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Paris Saponin II suppresses the growth of human ovarian cancer xenografts via modulating VEGF-mediated angiogenesis and tumor cell migration

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Abstract

Purpose

Paris Saponin II (PSII) is an active component of Rhizoma Paridis—an essential ingredient in traditional Chinese herbal medicines. PSII can induce cytotoxic effects in cancer cells and inhibit ovarian cancer growth. Since pathological angiogenesis (henceforth, angiogenesis) is often associated with gynecological cancers, here, we investigated whether PSII renders effects on angiogenesis and examined possible molecular mechanisms underlying the effects of PSII.

Methods

The effects of PSII on the biofunctions of endothelial cells (EC), the crucial components of blood vessels, were examined by standardized angiogenesis in vitro and ex vivo assays, Western blot analysis, ELISA, and kinase assay. Angiogenesis in a xenograft mouse model of ovarian cancer was evaluated by color Doppler ultrasound and immunohistochemistry.

Results

PSII exerted marked inhibitory effect on the growth of VEGF-stimulated human umbilical vein endothelial cells in a dose–time-dependent manner, inhibited cell’s motility, and interfered with tubulogenesis. PSII also blocked microvessel outgrowth in a rat aortic ring assay and compromised angiogenesis in a mouse model of ovarian carcinoma using either SKOV3 or HOC-7 cell lines. VEGF levels in PSII-treated EC and tumor cells were reduced. In EC, PSII blocked the activation of VEGFR2 in dose-dependent manner leading to the reduction of VEGF-induced phosphorylation on several intracellular pro-angiogenic kinase, including the extracellular signal-related kinase, Src family kinase, focal adhesion kinase, and AKT kinase.

Conclusions

The results provided the first insight into the anti-angiogenesis properties of Saponin family in solid tumors and suggested a promising therapeutic potential of PSII in the ovarian cancer treatment.

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Acknowledgements

This work was supported by the Fund of National Nature Science Foundations Grant No. 81001159/81202387/81101991, Sichuan Province Science and Technology plan Project No. 2013JY0013. We would like to thank Dr. Meifang Xiao and Dr. Hong Zou for providing us with PSI and PSII compounds. We thank Diane Hackett and Maude E. Veech for technical support. We also thank Dr. Tri Bui-Nguyen for his review and insightful comments on this project.

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Xue Xiao, Mei Yang, Shanling Liu & He Wang

  2. Laboratory of Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Xue Xiao, Mei Yang, Shanling Liu & He Wang

  3. Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Juan Zou, Qin Huang & Kaixuan Yang

  4. Department of Ultrasound, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Bo Zhang & Fan Yang

  5. West China School of Preclinical and Forensic Medicine, Sichuan University, No 17, Block 3, Renmin Road, Chengdu, 610041, People’s Republic of China

    Peng Bai

  6. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Xue Xiao & Jianguo Xiao

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  1. Xue Xiao
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Corresponding author

Correspondence to Peng Bai.

Additional information

Xue Xiao and Mei Yang have contributed equally to this paper.

Electronic supplementary material

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280_2014_2408_MOESM1_ESM.tif

Supplementary Fig.S1 PSII treatment induced apoptosis in both high-grade serous OC SKOV3 cells and low-grade serous OC HOC-7 cells in a dose-dependent and time-dependent manner (P<0.05). TUNEL data presented as the percentage of apoptotic cells (green fluorescence) per the total number of treated cells (blue fluorescence). Ten random fields were selected per slide. Representative figures of PSII-treated cells labeled for TUNEL and counterstained with 4,6-diamidino-2-phenylindole (DAPI) are provided. Columns, mean; bars, SE. (TIFF 13762 kb)

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Xiao, X., Yang, M., Xiao, J. et al. Paris Saponin II suppresses the growth of human ovarian cancer xenografts via modulating VEGF-mediated angiogenesis and tumor cell migration. Cancer Chemother Pharmacol 73, 807–818 (2014). https://doi.org/10.1007/s00280-014-2408-x

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  • DOI: https://doi.org/10.1007/s00280-014-2408-x

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