Cyclooxygenase inhibition and hyperthermia for the potentiation of the cytotoxic response in ovarian cancer cells.

Objectives: The progression of chemotherapy-resistant cancer confers poor prognosis and decreases overall survival in ovarian cancer patients. Adjuvants to traditional chemotherapy regimens have become attractive modalities for the clinical treatment of refractory or resistant ovarian cancer. We evaluated whether the addition of NSAID to hyperthermic chemotherapy would increase cytotoxicity in cisplatin- and taxane-treated ovarian cancer cells.

Methods: Western blot analysis was utilized to determine COX-2 protein expression levels in the 2008, cisplatin-sensitive, and C13*, cisplatin-resistant, cell lines. PGE2 levels were determined and analyzed as a function of cyclooxygenase activity by LC/MS/MS. Cells were treated with cisplatin, docetaxel or paclitaxel in combination with either NS-398 or sulindac sulfide at 37 degrees C, 41 degrees C or 43 degrees C. Cell viability was determined by a MTS cell proliferation assay.

Results: Both cell lines expressed COX-2 protein, and NS-398 and sulindac sulfide effectively blocked PGE2 production. The addition of a NSAID to cisplatin treatment in 2008 and C13* cells offered enhanced cytotoxicity and this effect was further enhanced at 41 degrees C. In docetaxel-treated 2008 cells, both NS-398 and sulindac sulfide offered enhanced cell kill; however, this result was not observed in paclitaxel-treated cells. Hyperthermia appeared to play no additional role in taxane cytotoxicity enhancement, however no antagonism was detected.

Conclusions: Our results suggest that the combination treatment (cisplatin or docetaxel in combination with NSAID) cause a dose-dependent enhancement of cytotoxicity. Hyperthermia may improve the results of intraperitoneal cisplatin therapy, thus warranting further evaluation in clinical studies.