Eur J Pharmacol.
2005 May 2;514(1):1-15.
Inhibition
of angiogenesis and tumor growth by beta and gamma-secretase
inhibitors.
Paris D, Quadros A, Patel N, DelleDonne A, Humphrey J, Mullan M.
The Roskamp Institute,
The involvement of beta-secretase
and gamma-secretase in producing the beta-amyloid component of senile plaques found in the brain of
Alzheimer's patients has fueled a major research effort to design selective
inhibitors of these proteases. Interestingly, gamma-secretase
cleaves several proteins including Notch, E-cadherin,
CD44 and ErbB-4 (erythroblastic leukemia viral oncogene homolog 4), which are important modulators of
angiogenesis. The beta-amyloid precursor protein,
which is cleaved by beta-secretase and gamma-secretase to produce beta-amyloid,
is highly expressed in the endothelium of neoforming
vessels suggesting that it might play a role during angiogenesis. These data
prompted us to explore the effects of beta and gamma-secretase
inhibitors of different structures on angiogenesis and tumor growth. Both the
gamma and beta-secretase inhibitors tested reduce
endothelial cell proliferation without inducing cellular toxicity, suppress the
formation of capillary structures in vitro and oppose the sprouting of microvessel outgrowths in the rat aortic ring model of
angiogenesis. Moreover, they potently inhibit the growth and vascularization of human glioblastoma
and human lung adenocarcinoma tumors xenotransplanted into nude mice. Altogether these data
suggest that the gamma and beta-secretases play an
essential role during angiogenesis and that inhibitors
of the beta and gamma-secretases may constitute new
classes of anti-angiogenic and anti-tumoral compounds.
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Keywords: Angiogenesis, Inhibition, beta, gamma-secretase, European Journal Pharmacology