Dual function of nonsteroidal anti-inflammatory drugs (NSAIDs): inhibition of cyclooxygenase and induction of NSAID-activated gene

J Pharmacol Exp Ther. 2002 Jun;301(3):1126-31. doi: 10.1124/jpet.301.3.1126.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of inflammatory disease and have a chemopreventive effect on colorectal cancer. NSAIDs inhibit cyclooxygenase (COX)-1 and/or COX-2 activity, but the chemopreventive effect may be, in part, independent of prostaglandin inhibition. NSAID-activated gene (NAG-1) was previously identified as a gene induced by some NSAIDs in cells devoid of COX activity. NAG-1 has proapoptotic and antitumorigenic activity in vitro and in vivo. To determine whether the induction of NAG-1 by NSAIDs is influenced by COX expression, we developed COX-1- and COX-2-overexpressing HCT-116 cells. COX expression did not affect NSAID-induced NAG-1 expression as assessed by transient and stable transfection. Also, NAG-1 expression was not affected by PGE(2) and arachidonic acid, suggesting that NAG-1 induction by NSAIDs occurs by a prostanoid-independent manner. We also report that indomethacin increased NAG-1 expression in a number of cells from tissues other than colorectal. In conclusion, NSAIDs have dual function, induction of NAG-1 expression and inhibition of COX activity that occurs in a variety of cell lines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arachidonic Acid / pharmacology
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / metabolism
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cytokines / biosynthesis*
  • Cytokines / genetics*
  • Dinoprostone / pharmacology
  • Gene Expression Regulation / drug effects*
  • Growth Differentiation Factor 15
  • Humans
  • Indomethacin
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / biosynthesis
  • Membrane Proteins
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Tumor Cells, Cultured

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Cytokines
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Isoenzymes
  • Membrane Proteins
  • Arachidonic Acid
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone
  • Indomethacin