Enhanced Inhibitory Effect of Meloxicam, A Cyclooxygenase-2 Inhibitor Combined with Cisplatin on the Growth of Human Ovarian Cancers

Abstract

Cyclooxygenase-2 (COX-2) inhibitors are regarded as potentially important for cancer treatment and some reports have demonstrated that combination of COX-2 inhibitors and other anticancer drugs may produce additive or synergistic activity in the treatment of some human cancers. In this study, we investigated the effects of combination of meloxicam, a selective COX-2 inhibitor, and cisplatin (CDDP), a platinum-type drug, on growth of epithelial ovarian cancer (EOC) cells as well as xenografted tumors derived from EOC cells and evaluated the ability of this combining treatment on cell proliferation, apoptosis, prostaglandin E2 level and angiogenesis. While proliferation of HTOA cells did not change in CDDP alone at a concentration between 0.005-0.5 μg/mL, it was significantly decreased by combination meloxicam and CDDP in a dose-dependent manner of CDDP. Meloxicam alone, CDDP alone or their combination significantly suppressed the growth of OVCAR-3 tumors xenographted subcutaneously and prolonged the survival of mice with malignant ascites derived from DISS cells as compared to control. Combination of meloxicam and CDDP decreased the expression of COX-2, microsomal prostaglandin E synthase and prostaglandin receptor-3 in tumors. Their combination significantly decreased prostaglandin E2 and vascular endothelial growth factor in serum as well as in ascites, and significantly reduced microvessel density and induced apoptosis in tumors. In conclusion, these results indicate that combination of meloxicam and CDDP may produce at least additive antitumor activity in the treatment of EOC. The inhibitory effect of their combination on growth of EOC suggests a potential to lead a novel therapeutic strategy against EOC.