A serum-stable branched dimeric anti-VEGF peptide blocks tumor growth via anti-angiogenic activity.
10.3858/emm.2010.42.7.052
- Author:
Jung Wook KIM
1
;
Tae Dong KIM
;
Bok Sil HONG
;
Oh Youn KIM
;
Wan Hee YOON
;
Chi Bom CHAE
;
Yong Song GHO
Author Information
1. Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea. ysgho@postech.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
angiogenesis inhibitors;
colorectal neoplasms;
peptides;
receptors, vascular endothelial growth factor;
vascular endothelial growth factors
- MeSH:
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
- From:Experimental & Molecular Medicine
2010;42(7):514-523
- CountryRepublic of Korea
- Language:English
-
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.
