The strigolactone analog GR-24 inhibits angiogenesis in vivo and in vitro by a mechanism involving cytoskeletal reorganization and VEGFR2 signalling.

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 first 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.

• Authors: Paloma Carrillo, Beatriz Martínez-Poveda, Miguel Ángel Medina, Ana R Quesada
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 168 Pg. 366-383 (10 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 31351052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• GR24 compound
• GR24 strigolactone
• Heterocyclic Compounds, 3-Ring
• Lactones
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Animals, Genetically Modified
• Cattle
• Chick Embryo
• Cytoskeleton (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Lactones (pharmacology)
• Signal Transduction (drug effects, physiology)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)
• Zebrafish