Selective inhibition of cyclooxygenase (COX)-2 inhibits endothelial cell proliferation by induction of cell cycle arrest.
High-level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. Selective inhibition of COX-2 was shown to reduce colorectal tumorigenesis in different models of carcinogenesis and to prevent metastasis in xenograft tumor models, as well as to suppress in vitro induced angiogenesis. Recently, COX-2 was reported to be expressed not only in malignant epithelial cells, but also in the neovasculature that feeds the tumor in a variety of solid human cancers. Thus, one of the possible mechanisms by which selective COX-2 inhibitor reduces tumor growth and metastasis is through inhibition of tumor angiogenesis. Although a report suggested a possible role of endothelial COX-1 in the process of angiogenesis, in a recent study, the selective inhibition of COX-2 was shown to strongly inhibit angiogenesis by inducing endothelial cell (EC) apoptosis. In the present study, using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the potential antiangiogenic effect of the selective COX-2 inhibitor and its mechanism of action, and clearly demonstrated that selective inhibition of COX-2 caused a dose-dependent decrease in the proliferative activity of ECs, as well as an inhibition of capillary-like tube formation. The inhibitory effect on EC proliferation was dependent on the cell cycle arrest to the G1 phase and not on cell apoptosis.
Department of Surgical Oncology, Faculty of Medical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kyazawa-tky@umin.ac.jp
Kentaro
K
Yazawa
Nelson H
NH
Tsuno
Joji
J
Kitayama
Kazushige
K
Kawai
Yurai
Y
Okaji
Masahiro
M
Asakage
Eiji
E
Sunami
Shoichi
S
Kaisaki
Nobukazu
N
Hori
Toshiaki
T
Watanabe
Koki
K
Takahashi
Hirokazu
H
Nagawa
D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology; D002448:Cell Adhesion; D049109:Cell Proliferation; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010080:Oxazoles / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D014471:Umbilical Veins; D000096926:Benzenesulfonamides
D001557:Benzenesulfonates; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D020778:Matrix Metalloproteinase 2; D008565:Membrane Proteins; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human