Abstract
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.
Original language | English |
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Pages (from-to) | 553-560 |
Number of pages | 0 |
Journal | Int J Cancer |
Volume | 86 |
Issue number | 4 |
DOIs | |
Publication status | Published - 15 May 2000 |
Keywords
- Adenoma
- Anti-Inflammatory Agents
- Non-Steroidal
- Anticarcinogenic Agents
- Apoptosis
- Carcinoma
- Colorectal Neoplasms
- Cyclooxygenase 2
- Cyclooxygenase 2 Inhibitors
- Cyclooxygenase Inhibitors
- HT29 Cells
- Humans
- Isoenzymes
- Membrane Proteins
- Nitrobenzenes
- Prostaglandin-Endoperoxide Synthases
- Prostaglandins E
- Synthetic
- Sulfonamides
- Tumor Cells
- Cultured