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.
Yazawa
Kentaro
K
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
Tsuno
Nelson H
NH
Kitayama
Joji
J
Kawai
Kazushige
K
Okaji
Yurai
Y
Asakage
Masahiro
M
Sunami
Eiji
E
Kaisaki
Shoichi
S
Hori
Nobukazu
N
Watanabe
Toshiaki
T
Takahashi
Koki
K
Nagawa
Hirokazu
H
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