Cyclooxygenase-2: a novel target for cancer chemotherapy?

J Cancer Res Clin Oncol. 2001 Jul;127(7):411-7. doi: 10.1007/s004320000225.


Epidemiologic studies have documented a 40-50% reduction in incidence of colorectal cancer in individuals taking nonsteroidal antiinflammatory drugs (NSAIDs). Since NSAIDs are known to inhibit cyclooxygenases (COX-1, COX-2), the basic mechanism of their antitumor effects is conceivably the altered metabolism of arachidonic acid and, subsequently, prostaglandins (PGs). Although COX-2, the inducible isoform, is regularly expressed at low levels in colonic mucosa, its activity increases dramatically following mutation of the APC (adenomatous polyposis coli) gene suggesting that beta-catenin/T-cell factor mediated Wnt-signaling activity may regulate COX-2 gene expression. In addition, hypoxic conditions and sodium butyrate exposure may also contribute to COX-2 gene transcription in human cancers. The development of selective COX-2 inhibitors has made it possible to further evaluate the role of COX-2 activity in colorectal carcinogenesis. To date, at least five mechanisms by which COX-2 contributes to tumorigenesis and the malignant phenotype of tumor cells have been identified, including: (1) inhibition of apoptosis; (2) increased angiogenesis; (3) increased invasiveness; (4) modulation of inflammation/immuno-suppression; and (5) conversion of procarcinogens to carcinogens. A clear positive correlation between COX-2 expression and inhibition of apoptosis has been established, associated with increased PGE2 levels resulting in modulation of pro- and anti-apoptotic factors (e.g., bcl-2, MAKs/ras, caspase-3, Par-4). In terms of angiogenesis and invasiveness, COX-2 activity was found to increase the expression of growth factors (e.g., VDEG, PDGF, bFGF) and matrix metalloproteinases (MMPs). Since COX-2 inhibitors have been demonstrated to interfere with tumorigenesis and apoptosis, COX-2 and its gene product may be attractive targets for therapeutic and chemoprotective strategies in colorectal cancer patients. This may lead to new perspectives that by controlling the cancer phenotype, rather than attempting to eradicate all affected cells, may provide significant benefits to the cancer patient.

Publication types

  • Review

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anticarcinogenic Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / prevention & control*
  • Cyclooxygenase 2
  • Cytoskeletal Proteins / metabolism
  • Endothelial Growth Factors
  • Enzyme Inhibitors / pharmacology*
  • Fibroblast Growth Factor 2 / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, APC / drug effects
  • Genes, APC / genetics
  • Humans
  • Immunosuppression
  • Inflammation
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / genetics*
  • Lymphokines / drug effects
  • Membrane Proteins
  • Mutation / drug effects
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / prevention & control
  • Phenotype
  • Platelet-Derived Growth Factor / drug effects
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Risk Factors
  • Trans-Activators*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • beta Catenin


  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Isoenzymes
  • Lymphokines
  • Membrane Proteins
  • Platelet-Derived Growth Factor
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • beta Catenin
  • Fibroblast Growth Factor 2
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases