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Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway.
- Source :
-
PloS one [PLoS One] 2013 Jul 05; Vol. 8 (7), pp. e68566. Date of Electronic Publication: 2013 Jul 05 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Angiogenesis is crucial for cancer initiation, development and metastasis. Identifying natural botanicals targeting angiogenesis has been paid much attention for drug discovery in recent years, with the advantage of increased safety. Isoliquiritigenin (ISL) is a dietary chalcone-type flavonoid with various anti-cancer activities. However, little is known about the anti-angiogenic activity of isoliquiritigenin and its underlying mechanisms. Herein, we found that ISL significantly inhibited the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) at non-toxic concentration. A series of angiogenesis processes including tube formation, invasion and migration abilities of HUVECs were also interrupted by ISL in vitro. Furthermore, ISL suppressed sprout formation from VEGF-treated aortic rings in an ex-vivo model. Molecular mechanisms study demonstrated that ISL could significantly inhibit VEGF expression in breast cancer cells via promoting HIF-1α (Hypoxia inducible factor-1α) proteasome degradation and directly interacted with VEGFR-2 to block its kinase activity. In vivo studies further showed that ISL administration could inhibit breast cancer growth and neoangiogenesis accompanying with suppressed VEGF/VEGFR-2 signaling, elevated apoptosis ratio and little toxicity effects. Molecular docking simulation indicated that ISL could stably form hydrogen bonds and aromatic interactions within the ATP-binding region of VEGFR-2. Taken together, our study shed light on the potential application of ISL as a novel natural inhibitor for cancer angiogenesis via the VEGF/VEGFR-2 pathway. Future studies of ISL for chemoprevention or chemosensitization against breast cancer are thus warranted.
- Subjects :
- Adenosine Triphosphate
Animals
Binding Sites
Breast Neoplasms drug therapy
Cell Line
Cell Movement drug effects
Cell Proliferation drug effects
Chalcones chemistry
Dietary Supplements
Disease Models, Animal
Female
Human Umbilical Vein Endothelial Cells drug effects
Human Umbilical Vein Endothelial Cells metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Mice
Molecular Conformation
Molecular Docking Simulation
Neovascularization, Pathologic drug therapy
Neovascularization, Physiologic drug effects
Proteasome Endopeptidase Complex metabolism
Protein Binding
Proteolysis drug effects
Tumor Burden drug effects
Vascular Endothelial Growth Factor A pharmacology
Vascular Endothelial Growth Factor Receptor-2 chemistry
Xenograft Model Antitumor Assays
Breast Neoplasms metabolism
Breast Neoplasms pathology
Chalcones pharmacology
Neovascularization, Pathologic metabolism
Signal Transduction drug effects
Vascular Endothelial Growth Factor A metabolism
Vascular Endothelial Growth Factor Receptor-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23861918
- Full Text :
- https://doi.org/10.1371/journal.pone.0068566