Tilmacoxib

Background: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the production of prostaglandins and its inhibitors have been shown to induce apoptosis in a variety of cancer cells. We reasoned that combination treatment of renal cell carcinoma (RCC) cells with COX-2 inhibitors and anticancer agents may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 synergizes with anticancer agents in cytotoxicity and apoptosis against RCC cells. Methods: The cytotoxicity of the selective COX-2 inhibitor JTE-522 and other anticancer agents against the RCC cell lines and the normal renal cell line was determined by the microculture tetrazolium dye assay. Results: JTE-522 was cytotoxic against the Caki-1 RCC cell line. JTE-522 and anti-Fas monoclonal antibody (CH-11) exhibited a synergistic cytotoxic effect against Caki-1 cells. In contrast, JTE-522 in combination with 5-fluorouracil, adriamycin, cis-diamminedichloroplatinum, or interferon-α, all commonly used clinically, resulted in an additive cytotoxic effect. Synergy achieved in cytotoxicity with JTE-522 and CH-11 was shown to be due to apoptosis. Conclusions: The present study demonstrated that the selective COX-2 inhibitor JTE-522 had a cytotoxic effect on RCC and that synergistic cytotoxicity against RCC was obtained with JTE-522 in combination with anti-Fas monoclonal antibody. These results suggest that selective COX-2 inhibitors in combination with immunotherapy may be useful in treating patients with RCC.

We have reported G1 progression and cyclooxygenase-2 (COX-2) induction during carcinogenesis of the squamous epithelium of the esophagus. As bile acid induces COX-2 expression and promotes carcinogenesis in the digestive tract, we investigated the effect of bile acid on the proliferation of squamous cell carcinoma of the esophagus (ESCC).

MTT assay, Western blot analysis of COX-2 and cell cycle-related molecules in the G1 phase (Rb, CDC25A, cyclin D1), and CDK2 kinase assay were performed on chenodeoxycholic acid (CDCA) exposure to ESCC cell lines (TE2R, TE3, TE13, TE15).

In the presence of gradient bile acid concentration (up to 100 microm), growth of ESCC cell lines was stimulated at a low concentration (maximally at 20-30 microm), but suppressed at a higher concentration. Only a low dose of bile acid induced the expression of cyclin D1 and CDC25A and showed high Rb phosphorylation and high CDK2 kinase activity. In contrast, bile acid progressively induced COX-2 expression in a dose-dependent manner, regardless of its biphasic effects on cell proliferation, and a COX-2 specific inhibitor (JTE-522) did not suppress growth stimulation by a low dose of bile acid.

Bile acid at a low dose stimulates the proliferation of ESCC by inducing G1-regulating molecules. However, COX-2 expression, which is also induced by bile acid, does not affect cell proliferation. Further work is needed to elucidate its role in carcinogenesis.