Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes

There art! about 600 million betel quid (BQ) chewers in the world. BQ chewi ng is associated with increased incidence of oral cancer and submucous fibr osis, ill this study, areca nut (AN) extract (200-800 mu g/ml) induced the prostaglandin E-2 (PCE2) production by 1.4-3.4-fold and 6-keto-PGF(1 alpha) production by 1.1-1.7-fold of gingival keratinocytes (GK), respectively, F ollowing 24 h of exposure. Exposure of GK to AN extract (>400 mu g/ml) led to cell retraction and intracellular vacuoles formation. At concentrations of 800 and 1200 mu g/ml, AN extract induced cell death at 21-24 and 32-52 % as detected by MTT assay and cellular lactate dehydrogenase release, respe ctively. Interestingly, AN-induced morphological changes of GK are reversib le, GK can still proliferate following exposure to AN extract. Cytotoxicity of AN extract cannot be inhibited by indomethacin (1 mu M) and aspirin (50 mu M), indicating that prostaglandin (PG) production is not the major fact or responsible for AN cytotoxicity, PGE(2) exhibited little effect on the g rowth of GK at concentrations ranging from 100-1000 pg/ml. Stimulating GK p roduction of PGs by AN extract could be due to induction of cycloosygenase- 2 (COX-2) mRNA expression and protein production. These results suggest tha t AN ingredients are critical in the pathogenesis of oral submucous fibrosi s and oral cancer via their stimulatory effects on the PGs, COX-2 productio n and associated tissue inflammatory responses, AN cytotoxicity to CK is no t directly mediated by COX-2 stimulation and PG production.