PUBLICATION
The strigolactone analog GR-24 inhibits angiogenesis in vivo and in vitro by a mechanism involving cytoskeletal reorganization and VEGFR2 signalling
- Authors
- Carrillo, P., Martínez-Poveda, B., Ángel Medina, M., Quesada, A.R.
- ID
- ZDB-PUB-190729-15
- Date
- 2019
- Source
- Biochemical pharmacology 168: 366-383 (Journal)
- Registered Authors
- Keywords
- Angiogenesis, Cytoskeleton, FAK, GR-24, VEGFR2
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Animals, Genetically Modified
- Cattle
- Chick Embryo
- Cytoskeleton/drug effects*
- Cytoskeleton/metabolism
- Dose-Response Relationship, Drug
- Heterocyclic Compounds, 3-Ring/pharmacology*
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Lactones/pharmacology*
- Signal Transduction/drug effects*
- Signal Transduction/physiology
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Zebrafish
- PubMed
- 31351052 Full text @ Biochem. Pharmacol.
Citation
Carrillo, P., Martínez-Poveda, B., Ángel Medina, M., Quesada, A.R. (2019) The strigolactone analog GR-24 inhibits angiogenesis in vivo and in vitro by a mechanism involving cytoskeletal reorganization and VEGFR2 signalling. Biochemical pharmacology. 168:366-383.
Abstract
Phytohormones have shown great potential as natural anticancer compounds, being interesting in cancer prevention and therapy. Strigolactones are a class of plant hormones involved in the inhibition of root branching and sprouting. The antiproliferative capacity of the synthetic strigolactone analog GR-24 has been described against breast cancer cell lines in vitro. In this study, we show for the fist time that GR-24 is a potent antiangiogenic compound in vivo and in vitro. In the in vivo tests, GR-24 shows a great inhibitory effect on vasculature formation in the chicken chorioallantoic membrane and in two different zebrafish models. Our in vitro results show that GR-24 inhibits the growth of endothelial cells and different cancer cell lines with a micromolar range of half inhibitory concentration (IC50) values. In addition, GR-24 inhibits key steps of the angiogenic process in vitro, such as tubulogenesis, invasion, extracellular matrix remodeling capacity, migration and adhesion of endothelial cells at non-cytotoxic concentrations. Our data point to an effect of GR-24 on cytoskeleton organization in endothelial cells, in addition to a decrease in focal adhesion kinase (FAK) presence in these cells. All these data, together with the observed increase in surface expression of vascular endothelial-cadherin (VE-cadherin) and platelet and endothelial cell adhesion molecule 1 (PECAM-1), suggest that GR-24 prevents angiogenesis by maintaining the quiescent phenotype in endothelial cells. The proposed mechanism of action underlying the antiangiogenic activity of GR-24 involves the inhibition of VEGFR2 phosphorylation, and the downstream reduction in activation of FAK, a key regulator protein implicated in angiogenesis. Our results suggest that GR-24 may be a promising new compound for antiangiogenic therapy of cancer and other angiogenesis-dependent diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping