Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398.

Acetylsalicylic acid (ASA) is known to prevent cancer development, but its mechanism of action remains unclear. In this study, we compared the efficacies of this nonspecific cyclooxygenase (COX) inhibitor with N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), a specific COX-2 inhibitor. COX-2-specific inhibitors are less toxic than ASA. Lung tumorigenesis was induced in A/J mice by the administration of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the drinking water for 7 weeks (weeks 0 to +7). Groups of 25 A/J mice were fed ASA (588, 294, 147, or 73 mg/kg diet) before and throughout the assay (weeks -2 to +23). ASA at a dose of 588 mg/kg diet was the most effective because it reduced lung tumor multiplicity 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 (r2 = 0.99). NS-398 inhibited lung tumor multiplicity by 34% and returned plasma PGE2 to basal levels observed in untreated mice. Among the NNK-exposed mice, ASA and NS-398 treatment decreased the mean of the lung tumor volumes. Incubation of 82-132 and LM2 murine lung tumor cells with ASA or NS-398 decreased cell proliferation by 50% at concentrations higher than 100 microM. Incubations of NNK with COX-1 and -2 produced both activation and detoxification products by alpha-carbon hydroxylation and N-oxydation pathways, 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.