The combination of the two therapies increased the expression of drug-sensitive protein NECTIN4,which may improve the resistance of PC3 cells to DOC.