COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

Br J Cancer. 2002 Aug 27;87(5):574-9. doi: 10.1038/sj.bjc.6600495.

Abstract

Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

Publication types

  • Comparative Study

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Cell Division / drug effects
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Cyclin D1 / analysis
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • DNA Replication / drug effects
  • Dinoprostone / biosynthesis
  • Dose-Response Relationship, Drug
  • Gastrins / antagonists & inhibitors*
  • Gastrins / blood
  • Gastrins / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Reporter
  • Isoenzymes / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Transplantation
  • Nitrobenzenes / pharmacology*
  • Proliferating Cell Nuclear Antigen / biosynthesis
  • Proliferating Cell Nuclear Antigen / genetics
  • Promoter Regions, Genetic / drug effects
  • Prostaglandin-Endoperoxide Synthases
  • Receptors, Cholecystokinin / drug effects*
  • Substrate Specificity
  • Sulfonamides / pharmacology*
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / pathology

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Gastrins
  • Isoenzymes
  • Neoplasm Proteins
  • Nitrobenzenes
  • Proliferating Cell Nuclear Antigen
  • Receptors, Cholecystokinin
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclin D1
  • gastrin 17
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone