Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix contortrix, inhibits angiogenesis |
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Authors: | Qing Zhou Marian T Nakada Catherine Arnold Kate Y Shieh Francis S Markland Jr |
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Institution: | (1) Department of Biochemistry & Molecular Biology and Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, California, USA;(2) Centocor, 200 Great Valley Parkway, Malvern, Pennsylvania, USA |
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Abstract: | Contortrostatin, a 13.5 kDa disulfide-linked homodimeric polypeptide possessing an Arg–Gly–Asp sequence, was isolated from
venom of the southern copperhead snake. Daily injection of contortrostatin into the primary tumor of human breast cancer MDA-MB-435
carried in nude mice significantly inhibited tumor growth and neovascularization of the tumor tissue. On the chick embryo
chorioallantoic membrane, contortrostatin inhibited angiogenesis induced by MDA-MB-435 cells, basic fibroblast growth factor,
and vascular endothelial growth factor. In addition, contortrostatin effectively blocked adhesion of human umbilical vein
endothelial cells (HUVEC) to immobilized vitronectin and significantly inhibited invasion of HUVEC through a Matrigel barrier.
Competitive binding assays and adhesion assays with different integrin antibodies suggested that integrin αvβ3 is a binding
site for contortrostatin on vascular endothelial cells. Detachment of HUVEC from vitronectin by contortrostatin induced apoptosis.
HUVEC adhered and spread well on immobilized contortrostatin without undergoing apoptosis, suggesting that it is the inhibition
of adhesion and spreading of HUVEC on extracellular matrix proteins, rather than binding of contortrostatin to integrins per se, that triggers apoptosis. We conclude that contortrostatin binds to αvβ3, and interferes with the anchorage-dependent survival
mechanism of the vascular endothelial cells, and the mobility of the cells. The consequent suppression of angiogenesis is
an important component of the antineoplastic activity of contortrostatin.
This revised version was published online in June 2006 with corrections to the Cover Date. |
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Keywords: | angiogenesis disintegrin integrin vitronectin receptor |
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