Inhibition of prostaglandin E(2) signaling through the EP(1) receptor does not affect prostacyclin production in human endothelial cells.
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.
Kaneshiro
Tatsuya
T
Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Okumura
Masae
M
Maalouf
Samer
S
Uflacker
Andre
A
Maruyama
Takayuki
T
Kawamori
Toshihiko
T
D001777:Blood Coagulation / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002208:Caproates / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000188:drug therapy; D000068579:Celecoxib; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics
D001643:Bridged Bicyclo Compounds; D002208:Caproates; D016207:Cytokines; D005343:Fibrinolytic Agents; C122148:ONO 8711; D047492:Peroxisome Proliferator-Activated Receptors; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; D013925:Thromboplastin; D011464:Epoprostenol; D000068579:Celecoxib; D015232:Dinoprostone