title: Celecoxib enhanced the cytotoxic effect of cisplatin in drug-resistant human gastric cancer cells by inhibition of cyclooxygenase-2.
abstract: 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.
authors.affiliation: Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Shen
authors.affiliation: Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: lv.qianzhou@zs-hospital.sh.cn.
authors.forename: Qian-Zhou
authors.initials: QZ
authors.lastname: Lv
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D000068579:Celecoxib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3; D000068579:Celecoxib; D015232:Dinoprostone; D002945:Cisplatin
keywords: Celecoxib; Cyclooxygenase-2; Gastric cancer; P-glycoprotein