cyclic-gmp and rofecoxib

Although it is often assumed that the antitumor effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to inhibition of cyclooxgenase (COX) activity, specifically COX-2, there is accumulating evidence that COX-2 independent mechanisms can also play an important role. Studies with sulindac sulfone (Aptosyn) and related derivatives have revealed a novel pathway of tumor growth inhibition and apoptosis mediated by activation of the guanosine 3',5' monophosphate (cGMP)-dependent enzyme protein kinase G (PKG). The present study indicates that concentrations of the NSAIDs celecoxib, indomethacin, and meclofenamic acid that inhibit growth of SW480 human colon cancer cells inhibit subcellular cGMP-phosphodiesterase (PDE) enzymatic activity and in intact cells induce a two- to threefold increase in intracellular levels of cGMP. This is associated with phosphorylation of the protein VASP, a marker of PKG activation, activation of JNK1 and a decrease in cellular levels of cyclin D1; effects seen with other agents that cause activation of PKG in these cells. On the other hand even a high concentration of the COX-2 specific inhibitor rofecoxib (500 microM) did not inhibit growth of SW480 cells. Nor did rofecoxib inhibit cGMP-PDE activity or cause other changes related to PKG activation in these cells. Since activation of the PKG pathways by celecoxib, indomethacin, and meclofenamic acid in this cell culture system required high concentrations of these compounds, it remains to be determined whether activation of this pathway contributes to the in vivo antitumor effects of specific NSAIDs.

Topics: Apoptosis; Celecoxib; Cell Adhesion Molecules; Cell Proliferation; Colonic Neoplasms; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclin D1; Cyclooxygenase Inhibitors; Enzyme Activation; Humans; Indomethacin; Lactones; Meclofenamic Acid; Microfilament Proteins; Mitogen-Activated Protein Kinase 8; Phosphoproteins; Phosphorylation; Pyrazoles; Sulfonamides; Sulfones; Tumor Cells, Cultured

The antinociceptive effect of rofecoxib, a preferential inhibitor of cyclooxygenase-2, was assessed in the pain-induced functional impairment model in the rat. Systemic administration of rofecoxib generated a dose-dependent antinociceptive effect in rats injected with uric acid into the knee joint of the right hindlimb in order to produce nociception. Ipsilateral intra-articular pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide (NO) synthesis), 1H-(1,2,4)-oxadiazolo (4,2-a)quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and the ATP-sensitive potassium channel blocker glibenclamide reversed the antinociceptive effect of rofecoxib p.o. However, ipsilateral intra-articular pretreatment with L-arginine (a NO substrate), or 3-morpholino-sydnonimine-HCl (SIN-1, a non-enzymatic donor of NO), potentiated the antinociceptive effect induced by rofecoxib. The present results suggest that, in addition to cyclooxygenase-2 inhibition, the antinociceptive effect of rofecoxib could also involve activation of the L-arginine-NO-cyclic GMP (cGMP) pathway, followed by opening of ATP-sensitive K+ channels at the peripheral level.

Topics: Adenosine Triphosphate; Analgesics; Animals; Arginine; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Lactones; Nitric Oxide; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Signal Transduction; Sulfones

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Cyclic GMP; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Guanylate Cyclase; Isoenzymes; Lactones; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Oxadiazoles; Pain; Prostaglandin-Endoperoxide Synthases; Quinoxalines; Rats; Rats, Wistar; Sulfones; Uric Acid