Abstract #5115: Selective Cyclooxygenase Inhibitors Increase Paclitaxel Sensitivity of Taxane-Resistant Ovarian Cancer Cell Lines via Suppression of p-glycoprotein Expression

Ovarian cancers usually develop chemoresistance after prolonged exposure to chemotherapeutic drugs, such as paclitaxel. Drug resistance is mainly developed via overexpression of p-glycoprotein encoded by multi-drug resistance 1 (MDR1) which effluxes various cytotoxic drugs and inhibit their accumulation within the cell. The expression of MDR1 was shown to be regulated by cyclooxygenase-2 (COX-2), a rate limiting enzyme of prostaglandin (PG) biosynthesis, which plays important roles in tumor development and progression in various human cancers. Thus, we have investigated whether a selective COX-2 inhibitor (NS398) attenuates the expression levels of MDR1 in taxane-resistant human ovarian cancer cell lines (HeyA8-MDR and SKOV3ip2-TR), leading to increased sensitivity to paclitaxel. MTT assay, flow cytometry analyses, Rhodamine 123 efflux assay, Western blotting and realtime RT-PCR were performed. Single treatments of paclitaxel or selective COX inhibitors did not significantly reduce cell viability of HeyA8-MDR and SKOV3ip2-TR. However, combination treatments of paclitaxel with NS398 or even with a selective COX-1 inhibitor (SC560) significantly enhanced paclitaxel sensitivity resulting in increased apoptosis of both cell lines expressing COX-2, but not COX-1. Increased apoptosis in cells treated with paclitaxel and SC560 suggests that COX inhibitor-induced increased sensitivity to paclitaxel in taxane-resistant ovarian cancer cells is PG independent. It is consistent with the result that the addition of PGE 2 did not reverse the synergistic effects of SC560 or NS398 with paclitaxel on cell viability. While selective COX inhibitors did not affect survival of these cell lines, Western blotting and realtime RT-PCR showed that they significantly reduced highly maintained basal levels of MDR1 mRNA and p-glycoprotein, respectively. Furthermore, in combination treatment with paclitaxel, both NS398 and SC560 significantly suppressed paclitaxel-induced overexpression of p-glycoprotein. In conclusion, our results suggest that COX inhibitors could be a potent therapeutic tool to promote paclitaxel sensitization of taxane-resistant ovarian cancer via suppression of p-glycoprotein which mainly contributes efflux of chemotherapeutic agents. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5115.