Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways
- Authors
- Li, X., Wang, X., Ye, H., Peng, A., and Chen, L.
- ID
- ZDB-PUB-120724-6
- Date
- 2012
- Source
- Cancer Chemotherapy and Pharmacology 70(3): 425-437 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/administration & dosage
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Carcinoma, Non-Small-Cell Lung/blood supply
- Carcinoma, Non-Small-Cell Lung/drug therapy*
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Collagen/metabolism
- Dose-Response Relationship, Drug
- Drug Combinations
- Human Umbilical Vein Endothelial Cells
- Humans
- Isoflavones/administration & dosage
- Isoflavones/pharmacology*
- Laminin/metabolism
- Lung Neoplasms/blood supply
- Lung Neoplasms/drug therapy*
- Lung Neoplasms/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Nude
- Neovascularization, Pathologic/drug therapy*
- Proteoglycans/metabolism
- Signal Transduction/drug effects
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 22814678 Full text @ Cancer Chemother. Pharmacol.
Purpose
We previously reported that barbigerone (BA), an isoflavone isolated from Suberect Spatholobus, exhibited inhibitory effects on proliferation of many cancer cell lines in vitro. The objective of this study was to explore whether BA could effectively suppress tumor angiogenesis and tumor growth.
Methods
Zebrafish model and Matrigel assay were performed to access the anti-angiogenesis effects of BA. A549 and SPC-A1 tumor xenografts in mice models were used to examine the antitumor activity of BA. The anti-angiogenic effects and underlying mechanisms were also investigated using human umbilical vein endothelial cells (HUVECs) and A549 cells.
Results
In zebrafish model, 2.5 µmol/L of BA significantly inhibited angiogenesis. Intravenous administration of BA effectively inhibited the tumor growth of A549 and SPC-A1 xenograft models in mice. The anti-angiogenic effect was indicated by CD31 immunohistochemical staining, Matrigel plug assay, and mouse aortic ring assay. BA could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tuber formation of HUVECs in a dose-dependent manner, suggesting that BA inhibited tumorigenesis by targeting angiogenesis. Western blots revealed that BA directly inhibited the phosphorylation of VEGFR2, followed by inhibiting the activations of its downstream protein kinases, including ERK, p38, FAK, AKT, and expression of iNOS, but had no effect on COX2. Additionally, BA could also down-regulate VEGF secretion in A549 cancer cells, which may correlate with the suppression of ERK, AKT activation, indicating that BA inhibits tumor angiogenesis and tumor growth through VEGFR2 signaling pathways.
Conclusions
These findings suggest that BA may be a novel candidate in inhibiting tumor angiogenesis and NSCLC tumor growth.