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The Cyclooxygenase 2-selective Inhibitor NS398 Inhibits Proliferation of Oral Carcinoma Cell Lines by Mechanisms Dependent and Independent of Reduced Prostaglandin E₂ Synthesis¹

Department of Oral and Dental Science, University of Bristol, Bristol BS1 2LY, United Kingdom [H. A. M., J. W. E., S. H., A. H.], and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom [D. J. E. E.]

Purpose: We investigated the potential of cyclooxygenase (COX)-2 as anappropriate chemopreventive and/or therapeutic target for oral cancer.

Experimental Design: Immunohistochemical analysis of COX-2 expression was carried out on 37 oral squamous cell carcinomas (OSCCs) and 23 normal oral epithelium samples. We investigated whether the COX-2-selective inhibitor NS398 induced growth inhibition in four human OSCC cell lines and whether this was COX-2 dependent.

Results: COX-2 staining was more intense in the carcinomas compared with normal epithelium (P < 0.001). Early-stage tumors (stages I and II) had significantly higher epithelial COX-2 staining than late-stage tumors (stages III and IV; P = 0.034), and overexpression of COX-2 was detected in hyperplastic and dysplastic epithelium. Treatment of OSCC cells with NS398 for 72 h at concentrations of 50 µM and above resulted in growth inhibition accompanied by a reversible G₀-G₁ arrest, but no apoptosis or terminal differentiation. However, a concentration of 10 µM was sufficient to abolish secreted prostaglandin E₂ (PGE₂) production. Over a longer treatment time, lower concentrations of NS398 were growth inhibitory. Growth inhibition of the OSCC cell line H357 was detected after treatment with 5 µM NS398 as well as 100 µM NS398 for 6–12 days. In cultures treated with 5 µM NS398, but not in those treated with 100 µM NS398, restoration of PGE₂ to control levels abrogated growth inhibition.

Conclusions: NS398 inhibits the growth of OSCC cells by mechanisms that are dependent and independent of suppression of PGE₂ synthesis. Molecular targeting of COX-2, PGE₂ synthase, or PGE₂ receptors may be useful as a chemopreventive or therapeutic strategy for oral cancer.

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