Cyclooxygenase-2 (COX-2)–Independent Anticarcinogenic Effects of Selective COX-2 Inhibitors

Abstract

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 induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation

“…Studies in various cancers have indicated that celecoxib possesses a unique capacity to induce apoptosis independent of COX-2 inhibition, making celecoxib a potent anticancer drug [8,25] . At the cellular level, our results showed that celecoxib induced apoptosis in both the HNE1 and CNE1-LMP1 cell lines and that apoptosis was associated with the downregulation of the anti-apoptotic proteins Survivin, Mcl-1 and Bcl-2.…”

“…The apoptosis induction and the down-regulation of critical downstream anti-apoptotic proteins (Survivin, Mcl-1 and Bcl-2) further indicated that celecoxib could work via the inhibition of STAT3 phosphorylation. Several studies demonstrated that inhibition of 3-phosphoinositide-dependent kinase 1 (PDK-1) and its downstream substrate, PKB/AKT, plays a central role in the induction of apoptosis and cell cycle arrest [8] . However, whether this is the case in NPC still requires further investigation.…”

“…One mechanism through which celecoxib acts to reduce cancer development is by the inhibition of COX-2 activity. Furthermore, celecoxib can also act through COX-2-independent mechanisms involving the arrest of cell cycle progression, angiogenesis and the induction of apoptosis [8] . COX-2 is overexpressed in 43% to 75% of NPCs, contributes to nodal metastases and is associated with poorer prognosis [9,10] .…”

Molecular characterisation of canine nonsteroidal anti-inflammatory drug-activated gene (NAG-1)

“…However, NSAIDs can also act through COX-independent mechanisms (Grosch et al, 2006). Induction of canine NAG-1 was observed only in the presence of piroxicam or SC-560.…”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…In addition, sulindac was shown to exert its growth inhibitory and anti-inflammatory action by inhibiting the activity of IκB kinase β (IKK β ) required to activate NF-κB [118]. Furthermore, NSAID treatment of COX-2 null cells were reported to induce arrest of cell proliferation, suggesting that NSAIDs also act through mechanisms not directly related to COX expression levels [119,120]. Naturally, the above findings raise the question of the underlying mode of action responsible for these observations.…”