Oncotarget

Research Papers:

Eriocalyxin B, a natural diterpenoid, inhibited VEGF-induced angiogenesis and diminished angiogenesis-dependent breast tumor growth by suppressing VEGFR-2 signaling

Grace Gar-Lee Yue, Minghua Liu, Zhili Zuo, Zhili Zuo, Julia Kin-Ming Lee, Mingyue Li, Stephen Kwok-Wing Tsui, Kwok-Pui Fung, Handong Sun, Jianxin Pu and Clara Bik-San Lau _

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Oncotarget. 2016; 7:82820-82835. https://doi.org/10.18632/oncotarget.12652

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Abstract

Xunian Zhou1,2, Grace Gar-Lee Yue2,3, Minghua Liu1, Zhili Zuo4, Julia Kin-Ming Lee2,3, Mingyue Li1, Stephen Kwok-Wing Tsui1, Kwok-Pui Fung1,2,3, Handong Sun4, Jianxin Pu4, Clara Bik-San Lau2,3

1School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China

2Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China

3State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China

4State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China

Correspondence to:

Clara Bik-San Lau, email: claralau@cuhk.edu.hk

Jianxin Pu, email: pujianxin@mail.kib.ac.cn

Keywords: Eriocalyxin B, angiogenesis, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), breast cancer

Received: April 23, 2016     Accepted: October 02, 2016     Published: October 14, 2016

ABSTRACT

Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid isolated from the plant Isodon eriocalyx var. laxiflora, has emerged as a promising anticancer agent. The effects of EriB on angiogenesis were explored in the present study. Here we demonstrated that the subintestinal vein formation was significantly inhibited by EriB treatment (10, 15 μM) in zebrafish embryos, which was resulted from the alteration of various angiogenic genes as shown in transcriptome profiling. In human umbilical vein endothelial cells, EriB treatment (50, 100 nM) could significantly block vascular endothelial growth factors (VEGF)-induced cell proliferation, tube formation, cell migration and cell invasion. Furthermore, EriB also caused G1 phase cell cycle arrest which was correlated with the down-regulation of the cyclin D1 and CDK4 leading to the inhibition of phosphorylated retinoblastoma protein expression. Investigation of the signal transduction revealed that EriB inhibited VEGF-induced phosphorylation of VEGF receptor-2 via the interaction with the ATP-binding sites according to the molecular docking simulations. The suppression of VEGFR-2 downstream signal transduction cascades was also observed. EriB was showed to inhibit new blood vessel formation in Matrigel plug model and mouse 4T1 breast tumor model. EriB (5 mg/kg/day) treatment was able to decrease tumor vascularization and suppress tumor growth and angiogenesis. Taken together, our findings suggested that EriB is a novel inhibitor of angiogenesis through modulating VEGFR-2 signaling pathway, which could be developed as a promising anti-angiogenic agent for treatment of angiogenesis-related human diseases, such as cancer.


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