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J Thorac Cardiovasc Surg 2005;130:1406-1412
© 2005 The American Association for Thoracic Surgery

General Thoracic Surgery

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

^a Department of Cardiothoracic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, Calif
^b Department of Chemistry, University of Southern California, Los Angeles, Calif
^c Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.

Read at the Eighty-fifth Annual Meeting of The American Association for Thoracic Surgery, San Francisco, Calif, April 10-13, 2005.

Received for publication April 14, 2005; revisions received June 9, 2005; accepted for publication July 19, 2005.

^_* Address for reprints: Ross M. Bremner MD, PhD, Department of Cardiothoracic Surgery, Keck School of Medicine, 1520 San Pablo St, Suite 4300, Los Angeles, CA 90033 (Email: rbremner{at}surgery.usc.edu).

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), prostaglandin E₂ 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-1ß–stimulated prostaglandin E₂ 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 µmol/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 metalloproteinase 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.

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