Journal Article

A peptide mimicking the binding sites of VEGF-A and VEGF-B inhibits VEGFR-1/-2 driven angiogenesis, tumor growth and metastasis

Farzaneh Behelgardi, Maryam, Asghari, S. Mohsen, Mansouri, Kamran, Zahri, Saber, Mashayekhi, Farhad

2018

Overview

Interfering with interactions of vascular endothelial growth factors (VEGFs) with their receptors (VEGFRs) effectively inhibits angiogenesis and tumor growth. We designed an antagonist peptide of VEGF-A and VEGF-B reproducing two discontinuous receptor binding regions of VEGF-B (loop 1 and loop3) covalently linked together by a receptor binding region of VEGF-A (loop3). The designed peptide (referred to as VGB4) was able to bind to both VEGFR1 and VEGFR2 on the Human Umbilical Vein Endothelial Cells (HUVECs) surface and inhibited VEGF-A driven proliferation, migration and tube formation in HUVECs through suppression of ERK1/2 and AKT phosphorylation. The whole-animal fluorescence imaging demonstrated that fluorescein isothiocyanate (FITC)-VGB4 accumulated in the mammary carcinoma tumors (MCTs). Administration of VGB4 led to the regression of 4T1 murine MCT growth through decreased expression of p-VEGFR1 and p-VEGFR2 and abrogation of ERK1/2 and AKT activation followed by considerable decrease of tumor cell proliferation (Ki67 expression) and angiogenesis (CD31 and CD34 expression), induction of apoptosis (increased p53 expression, TUNEL staining and decreased Bcl2 expression), and suppression of metastasis  (increased E-cadherin and decreased N-cadherin, NF-κB and MMP-9 expression). These findings indicate that VGB4 may be applicable for antiangiogenic and antitumor therapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 631/67 / 631/67/2328 / 82/29 / AKT protein / Angiogenesis / Angiogenesis Inhibitors - administration & dosage / Angiogenesis Inhibitors - pharmacology / Animals / Antineoplastic Agents / Apoptosis / Binding Sites / Biomimetic Materials - administration & dosage / Biomimetic Materials - chemistry / Biomimetic Materials - pharmacology / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - metabolism / Carcinoma / CD34 antigen / Cell Line, Tumor / Cell Movement - drug effects / Cell proliferation / Cell Proliferation - drug effects / Drug Design / E-cadherin / Endothelial cells / Female / Fluorescein isothiocyanate / Gelatinase B / Growth factors / Human Umbilical Vein Endothelial Cells / Humanities and Social Sciences / Humans / Injections, Intraperitoneal / Mammary gland / Metastases / Metastasis / Mice / Mimicry / multidisciplinary / N-Cadherin / NF-κB protein / p53 Protein / Peptides / Peptides - administration & dosage / Peptides - chemistry / Peptides - pharmacology / Phosphorylation / Phosphorylation - drug effects / Science / Science (multidisciplinary) / Tumors / Umbilical vein / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - chemistry / Vascular Endothelial Growth Factor B - antagonists & inhibitors / Vascular Endothelial Growth Factor B - chemistry / Vascular Endothelial Growth Factor Receptor-1 - metabolism / Vascular Endothelial Growth Factor Receptor-2 - metabolism / Vascular endothelial growth factor receptors / Xenograft Model Antitumor Assays