The effects of combining docetaxel and cyclooxygenase-2 inhibitors on proliferation and apoptosis in epithelial ovarian cancer.
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.
Munkarah
Adnan R
AR
Wayne State University School of Medicine, Detroit, Michigan, USA. amunkara@med.wayne.edu
Ali-Fehmi
Rouba
R
Jiang
John Z
JZ
Elhammady
Eslam
E
Malone
John M
JM
Saed
Ghassan M
GM
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D017931:DNA Primers; D000077143:Docetaxel; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D009578:Nitrobenzenes / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D017931:DNA Primers; D009578:Nitrobenzenes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013449:Sulfonamides; D043823:Taxoids; D051028:bcl-2-Associated X Protein; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000077143:Docetaxel; D051546:Cyclooxygenase 2