ono-8711 and Cardiovascular-Diseases

Accumulating evidence suggests that cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) may play an important role in colon carcinogenesis. Thus, blockage of this pathway may be a suitable strategy for colon cancer chemoprevention. Recent clinical studies suggest that COX-2 inhibitors cause adverse cardiovascular effects due to prostacyclin (PGI(2)) inhibition. To test our hypothesis that inhibition of PGE(2) signaling through E-prostanoid (EP) receptors may offer a safer cardiovascular profile than COX-2 inhibition, we analyzed expression of 6-keto PGF(1alpha), a hydrated form of PGI(2) and PGI(2) synthase, which was stimulated with cytokines in human umbilical vein endothelial cells (HUVECs) treated with the EP(1) receptor antagonist ONO-8711 or the COX-2 inhibitor celecoxib. ONO-8711 did not inhibit both 6-keto PGF(1alpha) production and PGIS expression, whereas celecoxib did in HUVECs. ONO-8711 also inhibited cytokine-induced tissue factor expression in HUVECs. These results suggest that ONO-8711 may be a safer chemopreventive agent with respect to cardiovascular events.

Topics: Blood Coagulation; Bridged Bicyclo Compounds; Caproates; Cardiovascular Diseases; Celecoxib; Cell Line; Cytokines; Dinoprostone; Endothelial Cells; Epoprostenol; Fibrinolytic Agents; Gene Expression Regulation; Humans; Peroxisome Proliferator-Activated Receptors; Pyrazoles; Receptors, Prostaglandin E; Response Elements; Signal Transduction; Sulfonamides; Thromboplastin