Tp53-dependentpati'ern of Cdkn2a/arfpathway Inactivation

Acetylsalicylic acid (ASA) is known to prevent cancer development, but its mechanism of action remains unclear. In this study, we compared the efTicacies of this nonspecific cyclooxygenase (COX) inhibitor with N-[2(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), a specific COX-2 inhibitor. COX-2-specificinhibitors are less toxic than ASA. Lung tumorigenesis was induced in A/J mice by the administration of the tobacco-specific nitrosamine 4-(methyinitrosamino)-l-(3-pyridyl)-1butanone (NNK) in the drinking water for 7 weeks (weeks 0 to +7). Groups of 25 A/i mice were fed ASA (588, 294, 147, or 73 mg/kg diet) before and throughout the assay (weeks —2to +23). ASA at a dose of 588 mg/kg diet was the most effective because it reduced lung tumor multi plicity by 53%. The preventive effect of ASA increased with the dose, being of 32, 30, and 44% for 73, 147, and 294 mg/kg diet, respectively. NNK increased plasma prostaglandin E2 (PGE2) basal levels by 413%, whereas ASA attenuated this elevation in a dose-response manner (r2 = 0.99). Plasma PGE2 levels in ASA + NNK-treated mice correlate with the logarithm of the number of tumors (r@= 0.99). NS-398 inhibited lung tumor multiplicity by 34% and returned plasma PGE2to basal levels observed in untreated mice. Among the NNK-exposed mice, ASA and NS-398 treatment decreased the mean of the lung tumor volume&Incu bation of 82—132 and LM2 murine lung tumor cells with ASA or NS-398 decreased cell proliferation by 50% at concentrations higher than 100 gM. Incubations of NNK with COX-1 and -2 produced both activation and detoxification products by a-carbon hydroxylation and N.oxydation path ways, respectively. Bioactivation of NNK was more extensive by COX-2 than COX-1. Anti-COX-1 and -2, arachidonic acid, ASA, and NS-398 inhibited NNK bioactivation by COX-1 and -2 from 22—49%. Our data suggest that NNK is bioactivated by COX-2 in lung tissues and that COX-2-specific inhibitors might be promising chemopreventive agents