Dimethyl celecoxib as a novel non-cyclooxygenase 2 therapy in the treatment of non-small cell lung cancer

Objectives: The cyclooxygenase 2 enzyme has become a therapeutic target in cancer treatment. Cyclooxygenase 2 blockade with selective inhibitors increases apoptosis and decreases the metastatic potential of lung cancer cells. Some of the antitumor effects of these inhibitors may occur through both cyclooxygenase 2-dependent and independent pathways. Our goal was to investigate these pathways using celecoxib (selective cyclooxygenase 2 inhibitor) and 2,5-dimethyl celecoxib, a structural analog modified to eliminate cyclooxygenase 2 inhibitory activity, while potentially maintaining antineoplastic properties. Methods: 2,5-Dimethyl celecoxib was synthesized in the Department of Chemistry at the University of Southern California. With the use of non-small cell lung cancer cells (A549), prosta-landin E, production was quantified by enzyme-linked immunosorbent assay to assess cyclooxygenase 2 activity. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay. Cell migration was performed using transwell inserts that were matrigel coated for invasion experiments. Gelatin zymography was used to assess matrix-metalloproteinase activity. Results: 2,5-Dimethyl celecoxib did not inhibit interleukin-1 beta-stimulated prostaglandin E-2 production, whereas celecoxib did even at low doses. Both celecoxib and 2,5-dimethyl celecoxib decreased tumor cell viability and proliferation with IC50 for celecoxib and 2,5-dimethyl celecoxib of 73 and 53 mu mol/L, respectively. Both drugs were also potent inducers of apoptosis, and both inhibited tumor cell migration and invasion. This was associated with down-regulation of matrix metal loproteinase activity. Conclusions: 2,5-Dimethyl celecoxib is a structural analog of celecoxib that lacks cyclooxygenase 2 inhibitory activity but exhibits significant antineoplastic properties comparable to celecoxib. This suggests that the antineoplastic activities of celecoxib are, at least in part, cyclooxygenase independent and that therapeutic strategies can be developed without the side effects of global cyclooxygenase 2 blockade.