The effects of combining docetaxel and cyclooxygenase-2 inhibitors on proliferation and apoptosis in epithelial ovarian cancer

Abstract

In-vitro studies have shown that taxanes can upregulate cellular cyclooxygenase-2 expression. The purpose of this study is to evaluate the effects of the combination, cyclooxygenase-2 inhibitor and docetaxel, on epithelial ovarian cancer cells. Four epithelial ovarian cancer cell lines (MDAH-2774, SKOV3, OVCAR and CaOV-3) were treated with the specific cyclooxygenase-2 inhibitor NS398 (10 or 100 mumol/l) and docetaxel (0.1, 1 or 10 mumol/l) in various combinations. Apoptosis in the ovarian cancer cells was assessed using TUNEL assay. Multiplex reverse transcription-PCR was used to determine mRNA levels of cyclooxygenase-2, bcl-2 and bax. Treatment of all epithelial ovarian cancer cells with docetaxel resulted in significant apoptotic death. Concurrent treatment of MDAH-2774, SKOV3 and OVCAR cells with docetaxel and NS398 resulted in the reduction of the taxane-induced apoptosis. Similar reduction was seen when the cells were exposed to NS398 for 4 h before docetaxel treatment. Conversely, treating the MDAH-2774 and SKOV3 cells with docetaxel followed by NS398 resulted in a significant increase in apoptosis compared with treatment with the taxane alone. bax mRNA levels were significantly reduced in SKOV3 cells treated concurrently with NS398 and docetaxel; bcl-2 mRNA levels showed no change. When combining docetaxel and a cyclooxygenase-2 inhibitor in the treatment of ovarian cancer cells, the sequencing of the drugs seems to have an important influence on the overall outcome. Using the cyclooxygenase-2 inhibitor before or concurrently with the taxane will result in a reduction of cellular apoptotic death. This might be due to a reduction in the expression of the proapototic gene bax.