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

R. Yao, N. Rioux, A. Castonguay, M. You

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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 induction of apoptosis and inhibition of COX (cyclooxygenase)-1, COX-2, and the incidence of K-ras mutation. The NSAIDs used in this study include acetylsalicylic acid (ASA) that is anti-inflammatory with COX-1 and COX-2 inhibition and N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398) that is a specific COX-2 inhibitor. We have previously demonstrated that ASA (147 and 294 mg/kg diet) and NS398 (7 mg/kg diet) inhibited lung tumorigenesis 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 types of K-ras mutations was found between the lung tumors treated with NNK and those treated with NNK/ASA and NNK/NS398. In NNK-treated mice, ASA (294 mg/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 inhibited the expression of COX-2. Finally, modulation of gene expression by NS398 and ASA (294 mg/kg diet) was determined using Atlas cDNA expression arrays. Expression of cyclin B2 was decreased and expression of Fas-L and BAD were increased in lung tissues treated with both NS398 and ASA. Treatment with NS398 also increased expression of p57kip2 and myosin. These genes modulated by NSAIDs may play a role in mediating the observed chemopreventive effects of the NSAIDs in the mouse lung. Our results demonstrate that lung tumor prevention with NSAIDs involve both the induction of apoptosis and the inhibition of COX-2 expression.

Original languageEnglish (US)
Pages (from-to)731-742
Number of pages12
JournalExperimental Lung Research
Volume26
Issue number8
DOIs
StatePublished - 2000

Keywords

  • Apoptosis
  • COXs
  • Chemoprevention
  • K-ras mutation
  • Mouse lung tumor
  • NNK
  • NSAIDs

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry

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