| BACKGROUND &OBJECTIVE: Drug resistance is a major cause of treatment failure in ovarian cancer. Other studies demonstrated that the expression of cylcooxygenase 2 (COX-2) gene is involved in the development and progression of many tumors, and especially in the development of MDR , angiogenesis and invasive potential of cancer cells, et al. Transfection experiments with COX-2 gene showed that enforced expression of the COX-2 may up-regulate expression of MDR1/P-gp. Overexpression of cylcooxygenase 2 (COX-2) and MDR1/P-glycoprotein in patients with ovarian cancer might be related to MDR, drug resistance and poor prognosis in ovarian cancers. Another study indicated that paclitaxel-induced stable COX-2 mRNA expression and upregulation of MDR1 expression in ovarian cancer might be related to paclitxel-resistance. Clinical immunohistochemical analysis of patients with ovarian cancer showed co-expression of cylcooxygenase 2 (COX-2) and MDR1/P-glycoprotein, and related poor prognosis in ovarian cancers. However, there has been no evidence to show that a correlation appears to exist between COX-2 and P-gp regulation in ovrian cancers. Other studies showed that down-regulation of MDR1/P-gp expression by the available COX-2 selective inhibitors was COX-2 independent. The relationship between COX-2 overexpression and development of multidrug resistance of ovarian cancer remains unclear, and no data has been reported until now about the association between COX-2 status and response to paclitaxel containing chemotherapy regimens.The present study aimed to investigate the link between COX-2 and COX-2-dependent MDR1 expression in human ovarian cancer cells, the influence of suppression of COX-2 transcriptional activity on expression of MDR1/P-gp of and the sensitivity of paclitaxel to human ovarian cancer cells. The study may open novel perspectives in the therapy of ovarian carcinoma through avoiding or reversing paclitaxel-induced MDR.METHODS: A2780/PTX cells, a paclitaxel resistant cell line, were treated with quercetin, an inhibitor of COX-2 gene promoter activity, and expression of COX-2 and MDR1 mRNA were determined using Reverse transcription polymerase chain reaction (RT-PCR), and expression of P-glycoprotein (P-gp) was measured by immuocytochemistry and ELISA in A2780/PTX cells, respectively; Growth inhibition of paclitaxel on A2780/PTX cells was determined using MTT assay.RESULTS: Inhibition of COX-2 transcription down-regulated the expression of COX-2 and MDR1 mRNA significantly(P<0.05)with dose- and time-dependent manner in A2780/PTX cells. Pearson's correlation analysis showed that the co-expression relationship exist between COX-2 and MDR1 (R = 0.748, P <0.01).Inhibition of COX-2 transcription decreased protein levels of MDR1(P-gp) significantly in A2780/PTX cells.Growth inhibition of paclitaxel on A2780/PTX cells and the sensitivity of A2780/PTX cells to paclitaxel were significantly enhanced by inhibiting COX-2 transcription. The IC50 values of paclitaxel for A2780/PTX cells treated with quercetin (15μmol/L, 30μmol/L) were 2.114±0.122μmol/L and 0.778±0.037μmol/L, respectively ; and the index of drug resisitance ID(IC50 test/ IC50 contl) were 0.64 and 0.24 with decreased by 1.56- and 4.17-fold,respectively, compared with the control(P<0.05).CONCLUSION: Our findings showed that MDR1/P-gp overexpression of A2780/PTX cells might be COX-2 dependent and a causal link exist between COX-2 and MDR1/P-gp in A2780/PTX cells. Inhibition of COX-2 transcriptional activity could down-regulate the expression of MDR1 mRNA greatly and enhance the sensitivity of A2780/PTX cells to paclitaxel. Taken together, our study suggested that COX-2 gene may be an important target gene for COX-2-dependent MDR1/P-gp overexpression in paclitaxel-resistant ovarian carcinoma. Down-regulation of MDR1/P-gp by suppression of COX-2 transcriptional activity might avoid or reverse paclitaxel-induced MDR and improve the efficacy of treatment with paclitaxel in ovarian carcinoma.
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