Nonsteroidal antiinflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Overexpression of COX-2 increases cell proliferation and inhibits apoptosis. However, selective COX-2 inhibitors can also act through COX-independent mechanisms. In this review, we describe the COX-2–independent molecular targets of these COX-2 inhibitors and discuss how these targets may be involved in the anticarcinogenic activities of these selective COX-2 inhibitors. We also compare the concentrations of these inhibitors used in in vitro and in vivo experiments and discuss the implications of the in vitro studies for clinical management of cancer with these drugs.

Celecoxib, a cyclooxygenase‐2 (COX‐2) selective nonsteroidal anti‐inflammatory drug, is a new anticarcinogenic agent. Its antitumor effects depend on the one hand on its COX‐2‐inhibiting potency, but on the other hand on COX‐2‐independent mechanisms, which until now have not been fully understood. Here, we investigated whether celecoxib has an impact on the APC/β‐catenin pathway, which has been shown to play a pivotal role in the development of various cancers, especially of the colon. After only 2 h of treatment of human Caco‐2 colon carcinoma cells with 100 µM celecoxib, we observed a rapid translocation of β‐catenin from its predominant membrane localization to the cytoplasm. Inhibition of the glycogen‐synthasekinase‐3β (GSK‐3β) by LiCl prevented this celecoxib‐induced translocation, suggesting that phosphorylation of β‐catenin by the GSK‐3β kinase was essential for this release. Furthermore, the cytosolic accumulation was accompanied by a rapid increase of β‐catenin in the nuclei, starting already 30 min after celecoxib treatment. The DNA binding activity of β‐catenin time dependently decreased 2 h after celecoxib treatment. After this cellular reorganization, we observed a caspase‐ and proteasome‐dependent degradation of β‐catenin after 8 h of drug incubation. Celecoxib‐induced β‐catenin degradation was also observed in various other tumor cell lines (HCT‐116, MCF‐7, and LNCAP) but was not seen after treatment of Caco‐2 cells with either the anticarcinogenic nonsteroidal anti‐inflammatory drug R‐flurbiprofen or the highly COX‐2‐selective inhibitor rofecoxib. These findings indicate that the anticarcinogenic effects of celecoxib can be explained, at least partly, by an extensive degradation of β‐catenin in human colon carcinoma cells.