Inhibition of angiogenesis and tumor growth by β and γ-secretase inhibitors

The involvement of β-secretase and γ-secretase in producing the β-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, γ-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 β-amyloid precursor protein, which is cleaved by β-secretase and γ-secretase to produce β-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 β and γ-secretase inhibitors of different structures on angiogenesis and tumor growth. Both the γ and β-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 γ and β-secretases play an essential role during angiogenesis and that inhibitors of the β and γ-secretases may constitute new classes of anti-angiogenic and anti-tumoral compounds.