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The anti-angiogenic effect of halofuginone Inhibition of collagen type I tube formation, matrix metalloproteinase-2 activities and extracellular matrix deposition



The anti-angiogenic effect of halofuginone Inhibition of collagen type I tube formation, matrix metalloproteinase-2 activities and extracellular matrix deposition



Blood 96(11 Part 1): 34a, November 16



Angiogenesis is essential for the growth and spread of hematooncological tumors. It is a multifactorial process involving type I collagen tube formation which directs the migration and assembly of endothelial cells, MMP-2 degradation of ECM proteins including collagen and new capillary basement membrane (BM)-like ECM deposition. Halo, a low molecular weight (495Da) quinazolinone alkaloid was previously shown by us to inhibit collagen alpha1 (I) gene expression and synthesis. We therefore hypothesized that Halo may inhibit angiogenesis. We evaluated the potential antiangiogenic effect of Halo both in vitro and in vivo using several assays: 1) Capillary-like tube formation with Bovine aortic and human umbilical endothelial cells. 2) Rat aortic ring microvessel formation and 3) Murine micropocket bFGF induced corneal angiogenesis. In vitro in the presence of Halo (50 ng/ml) both bovine and human endothelial cells lost their ability to form new capillary vessels and appeared as unorganized cell aggregates. Similarly Halo (100ng/ml) completely inhibited microvessel formation from rat aortic rings embedded in collagen type I gel. As collagen type I is one of the major constituents of the stroma we evaluated the effect of Halo on ECM deposition by cultured vascular endothelial cells assessed by incorporation of radiolabeled sulfate. Eighty five percent inhibition of ECM deposition was observed in cultures incubated with 50ng/ml Halo. In addition microscopic examinations of the denuded culture dishes revealed a very thin or no ECM. We next evaluated the effect of Halo on MMP-2 enzymatic activity by vascular endothelial cells and demonstrated an almost complete inhibition of MMP-2 expression and enzymatic activity as well as BM invasion by 100ng/ml Halo. Finally, in vivo Halo administered either P.O (5mg/kg) or I.P. (2mg/mouse/day) for 7 days caused profound inhibition of bFGF induced corneal neovascularization in the murine micropocket corneal angiogenesis model (the area of neovascularization was reduced from 1.7+0.3 mm2 to 0.6+0.2 mm2 in the control and Halo (either P.O or I.P) treated mice, respectively. In summary, Halo inhibits several steps in the angiogenetic process: MMP-2 expression and BM invasion, capillary-like tube formation and vascular sprouting as well as deposition of subendothelial ECM and finally bFGF induced neovascularization in vivo. This makes Halo a promising candidate for further evaluation in anti-angiogenic therapy.

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