PUBLICATION
Two natural eudesmane-type sesquiterpenes from Laggera alata inhibit angiogenesis and suppress breast cancer cell migration through VEGF- and Angiopoietin 2-mediated signaling pathways
- Authors
- Liang, N., Li, Y., Chung, H.Y.
- ID
- ZDB-PUB-170524-4
- Date
- 2017
- Source
- International Journal of Oncology 51(1): 213-222 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Apoptosis/drug effects
- Asteraceae/chemistry*
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/blood supply
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Breast Neoplasms/prevention & control*
- Cell Movement/drug effects*
- Cell Proliferation/drug effects
- Cells, Cultured
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Female
- Human Umbilical Vein Endothelial Cells
- Humans
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control*
- Sesquiterpenes, Eudesmane/pharmacology*
- Signal Transduction
- Vascular Endothelial Growth Factor A/metabolism*
- Vesicular Transport Proteins/metabolism*
- Zebrafish/embryology
- Zebrafish/metabolism
- PubMed
- 28534941 Full text @ Int. J. Oncol.
Citation
Liang, N., Li, Y., Chung, H.Y. (2017) Two natural eudesmane-type sesquiterpenes from Laggera alata inhibit angiogenesis and suppress breast cancer cell migration through VEGF- and Angiopoietin 2-mediated signaling pathways. International Journal of Oncology. 51(1):213-222.
Abstract
Eudesmane-type sesquiterpenes are natural sesquiterpenes with anti-inflammatory properties, but their anti-angiogenic activities are not known. The present study demonstrated that 5α-hydroxycostic acid and hydroxyisocostic acid, two eudesmane-type sesquiterpenes (ETSs), isolated from the herb Laggera alata, possessed anti-angiogenic effects. Under non-toxic dosage, ETSs suppressed VEGF‑induced proliferation in human umbilical vein endothelial cells (HUVECs) and vessel formation in zebrafish embryos. Moreover, ETSs inhibited VEGF-stimulated HUVEC migration, stress fibers and tube formation. Results from real‑time PCR analysis involving in vivo and in vitro experiments indicated that pro-angiogenic-related mRNA levels were downregulated, including VEGFA, VEGFR2 and Tie2 genes after ETS treatments. Western blot analysis showed that ETSs suppressed VEGF-stimulated VEGFR2 phosphorylation and activation of its downstream molecules, such as Src/AKT/eNOS, FAK, PLCγ/ERK1/2 and p38. Moreover, the VEGF-stimulation of angiopoietin 2 (Ang2) mRNA level increase was significantly downregulated in the presence of ETSs. ETSs inhibited Ang2-induced phosphorylation of the receptor Tie2 in HUVECs, which indicated that ETSs not just suppressed VEGF/VEGFR2 axis, but also the Ang2/Tie2 one. Furthermore, the wound-healing assay revealed that ETSs reduced the migration of Ang2-stimulated human breast cancer (MCF-7) cells. Mechanistically, the anti-migration effect of ETSs correlated with the blockade of Ang2-induced E-cadherin loss and AKT activation. Collectively, the present study suggests that ETSs possess anti-angiogenic ability by interfering the VEGF- and Ang2-related pathways, and they may be good drug candidates.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping