S-1 And Cyclooxygenase-2 Inhibitor, Celecoxib Synergistically Induce Apoptosis In Pancreatic Cancer Cells In Vitro And In Vivo

Pancreatic adenocarcinoma(PADC) is one of the most common cancers, and it also is a short pathogenesis, rapid development and highly lethal disease. S-1 and celecoxib synergistically increased apoptosis in PC, and it may offer a novel role with important implications in designing new therapeutics for anti-tumor effects.Objectives: This study aimed to investigate the effects and mechanisms of S-1 and cyclooxygenase-2 inhibitor, celecoxib synergistically induce apoptosis induce in PCs.Methods: We analyzed the combined effect of S-1 and a COX-2 inhibitor, celecoxib, on in vitro growth suppression of PC using the PC cell lines PANC-1 and the in vivo nude mouse xenotransplantation model using PANC-1 cells. Treatment with S-1 and celecoxib synergistically inhibited cell proliferation in a dose- and time-dependent manner. By MTT assay effects of drugs on the proliferation of pancreatic cancer cells to assess the effect of combination therapy. Using Western blotting to assay the expression of Survivin protein, Bcl-2 protein, Caspase-3 protein, BAX protein and PARP protein. Apoptosis was identified by 4’, 6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. The combined regimen with S-1 and celecoxib reduced the growth of xenotransplanted PCs in nude mice, by immunohistochemistry assay the expression of Survivin in each group.Results: Proliferation assay and flow cytometry demonstrated S-1 and celecoxib dose-dependent inhibitory effect and determined its induction of cells apoptosis, respectively. Wounding heal assay and cell matrix adhesion assay showed that S-1 and celecoxib significantly inhibited the abilities of the invasion, migration and adhesion of the PANC-1 cells. Moreover, quantitative real time PCR and Western blot analysis found that S-1 and celecoxib increased Bax expression while reduced Bcl-2 and Survivin expressions and significantly activated caspase-3.Conclusions: S-1 and celecoxib synergistically inhibits the growth of the PC cell lines PANC-1.The mechanism of induced the apoptosis may be related to it inhibits the expression of anti-apoptotic proteins such as Survivin and Bcl-2,and inhibits the expression of COX-2. Also it can enhance the expression activation of Caspase-3 protein and stagnate the cell cycle. For further study, we could find that S-1 and celecoxib synergistically inhibits the abilities of invasion, migration and adhesion of the PC cell lines PANC-1.