Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1

Neuropilin-1 (NRP-1), a non-tyrosine kinase receptor of vascular endothelial growth factor-165 (VEGF 165), was found expressed on endothelial and some tumor cells. Since its overexpression is correlated with tumor angiogenesis and progression, the targeting of NRP-1 could be a potential anti-cancer...

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Bibliographic Details
Published in:Life sciences (1973) 2006-11, Vol.79 (25), p.2370-2381
Main Authors: Starzec, Anna, Vassy, Roger, Martin, Antoine, Lecouvey, Marc, Di Benedetto, Mélanie, Crépin, Michel, Perret, Gérard Y.
Format: Article
Language:English
Subjects:
Angiogenesis
Angiogenesis Inhibitors - therapeutic use
Animals
Antineoplastic Agents - therapeutic use
Blotting, Western
Cells, Cultured
CHO Cells
Coculture Techniques
Cricetinae
Cross-Linking Reagents
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Female
Fibroblasts - cytology
Fibroblasts - metabolism
Humans
Immunoenzyme Techniques
Iodine Radioisotopes
KDR
Mammary Neoplasms, Experimental - blood supply
Mammary Neoplasms, Experimental - drug therapy
Mammary Neoplasms, Experimental - metabolism
Mice
Mice, Nude
Neovascularization, Pathologic - drug therapy
Neuropilin-1
Neuropilin-1 - metabolism
Peptide Fragments - therapeutic use
Protein Binding
Tumor growth
Umbilical Veins
Vascular Endothelial Growth Factor A - antagonists & inhibitors
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-1 - metabolism
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 - metabolism
VEGF-165
Xenograft Model Antitumor Assays
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Summary:Neuropilin-1 (NRP-1), a non-tyrosine kinase receptor of vascular endothelial growth factor-165 (VEGF 165), was found expressed on endothelial and some tumor cells. Since its overexpression is correlated with tumor angiogenesis and progression, the targeting of NRP-1 could be a potential anti-cancer strategy. To explore this hypothesis, we identified a peptide inhibiting the VEGF 165 binding to NRP-1 and we tested whether it was able to inhibit tumor growth and angiogenesis. To prove the target of peptide action, we assessed its effects on binding of radiolabeled VEGF 165 to recombinant receptors and to cultured cells expressing only VEGFR-2 (KDR) or NRP-1. Antiangiogenic activity of the peptide was tested in vitro in tubulogenesis assays and in vivo in nude mice xenotransplanted in fat-pad with breast cancer MDA-MB-231 cells. Tumor volumes, vascularity and proliferation indices were determined. The selected peptide, ATWLPPR, inhibited the VEGF 165 binding to NRP-1 but not to tyrosine kinase receptors, VEGFR-1 (flt-1) and KDR; nor did it bind to heparin. It diminished the VEGF-induced human umbilical vein endothelial cell proliferation and tubular formation on Matrigel and in co-culture with fibroblasts. Administration of ATWLPPR to nude mice inhibited the growth of MDA-MB-231 xenografts, and reduced blood vessel density and endothelial cell area but did not alter the proliferation indices of the tumor. In conclusion, ATWLPPR, a previously identified KDR-interacting peptide, was shown to inhibit the VEGF 165 interactions with NRP-1 but not with KDR and to decrease the tumor angiogenesis and growth, thus validating, in vivo, NRP-1 as a possible target for antiangiogenic and antitumor agents.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2006.08.005