Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo.
Cyclooxygenase-2 (COX-2) is expressed within neovascular structures that support many human cancers. Inhibition of COX-2 by celecoxib delays tumor growth and metastasis in xenograft tumor models as well as suppresses basic fibroblast growth factor 2 (FGF-2)-induced neovascularization of the rodent cornea. The present studies were undertaken to evaluate possible mechanisms of the antiangiogenic and anticancer effects of celecoxib. Prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)) were increased in rat corneas implanted with slow-release pellets containing FGF-2 (338.6 ng of PGE(2)/g and 17.53 ng of TXB(2)/g) compared with normal rat corneas (63.1 ng of PGE(2)/g and 2.0 ng of TXB(2)/g). Celecoxib at 30 mg/kg/day p.o. inhibited angiogenesis (78.6%) and prostaglandin production by 78% for PGE(2) (72.65 ng/g) and 68% for TXB(2) (5.55 ng/g). Decreased prostaglandin production in corneas was associated with a 2.5-fold cellular increase in apoptosis and a 65% decrease in proliferation. Similar reductions in proliferation were observed in neovascular stroma (65-70%) of celecoxib-treated (dietary 160 ppm/day) xenograft tumors as well as in tumor cells (50-75%). Apoptosis was also increased in the tumor cells (2.2-3.0-fold) in response to celecoxib. Thus, the antitumor activity of celecoxib may be attributable, at least in part, to a direct effect on host stromal elements, such as the angiogenic vasculature.
Leahy
Kathleen M
KM
Pharmacia, Mail Zone AA4C, 700 Chesterfield Parkway, Chesterfield, Missouri 63017, USA. kathleen.m.leahy@pharmacia.com
Ornberg
Richard L
RL
Wang
Yu
Y
Zweifel
Ben S
BS
Koki
Alane T
AT
Masferrer
Jaime L
JL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D003315:Cornea / Q000098:blood supply; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011720:Pyrazoles; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D016222:Fibroblast Growth Factor 2; D013929:Thromboxane B2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone