Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy

Celecoxib (Celebrex®) was developed as a selective cyclooxygenase-2 (COX-2) inhibitor for the treatment of chronic pain. However, it now appears that this compound harbours additional pharmacologic activities that are entirely independent of its COX-2-inhibitory activity. This review presents the recently emerged direct non-COX-2 targets of celecoxib and their proposed role in mediating this drug's antitumour effects

Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo

BACKGROUND: 2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex(®)) that lacks COX-2-inhibitory function. However, despite its inability to block COX-2 activity, DMC is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo, indicating that both of these drugs are able to involve targets other than COX-2 to exert their recognized cytotoxic effects. However, the molecular components that are involved in mediating these drugs' apoptosis-stimulatory consequences are incompletely understood. RESULTS: We present evidence that celecoxib and DMC are able to down-regulate the expression of survivin, an anti-apoptotic protein that is highly expressed in tumor cells and known to confer resistance of such cells to anti-cancer treatments. Suppression of survivin is specific to these two drugs, as other coxibs (valdecoxib, rofecoxib) or traditional NSAIDs (flurbiprofen, indomethacin, sulindac) do not affect survivin expression at similar concentrations. The extent of survivin down-regulation by celecoxib and DMC in different tumor cell lines is somewhat variable, but closely correlates with the degree of drug-induced growth inhibition and apoptosis. When combined with irinotecan, a widely used anticancer drug, celecoxib and DMC greatly enhance the cytotoxic effects of this drug, in keeping with a model that suppression of survivin may be beneficial to sensitize cancer cells to chemotherapy. Remarkably, these effects are not restricted to in vitro conditions, but also take place in tumors from drug-treated animals, where both drugs similarly repress survivin, induce apoptosis, and inhibit tumor growth in vivo. CONCLUSION: In consideration of survivin's recognized role as a custodian of tumor cell survival, our results suggest that celecoxib and DMC might exert their cytotoxic anti-tumor effects at least in part via the down-regulation of survivin – in a manner that does not require the inhibition of cyclooxygenase-2. Because inhibition of COX-2 appears to be negligible, it might be worthwhile to further evaluate DMC's potential as a non-coxib alternative to celecoxib for anti-cancer purposes

Inhibition of histone H1 kinase expression, retinoblastoma protein phosphorylation, and cell proliferation by the phosphatase inhibitor okadaic acid.

Phosphorylation events are major regulatory mechanisms of signal transduction pathways that regulate gene expression and cell growth. To study the potential involvement of serine-threonine specific phosphatases in these processes we used okadaic acid (OA), an inhibitor of type 1 and type 2A protein phosphatases. Here we present evidence that OA arrests cells at defined points in the cell cycle. Concomitantly, expression and associated histone H1 kinase activity of cdc2 and cyclin A, two cell cycle regulatory proteins, are repressed by this agent. Furthermore, phosphorylation of the tumor suppressor protein retinoblastoma, an event thought to be necessary in order to permit cells to proliferate, is inhibited when OA is present. These effects are fully reversible since removal of OA restores cdc2 and cyclin A expression as well as histone H1 kinase activity, and the cells resume growth. Since cdc2 and cyclin A have previously been shown to be absolutely required for cell cycle progression it is likely that blockage of synthesis of these components contributes to the cytostatic effects of OA. Furthermore, our results suggest a positive role for OA sensitive protein phosphatases in the regulation of expression of these cell cycle regulatory proteins

Inhibition of histone H1 kinase expression, retinoblastoma protein phosphorylation, and cell proliferation by the phosphatase inhibitor okadaic acid.

Phosphorylation events are major regulatory mechanisms of signal transduction pathways that regulate gene expression and cell growth. To study the potential involvement of serine-threonine specific phosphatases in these processes we used okadaic acid (OA), an inhibitor of type 1 and type 2A protein phosphatases. Here we present evidence that OA arrests cells at defined points in the cell cycle. Concomitantly, expression and associated histone H1 kinase activity of cdc2 and cyclin A, two cell cycle regulatory proteins, are repressed by this agent. Furthermore, phosphorylation of the tumor suppressor protein retinoblastoma, an event thought to be necessary in order to permit cells to proliferate, is inhibited when OA is present. These effects are fully reversible since removal of OA restores cdc2 and cyclin A expression as well as histone H1 kinase activity, and the cells resume growth. Since cdc2 and cyclin A have previously been shown to be absolutely required for cell cycle progression it is likely that blockage of synthesis of these components contributes to the cytostatic effects of OA. Furthermore, our results suggest a positive role for OA sensitive protein phosphatases in the regulation of expression of these cell cycle regulatory proteins