Inhibition of paclitaxel-induced apoptosis by the specific COX-2 inhibitor, NS398, in epithelial ovarian cancer cells.
OBJECTIVE
In vitro studies have revealed that treatment of various human cancer cell lines with specific cyclo-oxygenase 2 (COX-2) inhibitors induces apoptotic cell death. It is currently proposed that the combination of COX-2 inhibitors with chemotherapeutic agents improves the efficacy of cancer treatment.


METHODS
In this study we sought to determine the effects of combining paclitaxel and the COX-2 inhibitor NS398 on apoptosis of epithelial ovarian cancer (EOC) cells. Two EOC cell lines, SKOV3 and MDAH2774, were exposed to increasing concentrations of paclitaxel (0.1, 10, and 100 microM) and NS398 (10, 100 microM) as well as a combination of both drugs. Apoptosis was evaluated by the Tunel assay. The fluorescein-labeled DNA was visualized directly by fluorescence microscopy and quantitated by flow cytometry.


RESULTS
While NS398 did not significantly alter apoptosis of either EOC cell lines after 24 h of continuous exposure, treatment of both cell lines with paclitaxel resulted in a significant increase in the rate of apoptosis (60-70%). Concomitant treatment of both SKOV3 and MDAH2774 cells with paclitaxel and NS398 resulted in marked impairment of paclitaxel-induced apoptosis. Similarly, sequential treatment during which both cell lines were treated with NS398 for 4 h, triple-washed, and then exposed to paclitaxel for 24 h resulted in a significant inhibition of paclitaxel-induced apoptosis. Similar inhibition was seen when NS398 was replaced by aspirin.


CONCLUSIONS
Combining COX-2 inhibitors and paclitaxel does not have an additive or synergistic tumoricidal effect. On the contrary, NS398 treatment markedly inhibited the apoptotic effects of paclitaxel in each of these two EOC cell lines.
Munkarah
A R
AR
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wayne State University, Detroit, MI, USA. amunkara@med.wayne.edu
Genhai
Z
Z
Morris
R
R
Baker
V V
VV
Deppe
G
G
Diamond
M P
MP
Saed
G M
GM
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017239:Paclitaxel; D001241:Aspirin