PUBLICATION
N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors
- Authors
- Nawaz, I.M., Chiodelli, P., Rezzola, S., Paganini, G., Corsini, M., Lodola, A., Di Ianni, A., Mor, M., Presta, M.
- ID
- ZDB-PUB-191029-16
- Date
- 2018
- Source
- Angiogenesis 21: 47-59 (Journal)
- Registered Authors
- Presta, Marco
- Keywords
- Angiogenesis, BOC2, FGF2, Heparin binding, VEGF
- MeSH Terms
-
- Animals
- CHO Cells
- Cattle
- Cell Line, Tumor
- Chick Embryo
- Cricetulus
- Fibroblast Growth Factor 2*/antagonists & inhibitors
- Fibroblast Growth Factor 2*/chemistry
- Fibroblast Growth Factor 2*/metabolism
- Human Umbilical Vein Endothelial Cells/cytology
- Human Umbilical Vein Endothelial Cells/metabolism*
- Humans
- Neovascularization, Physiologic/drug effects*
- Neovascularization, Physiologic/physiology
- Oligopeptides*/chemistry
- Oligopeptides*/pharmacology
- Receptors, Formyl Peptide/metabolism
- Signal Transduction/drug effects
- Surface Plasmon Resonance
- Vascular Endothelial Growth Factor A*/antagonists & inhibitors
- Vascular Endothelial Growth Factor A*/chemistry
- Vascular Endothelial Growth Factor A*/metabolism
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Zebrafish
- PubMed
- 29030736 Full text @ Angiogenesis
Citation
Nawaz, I.M., Chiodelli, P., Rezzola, S., Paganini, G., Corsini, M., Lodola, A., Di Ianni, A., Mor, M., Presta, M. (2018) N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors. Angiogenesis. 21:47-59.
Abstract
The peptides N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) and BOC-Met-Leu-Phe (BOC1) are widely used antagonists of formyl peptide receptors (FPRs), BOC2 acting as an FPR1/FPR2 antagonist whereas BOC1 inhibits FPR1 only. Extensive investigations have been performed by using these FPR antagonists as a tool to assess the role of FPRs in physiological and pathological conditions. Based on previous observations from our laboratory, we assessed the possibility that BOC2 may exert also a direct inhibitory effect on the angiogenic activity of vascular endothelial growth factor-A (VEGF-A). Our data demonstrate that BOC2, but not BOC1, inhibits the angiogenic activity of heparin-binding VEGF-A165 with no effect on the activity of the non-heparin-binding VEGF-A121 isoform. Endothelial cell-based bioassays, surface plasmon resonance analysis, and computer modeling indicate that BOC2 may interact with the heparin-binding domain of VEGF-A165, thus competing for heparin interaction and preventing the binding of VEGF-A165 to tyrosine kinase receptor VEGFR2, its phosphorylation and downstream signaling. In addition, BOC2 inhibits the interaction of a variety of heparin-binding angiogenic growth factors with heparin, including fibroblast growth factor 2 (FGF2) whose angiogenic activity is blocked by the compound. Accordingly, BOC2 suppresses the angiogenic potential of human tumor cell lines that co-express VEGF-A and FGF2. Thus, BOC2 appears to act as a novel multi-heparin-binding growth factor antagonist. These findings caution about the interpretation of FPR-focusing experimental data obtained with this compound and set the basis for the design of novel BOC2-derived, FPR independent multi-target angiogenesis inhibitors.
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Mutations / Transgenics
Human Disease / Model
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