Celecoxib enhanced the cytotoxic effect of cisplatin in drug-resistant human gastric cancer cells by inhibition of cyclooxygenase-2

Recently studies indicated that cyclooxygenase-2 might induce P-glycoprotein expression, and was involved in the development of drug resistance phenotype in human gastric cancer cells. The present study was to explore the correlation of celecoxib, a cyclooxygenase-2 specific inhibitor, and P-glycoprotein in drug-resistant gastric cancer cells. The results showed the over-expression of cyclooxygenase-2 and P-glycoprotein in cisplatin-resistant gastric cancer SGC-7901 cells (SGC-7901/DDP), suggesting the possible involvement of cyclooxygenase-2 in the development of P-glycoprotein-mediated drug resistance. Celecoxib was more effective in SGC-7901/DDP cells with a lower inhibitory concentration compared to that in SGC-7901 cells, supporting such a cyclooxygenase-2-dependent drug resistance in SGC-7901/DDP cells. Further studies revealed down-regulation of cyclooxygenase-2 and P-glycoprotein expression by celecoxib, and a decline in prostaglandin E2 release and protein kinase A level. Celecoxib-induced apoptosis of SGC-7901/DDP cells led to increased p53 expression, decreased Bcl-2/Bax ratio and up-regulated caspase-3 level. Also, celecoxib induced apoptosis in SGC-7901/DDP cells synergistically with cisplatin. Our study suggested that celecoxib might enhance the cytotoxic effect of chemotherapeutic agents in drug-resistant human gastric cancer cells through a cyclooxygenase-2-dependent manner.