Inhibition of COX-2 and induction of apoptosis: Two determinants of nonsteroidal anti-inflammatory drugs' chemopreventive efficacies in mouse lung tumorigenesis

Recent studies suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit lung tumorigenesis under conditions that are immunosuppressive. We hypothesized that this inhibition of mouse lung tumorigenesis requires ind uction of apoptosis and inhibition of COX (cyclooxygenase)-1, COX-2, and th e incidence of K-ras mutation. The NSAIDs used in this study include acetyl salicylic acid (ASA) that is anti-inflammatory with COX-1 and COX-2 inhibit ion and N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398) that is a specific COX-2 inhibitor. We have previously demonstrated that ASA (1 47 and 294 mg/kg diet) and NS398 (7 mg/kg diet) inhibited lung tumorigenesi s by 31%, 44%, and 34%, respectively, in 4-(methylnitrosamino)-1-(3-pyridyl )-1-butanone (NNK)-treated A/J mice. No difference in the incidence and typ es of K-ras mutations was found between the lung tumors treated with NNK an d those treated with NNK/ASA and NNK/NS398. In NNK-treated mice, ASA (294 m g/kg diet) or NS398 significantly increased the apoptotic index, from 0.07 to 0.30 or to 0.33, respectively. ASA (294 mg/kg diet) and NS398 also inhib ited the expression of COX-2. Finally, modulation of gene expression by NS3 98 and ASA (294 mg/kg diet) was determined using Atlas cDNA expression arra ys. Expression of cyclin B2 was decreased and expression of Fas-L and BAD w ere increased in lung tissues treated with both NS398 and ASA. Treatment wi th NS398 also increased expression of p57(kip2) and myosin. These genes mod ulated bg NSAIDs may play a rot in mediating the observed chemopreventive e ffects of the NSAIDs in the mouse lung. Our results demonstrate that lung t umor prevention with NSAIDs involve both the induction of apoptosis and the inhibition of COX-2 expression.