Exp Mol Med.  2010 Jul;42(7):514-523. 10.3858/emm.2010.42.7.052.

A serum-stable branched dimeric anti-VEGF peptide blocks tumor growth via anti-angiogenic activity

• Kim JW
• Kim TD
• Hong BS
• Kim OY
• Yoon WH
• Chae CB
• Gho YS

• KMID: 1104211
• DOI: http://doi.org/10.3858/emm.2010.42.7.052

Abstract

Angiogenesis is critical and indispensable for tumor progression. Since VEGF is known to play a central role in angiogenesis, the disruption of VEGF-VEGF receptor system is a promising target for anti-cancer therapy. Previously, we reported that a hexapeptide (RRKRRR, RK6) blocked the growth and metastasis of tumor by inhibiting VEGF binding to its receptors. In addition, dRK6, the D-form derivative of RK6, retained its biological activity with improved serum stability. In the present study, we developed a serum-stable branched dimeric peptide (MAP2-dRK6) with enhanced anti-VEGF and anti-tumor activity. MAP2-dRK6 is more effective than dRK6 in many respects: inhibition of VEGF binding to its receptors, VEGF- and tumor conditioned medium-induced proliferation and ERK signaling of endothelial cells, and VEGF-induced migration and tube formation of endothelial cells. Moreover, MAP2-dRK6 blocks in vivo growth of VEGF-secreting colorectal cancer cells by the suppression of angiogenesis and the subsequent induction of tumor cell apoptosis. Our observations suggest that MAP2-dRK6 can be a prospective therapeutic molecule or lead compound for the development of drugs for various VEGF-related angiogenic diseases.

Keyword

angiogenesis inhibitors; colorectal neoplasms; peptides; receptors, vascular endothelial growth factor; vascular endothelial growth factors

MeSH Terms

Amino Acid Sequence
Angiogenesis Inhibitors/*pharmacology
Animals
Cell Movement/drug effects
Cell Proliferation/drug effects
Colorectal Neoplasms/*pathology/secretion
Endothelial Cells/cytology/drug effects/enzymology
Enzyme Activation/drug effects
Extracellular Signal-Regulated MAP Kinases/metabolism
Humans
Mice
Mice, Nude
Molecular Sequence Data
Neovascularization, Pathologic/pathology/prevention & control
Neovascularization, Physiologic/drug effects
Peptides/chemistry/*pharmacology
Protein Multimerization/*drug effects
Protein Stability/drug effects
Rats
Serum
Vascular Endothelial Growth Factor A/*antagonists & inhibitors/secretion