The cyclooxygenase 2-selective inhibitor NS398 inhibits proliferation of oral carcinoma cell lines by mechanisms dependent and independent of reduced prostaglandin E2 synthesis.
OBJECTIVE
We investigated the potential of cyclooxygenase (COX)-2 as anappropriate chemopreventive and/or therapeutic target for oral cancer.


METHODS
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.
Minter
Helena A
HA
Department of Oral and Dental Science, University of Bristol, United Kingdom.
Eveson
John W
JW
Huntley
Suzanne
S
Elder
Douglas J E
DJ
Hague
Angela
A
D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology / Q000473:pathology; D008565:Membrane Proteins; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone