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Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways

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Abstract

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.

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Acknowledgments

The authors greatly appreciate the financial support from National Key Technologies R&D Program of China (2012ZX09103101-009).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Chengdu, 610041, Sichuan, China

    Xiuxia Li, Xuewei Wang, Haoyu Ye, Aihua Peng & Lijuan Chen

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  1. Xiuxia Li
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  2. Xuewei Wang
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  3. Haoyu Ye
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  5. Lijuan Chen
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Corresponding author

Correspondence to Lijuan Chen.

Additional information

Xiuxia Li and Xuewei Wang contributed equally to this work.

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Li, X., Wang, X., Ye, H. et al. Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways. Cancer Chemother Pharmacol 70, 425–437 (2012). https://doi.org/10.1007/s00280-012-1923-x

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  • DOI: https://doi.org/10.1007/s00280-012-1923-x

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