Selective cyclooxygenase‐2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells

Abstract

Although the in£uence of selective cyclooxygenase (COX)-2 inhibitors on the proliferation of colon adenocarcinoma cells have been the subject of much investigation, relatively little research has compared the e¡ects of di¡erent COX-2 inhibitors. Celecoxib strongly suppressed the proliferation of COX-2 expressing HT-29 cells at 10^40 W WM. NS-398 and nimesulide also inhibited cell proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib induced apoptosis of HT-29 cells, as detected on the basis of DNA fragmentation, TUNEL positivity, and caspase-3/7 activation. DNA fragmentation was also increasd in COX-2 non-expressing cell lines (SW-480 and HCT-116) by exposure to celecoxib for 6^24 h. All six COX-2 inhibitors suppressed the production of prostaglandin E 2 by HT-29 cells, suggesting that the pro-apoptotic e¡ect of celecoxib was unrelated to inhibition of COX-2. Inactivation of Akt might explain the di¡erential pro-apoptotic effect of these selective COX-2 inhibitors on colon adenocarcinoma cells.

Effect of nonsteroidal anti-inflammatory drugs on β-catenin protein levels and catenin-related transcription in human colorectal cancer cells

“…The IC 50 values for the individual NSAIDs were similar to those previously reported (Hixson et al, 1994;Piazza et al, 1997b;Yamazaki et al, 2002). As previously described, rofecoxib had little antiproliferative activity compared with the other NSAIDs that were tested (Yamazaki et al, 2002), although the concentration range of this NSAID was restricted by poor solubility. We also confirmed a previous report that the sulphide metabolite of sulindac has more potent antiproliferative activity than sulindac sulphone (Piazza et al, 1997b).…”

“…Although the effects of the NSAIDs used in this study on proliferation and apoptosis of SW480 human CRC cells have been previously described (Hixson et al, 1994;Piazza et al, 1997b;Smith et al, 2000;Yamazaki et al, 2002), there has been no previous study of the effects of a series of NSAIDs on expression of b-catenin and the cell cycle regulatory protein cyclin D1 by these cells. Therefore, we decided to confirm the data on NSAID-induced changes in SW480 human CRC cell kinetics so that a direct comparison of changes in b-catenin and cyclin D1 protein levels could be made with effects on proliferation and apoptosis in the same set of experiments.…”

“…Therefore, this cell line may not be representative of all colorectal epithelial cells at early stages of colorectal carcinogenesis (a minority of which contain COX-2 protein; Chapple et al, 2000). However, several Groups have not reported differences in the effects of NSAIDs on COX-2-positive compared with COX-2-negative human CRC cell lines (Hixson et al, 1994;Yamazaki et al, 2002), including changes in b-catenin levels (Rice et al, 2003), thus justifying the use of SW480 human CRC cells in our experiments.…”

“…Therefore, we decided to confirm the data on NSAID-induced changes in SW480 human CRC cell kinetics so that a direct comparison of changes in b-catenin and cyclin D1 protein levels could be made with effects on proliferation and apoptosis in the same set of experiments. The concentration range that was used for each NSAID was based on previous data from experiments using human CRC cells (Hixson et al, 1994;Piazza et al, 1997b;Smith et al, 2000;Yamazaki et al, 2002). The question of whether the high concentrations of NSAIDs, which are employed in studies using human CRC cells in vitro, are relevant to the antineoplastic activity of these agents in vivo is currently a subject of debate (Hwang et al, 2002;Hull et al, 2003).…”

Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?

“…The extent of growth inhibition by celecoxib is related, at least in part, by proapoptotic effect induced by COX-2 inhibitors. As reported recently by others Yamazaki et al, 2002), the proapoptotic effect of celecoxib seems to be unrelated to the inhibition of COX-2.…”