PUBLICATION
Cholenic acid derivative UniPR1331 impairs tumor angiogenesis via blockade of VEGF/VEGFR2 in addition to Eph/ephrin
- Authors
- Rusnati, M., Paiardi, G., Tobia, C., Urbinati, C., Lodola, A., D'Ursi, P., Corrado, M., Castelli, R., Wade, R.C., Tognolini, M., Chiodelli, P.
- ID
- ZDB-PUB-210825-3
- Date
- 2021
- Source
- Cancer Gene Therapy 29(7): 908-917 (Journal)
- Registered Authors
- Tobia, Chiara
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Endothelial Cells/metabolism
- Ephrins*/metabolism
- Ephrins*/pharmacology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Vascular Endothelial Growth Factor A/metabolism
- Vascular Endothelial Growth Factor Receptor-2*/metabolism
- Zebrafish/metabolism
- PubMed
- 34426652 Full text @ Cancer Gene Ther.
Citation
Rusnati, M., Paiardi, G., Tobia, C., Urbinati, C., Lodola, A., D'Ursi, P., Corrado, M., Castelli, R., Wade, R.C., Tognolini, M., Chiodelli, P. (2021) Cholenic acid derivative UniPR1331 impairs tumor angiogenesis via blockade of VEGF/VEGFR2 in addition to Eph/ephrin. Cancer Gene Therapy. 29(7):908-917.
Abstract
Angiogenesis, the formation of new blood vessels from preexisting ones, is crucial for tumor growth and metastatization, and is considered a promising therapeutic target. Unfortunately, drugs directed against a specific proangiogenic growth factor or receptor turned out to be of limited benefit for oncology patients, likely due to the high biochemical redundancy of the neovascularization process. In this scenario, multitarget compounds that are able to simultaneously tackle different proangiogenic pathways are eagerly awaited. UniPR1331 is a 3β-hydroxy-Δ5-cholenic acid derivative, which is already known to inhibit Eph-ephrin interaction. Here, we employed an analysis pipeline consisting of molecular modeling and simulation, surface plasmon resonance spectrometry, biochemical assays, and endothelial cell models to demonstrate that UniPR1331 directly interacts with the vascular endothelial growth factor receptor 2 (VEGFR2) too. The binding of UniPR1331 to VEGFR2 prevents its interaction with the natural ligand vascular endothelial growth factor and subsequent autophosphorylation, signal transduction, and in vitro proangiogenic activation of endothelial cells. In vivo, UniPR1331 inhibits tumor cell-driven angiogenesis in zebrafish. Taken together, these data shed light on the pleiotropic pharmacological effect of UniPR1331, and point to Δ5-cholenic acid as a promising molecular scaffold for the development of multitarget antiangiogenic compounds.
Errata / Notes
This article is corrected by ZDB-PUB-220906-266.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping