The cyclooxygenase 2-selective inhibitor NS398 inhibits proliferation of oral carcinoma cell lines by mechanisms dependent and independent of reduced prostaglandin E2 synthesis

Helena A Minter, John W Eveson, Suzanne Huntley, Douglas J E Elder, Angela Hague
Clinical Cancer Research 2003, 9 (5): 1885-97

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 micro M and above resulted in growth inhibition accompanied by a reversible G(0)-G(1) arrest, but no apoptosis or terminal differentiation. However, a concentration of 10 micro M was sufficient to abolish secreted prostaglandin E(2) (PGE(2)) 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 micro M NS398 as well as 100 micro M NS398 for 6-12 days. In cultures treated with 5 micro M NS398, but not in those treated with 100 micro M NS398, restoration of PGE(2) to control levels abrogated growth inhibition.

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

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