Celecoxib Antagonizes the Cytotoxicity of Cisplatin in Human Esophageal Squamous Cell Carcinoma Cells by Reducing Intracellular Cisplatin Accumulation

Abstract

High cyclooxygenase 2 (COX-2) expression has been reported to be clinically associated with reduced cisplatin-based therapy efficacy in esophageal cancer. However, the benefit of including COX-2-selective inhibitors in therapeutic regimens remains uncertain. Thus, we sought to determine the effects of COX inhibitors on the cytotoxicity of cisplatin and to further explore the mechanism involved in human esophageal squamous cell carcinoma cells. Among the four tested COX inhibitors [celecoxib, 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-236), nimesulide, and indomethacin], all of which substantially suppressed prostaglandin E(2) production to a similar extent; only the COX-2-selective inhibitors celecoxib and SC-236 antagonized cisplatin-induced cytotoxicity and apoptosis in both cisplatin-resistant cells and their wild-type counterparts. Knockdown of COX-2 by small interference RNA failed to mimic the antagonizing effects of celecoxib and SC-236, implying that their action is COX-2-independent. Further mechanistic analysis revealed that the antagonizing effect of celecoxib and SC-236 on cytotoxic action of cisplatin was associated with decreased whole-cell cisplatin accumulation and DNA platination. Reduced influx, accompanied by the reduction of protein level of copper transporter 1, accounts for decreased intracellular cisplatin accumulation. In addition, combined treatment did not elicit greater antitumor activity than cisplatin or celecoxib monotherapy in vivo in an esophageal cancer xenograft model. Collectively, these data demonstrate that celecoxib antagonizes the cytotoxicity of cisplatin by decreasing intracellular cisplatin and DNA platination. The combination treatment also shows no beneficial effect compared with cisplatin or celecoxib monotherapy in vivo. Therefore, current clinical trials with celecoxib in combination with cisplatin should be approached with caution.