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) i nhibitor NS-398 on proliferation, apoptosis and COX-2 regulation in 3 pre-m alignant human colorectal adenoma cell lines (RG/C2, AA/C1, RR/C1) and comp ared 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 prov iding 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 mu M 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, ye t each line was similarly sensitive to NS-398. There was a positive correla tion between overall sensitivity of the cell lines (determined by the attac hed cell yield) and sensitivity to NS-398-induced apoptosis, suggesting tha t apoptosis is the dominant antiproliferative 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 ad enoma cell lines. This was studied further in HT29 cultures, where treatmen t with NS-398 inhibited COX-2 activity, reducing prostaglandin E-2 secretio n. Here, neither the increase in COX-2 protein expression nor the anti-prol iferative 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 mecha nistically linked to the observed induction of COX-2 protein expression upo n treatment with NS-398. Int. J. Cancer 86: 553-560, 2000. (C) 2000 Wiley-L iss, Inc.