AGM-1470, a potent angiogenesis inhibitor, prevents the entry of normal but not transformed endothelial cells into the G1 phase of the cell cycle.
AGM-1470 is a potent angiogenesis inhibitor that is very effective in inhibiting endothelial cell proliferation in both in vitro and in vivo models and that prevents tumor growth in vivo. Although this molecule appears to be a most promising anticancer drug, its mechanism of action has not yet been elucidated. In this study, we examined the effects of AGM-1470 on the cell cycle of normal and transformed endothelial cells. We showed that AGM-1470, at picomolar concentrations, specifically inhibits the proliferation of both bovine aortic endothelial cells and human umbilical vein endothelial cells. AGM-1470 was ineffective in significantly inhibiting the proliferation of Ea.hy926 cells, a hybrid cell line obtained by the fusion of human umbilical vein endothelial cells with a human carcinoma cell line, or cEnd.1 cells, a polyoma middle T oncogene-transformed endothelioma cell line derived from mouse embryo. Using a double labeling technique with anti-Ki67 antibodies and propidium iodide, we demonstrated, with flow cytometry analysis, that AGM-1470 specifically prevents the entry of endothelial cells into the G1 phase of the cell cycle. We also showed that AGM-1470 was ineffective in inhibiting endothelial cell migration toward laminin or capillary-like tube formation inside a type I collagen matrix induced by phorbol esters. Our data strongly suggest that AGM-1470 is a molecule that specifically inhibits a cell cycle control pathway active in normal cells but which could be bypassed or altered in transformed cells.
Antoine
N
N
Laboratory of Histology, University of Liège, Belgium.
Greimers
R
R
De Roanne
C
C
Kusaka
M
M
Heinen
E
E
Simar
L J
LJ
Castronovo
V
V
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001011:Aorta; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects; D007700:Kinetics; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol