Structure and inhibitory effects on angiogenesis and tumor development of a new vascular endothelial growth inhibitor.

Abstract

Blocking angiogenesis is an attractive strategy to inhibit tumor growth, invasion, and metastasis. We describe here the structure and the biological action of a new cyclic peptide derived from vascular endothelial growth factor (VEGF). This 17-amino acid molecule designated cyclopeptidic vascular endothelial growth inhibitor (cyclo-VEGI, CBO-P11) encompasses residues 79-93 of VEGF which are involved in the interaction with VEGF receptor-2. In aqueous solution, cyclo-VEGI presents a propensity to adopt a helix conformation that was largely unexpected because only beta-sheet structures or random coil conformations have been observed for macrocyclic peptides. Cyclo-VEGI inhibits binding of iodinated VEGF165 to endothelial cells, endothelial cells proliferation, migration, and signaling induced by VEGF165. This peptide also exhibits anti-angiogenic activity in vivo on the differentiated chicken chorioallantoic membrane. Furthermore, cyclo-VEGI significantly blocks the growth of established intracranial glioma in nude and syngeneic mice and improves survival without side effects. Taken together, these results suggest that cyclo-VEGI is an attractive candidate for the development of novel angiogenesis inhibitor molecules useful for the treatment of cancer and other angiogenesis-related diseases.

• Authors: Lior Zilberberg, Svetlana Shinkaruk, Olivier Lequin, Benoit Rousseau, Martin Hagedorn, Francesco Costa, Dario Caronzolo, Maurice Balke, Xavier Canron, Odile Convert, Georges Laïn, Karine Gionnet, Mario Goncalvès, Mireille Bayle, Lorenzo Bello, Gerard Chassaing, Gérard Deleris, Andreas Bikfalvi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 37 Pg. 35564-73 (Sep 12 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12837752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Endothelial Growth Factors
• Intercellular Signaling Peptides and Proteins
• Lymphokines
• Peptides, Cyclic
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• cyclo-VEGI
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases

Topics

• Allantois (drug effects)
• Amino Acid Sequence
• Angiogenesis Inhibitors (chemistry, pharmacology, therapeutic use)
• Animals
• Capillaries
• Cattle
• Cell Division (drug effects)
• Chick Embryo
• Chorion (drug effects)
• Endothelial Growth Factors (chemistry, pharmacology, therapeutic use)
• Endothelium, Vascular (cytology, drug effects, physiology)
• Glioma (blood supply, drug therapy)
• Humans
• Intercellular Signaling Peptides and Proteins (chemistry)
• Lymphokines (chemistry)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Molecular
• Molecular Sequence Data
• Neovascularization, Physiologic (drug effects)
• Peptides, Cyclic (chemistry, pharmacology, therapeutic use)
• Phosphorylation
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-1 (drug effects, physiology)
• Vascular Endothelial Growth Factor Receptor-2 (drug effects, physiology)
• Vascular Endothelial Growth Factors