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The anti-angiogenic effect of halofuginone (halo): inhibition of collagen type i tube formation, matrix metalloproteinase-2 (mmp-2) acnvntes and extracelluar matrix (ecm) deposition [abstract]
Year:
2000
Source of publication :
Blood
Authors :
Pines, Mark
;
.
Volume :
96
Co-Authors:
Nagler, A., BMT, Israel
Elkin, E., Oncology, Israel
Miao, H.-Q., Oncology, Israel
Reich, Pharmacology, Hadassah, Jerusalem, Israel
Pines, M., Volcany Center, Israel
Vlodavsky, I., Oncology, Israel
Facilitators :
From page:
0
To page:
0
(
Total pages:
1
)
Abstract:

Angiogenesis is essential for the growth and spread of hematooncological tumors.il is a multifactorial process involving type I collagen tube formation which directs the migrati m 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 molecu ar weight (495Da) quinazolinone alkaloid was previously shown by us to inhibit collagen i xl (I) gene expression and synthesis. We therefore hypothesized that Halo may inhirit angiogenesis. We evaluated the potential antiangiogenic effect of Halo both in vitro anc 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 (50ng/ ml) both bovine and human endothelial cells lost their ability to form new capillary vess ;ls and appeared as unorganized cell aggregates. Similarly Halo ( 1 OOng/ml) completely inhibii ed 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 denuc ed 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 aim st 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 corm:al 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 H do (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 U e formation and vascular sprouting as well as deposition of subendothelial ECM and fimlly bFGF induced neovascularization in vivo. This makes Halo a promising candidate for further evaluation in anti-angiogenic therapy. [.

Note:

P. 94A

Related Files :
collagen type 1
Halofuginone
inhibition
Matrix metalloproteinase-2
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More details
DOI :
Article number:
0
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
29995
Last updated date:
02/03/2022 17:27
Creation date:
17/04/2018 00:51
Scientific Publication
The anti-angiogenic effect of halofuginone (halo): inhibition of collagen type i tube formation, matrix metalloproteinase-2 (mmp-2) acnvntes and extracelluar matrix (ecm) deposition [abstract]
96
Nagler, A., BMT, Israel
Elkin, E., Oncology, Israel
Miao, H.-Q., Oncology, Israel
Reich, Pharmacology, Hadassah, Jerusalem, Israel
Pines, M., Volcany Center, Israel
Vlodavsky, I., Oncology, Israel
The anti-angiogenic effect of halofuginone (halo): inhibition of collagen type i tube formation, matrix metalloproteinase-2 (mmp-2) acnvntes and extracellua r matrix (ecm) deposition

Angiogenesis is essential for the growth and spread of hematooncological tumors.il is a multifactorial process involving type I collagen tube formation which directs the migrati m 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 molecu ar weight (495Da) quinazolinone alkaloid was previously shown by us to inhibit collagen i xl (I) gene expression and synthesis. We therefore hypothesized that Halo may inhirit angiogenesis. We evaluated the potential antiangiogenic effect of Halo both in vitro anc 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 (50ng/ ml) both bovine and human endothelial cells lost their ability to form new capillary vess ;ls and appeared as unorganized cell aggregates. Similarly Halo ( 1 OOng/ml) completely inhibii ed 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 denuc ed 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 aim st 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 corm:al 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 H do (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 U e formation and vascular sprouting as well as deposition of subendothelial ECM and fimlly bFGF induced neovascularization in vivo. This makes Halo a promising candidate for further evaluation in anti-angiogenic therapy. [.

P. 94A

Scientific Publication
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