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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3035-3044.
Prepublished online as a Blood First Edition Paper on July 11, 2006; DOI 10.1182/blood-2006-05-023580.
 Previous Article | Next Article 
Submitted October 27, 2005
Accepted June 19, 2006
Blockade of  v 3 and v5
integrins by RGD mimetics induces anoikis and not
integrin-mediated death in human endothelial cells
Sylvie Maubant, Dominique Saint-Dizier, Morgane Boutillon, Francoise Perron-Sierra, Patrick J Casara, John A Hickman, Gordon C Tucker, and Ellen Van Obberghen-Schilling*
CNRS UMR 6543, Centre Antoine Lacassagne, Nice, France
Cancer Drug Discovery Division, Institut de Recherches Servier, Croissy-sur-Seine, France
Medicinal Chemistry Division, Institut de Recherches Servier, Croissy-sur-Seine, France
* Corresponding author; email: vanobber{at}unice.fr.
Alpha-v integrins are thought to play an important role
in tumor angiogenesis. However, discrepancies between
findings with RGD mimetics which block angiogenesis in
animal models, and knockout mice, where loss of some &
[alpha]v integrins enhances tumor angiogenesis, raise
questions concerning the function of these integrins and
the precise role of  v substrate mimetics in anti
angiogenic therapies. Here, we have examined the effects
of a novel non-peptidic RGD mimetic, S 36578 2, on human
endothelial cells in order to elucidate its antagonist
activity, and identify possible agonist functions. S
36578 2 is highly selective for v 3 and &
[alpha]v 5 integrins and induces
detachment, caspase-8 activation and apoptosis in human
umbilical endothelial cells (HUVEC) plated on
vitronectin. Importantly, the compound has no effect on
morphology or survival of cells plated on interstitial
matrix components such as fibronectin and it does not
potentiate the apoptotic process in suspended cells.
Identical results were obtained with a cyclic RGD
peptide with similar target specificity. In
microvascular endothelial cells, S 36578 2-induced death
was also linked to its anti-adhesive effect, with
established lines being markedly more resistant than
primary cultures to the anti-adhesive and pro-apoptotic
effects. Altogether, these findings have important
implications for the development of this class of anti-
angiogenics.
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