A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells

Gastroenterology. 1997 Dec;113(6):1883-91. doi: 10.1016/s0016-5085(97)70007-6.


Background & aims: Constitutive expression of cyclooxygenase 2 (COX-2) has been found in 85% of colorectal cancers. Ras mutations are found in 50% of colorectal adenocarcinomas. The aim of this study was to determine the role of COX-2 in ras-induced transformation in rat intestinal epithelial (RIE) cells.

Methods: Cell growth was determined by cell counts. The expression of COX-2 was examined by Northern and Western analyses. For tumorigenicity assays, cells were inoculated into dorsal subcutaneous tissue of athymic nude mice. DNA-fragmentation assays were performed to detect apoptosis.

Results: The expression of COX-2 was increased in RIE-Ras cells at both messenger RNA (9-fold) and protein (12-fold) levels. Prostaglandin I2 levels were elevated 2.15-fold in RIE-Ras cells. Serum deprivation further increased COX-2 expression 3.8-fold in RIE-Ras cells. Treatment with a selective COX-2 antagonist (SC58125) inhibited the growth of RIE-Ras cells through inhibition of cell proliferation and by induction of apoptosis. SC-58125 treatment reduced the colony formation in Matrigel by 83.0%. Intraperitoneal administration of SC-58125 suppressed RIE-Ras tumor growth in nude mice by 60.3% in 4 weeks. SC-58125 treatment also induced apoptosis in RIE-Ras cells as indicated by increased DNA fragmentation.

Conclusions: Overexpression of COX-2 may contribute to tumorigenicity of ras-transformed intestinal epithelial cells. Selective inhibition of COX-2 activity inhibits growth of ras-transformed intestinal epithelial cells and induces apoptosis.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinogenicity Tests
  • Cell Division / drug effects
  • Cell Transformation, Neoplastic / pathology*
  • Collagen / pharmacology
  • Cyclooxygenase 2
  • DNA / antagonists & inhibitors
  • DNA / biosynthesis
  • Drug Combinations
  • Enzyme Inhibitors / pharmacology*
  • Genes, ras / physiology*
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / pathology*
  • Intestinal Neoplasms / pathology
  • Isoenzymes / metabolism*
  • Laminin / pharmacology
  • Mice
  • Mice, Nude
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Proteoglycans / pharmacology
  • Pyrazoles / pharmacology
  • Rats


  • Drug Combinations
  • Enzyme Inhibitors
  • Isoenzymes
  • Laminin
  • Proteoglycans
  • Pyrazoles
  • matrigel
  • 1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole
  • Collagen
  • DNA
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases