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

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 μM 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 E2 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 E2. 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. Int. J. Cancer 86:553–560, 2000. © 2000 Wiley‐Liss, Inc.