Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398

Int J Cancer. 2000 May 15;86(4):553-60. doi: 10.1002/(sici)1097-0215(20000515)86:4<553::aid-ijc18>3.0.co;2-9.


We determined the effect of the highly selective cyclooxygenase-2 (COX-2) inhibitor NS-398 on proliferation, apoptosis and COX-2 regulation in 3 pre-malignant human colorectal adenoma cell lines (RG/C2, AA/C1, RR/C1) and compared its effect on 3 colorectal carcinoma cell lines (HT29, KS, JW2). COX-2 protein was expressed in each cell line derived from an adenoma, thus providing evidence that COX-2 is expressed in the tumour cells themselves at an early stage in human colorectal adenoma formation. NS-398 (20 to 100 microM for 96 h) induced apoptosis and inhibited the proliferation of the adenoma cell lines. Of the 3 carcinoma lines, only HT29 expressed COX-2 protein, yet each line was similarly sensitive to NS-398. There was a positive correlation between overall sensitivity of the cell lines (determined by the attached cell yield) and sensitivity to NS-398-induced apoptosis, suggesting that apoptosis is the dominant anti-proliferative effect of NS-398. Two of the 3 adenoma cell lines (RG/C2, AA/C1) were less sensitive than the carcinoma cell lines. NS-398 up-regulated COX-2 protein expression in the HT29 and adenoma cell lines. This was studied further in HT29 cultures, where treatment with NS-398 inhibited COX-2 activity, reducing prostaglandin E(2) secretion. Here, neither the increase in COX-2 protein expression nor the anti-proliferative and apoptosis-inducing effect of NS-398 was prevented by addition of exogenous prostaglandin E(2). Apoptosis appears to be the dominant anti-proliferative effect of NS-398 and, in COX-2 expressing cells, may be mechanistically linked to the observed induction of COX-2 protein expression upon treatment with NS-398.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / enzymology
  • Adenoma / pathology*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis*
  • Carcinoma / enzymology
  • Carcinoma / pathology
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / pathology*
  • Colorectal Neoplasms / prevention & control
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • HT29 Cells
  • Humans
  • Isoenzymes / biosynthesis*
  • Membrane Proteins
  • Nitrobenzenes / pharmacology*
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandins E, Synthetic / pharmacology
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured


  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticarcinogenic Agents
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Nitrobenzenes
  • Prostaglandins E, Synthetic
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • 16,16-dimethylprostaglandin E
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases