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01.04.2014 | Original Article

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

verfasst von: Xue Xiao, Mei Yang, Jianguo Xiao, Juan Zou, Qin Huang, Kaixuan Yang, Bo Zhang, Fan Yang, Shanling Liu, He Wang, Peng Bai

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2014

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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.

Nur mit Berechtigung zugänglich

Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18PubMedCrossRef

Folkman J (2007) Angiogenesis: an organizing principle for drug discovery. Nat Rev Drug Discov 6:273–286PubMedCrossRef

Gomez-Raposo C, Mendiola M, Barriuso J, Casado E, Hardisson D, Redondo A (2009) Angiogenesis and ovarian cancer. Clin Transl Oncol 11:564–571PubMedCrossRef

Yap TA, Carden CP, Kaye SB (2009) Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer 9:167–181PubMedCrossRef

Schmitt J, Matei D (2012) Targeting angiogenesis in ovarian cancer. Cancer Treat Rev 38:272–283PubMedCrossRef

Albini A, Indraccolo S, Noonan DM, Pfeffer U (2010) Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive drugs. Clin Exp Metastasis 27:419–439PubMedCrossRef

Nor JE, Christensen J, Mooney DJ, Polverini PJ (1999) Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 154:375–384PubMedCentralPubMedCrossRef

Kaneko T, Zhang Z, Mantellini MG, Karl E, Zeitlin B, Verhaegen M, Soengas MS, Lingen M, Strieter RM, Nunez G, Nor JE (2007) Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth. Cancer Res 67:9685–9693PubMedCrossRef

Nor JE, Christensen J, Liu J, Peters M, Mooney DJ, Strieter RM, Polverini PJ (2001) Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer Res 61:2183–2188PubMed

10.

Karl E, Warner K, Zeitlin B, Kaneko T, Wurtzel L, Jin T, Chang J, Wang S, Wang CY, Strieter RM, Nunez G, Polverini PJ, Nor JE (2005) Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer Res 65:5063–5069PubMedCrossRef

11.

Cosgrove D (2003) Angiogenesis imaging–ultrasound. Br J Radiol 76(1):S43–S49PubMedCrossRef

12.

Howard-Claudio C (2005) MRI methods for the detection of angiogenesis. Appl Radiol 34:9–24

13.

Man S, Gao W, Zhang Y, Jin X, Ma C, Huang X, Li Q (2009) Characterization of steroidal saponins in saponin extract from Paris polyphylla by liquid chromatography tandem multi-stage mass spectrometry. Anal Bioanal Chem 395:495–505PubMedCrossRef

14.

Liang Y, Liu Z, Gao W, Man S (2012) Determination of nine steroidal saponins in Paris polyphylla from different areas of Guizhou province by HPLC. Zhongguo Zhong Yao Za Zhi 37:2309–2312PubMed

15.

Man S, Gao W, Zhang Y, Wang J, Zhao W, Huang L, Liu C (2010) Qualitative and quantitative determination of major saponins in Paris and trillium by HPLC-ELSD and HPLC-MS/MS. J Chromatogr B Anal Technol Biomed Life Sci 878:2943–2948CrossRef

16.

Xiao X, Bai P, Bui NTM, Xiao J, Liu S, Yang G, Hu L, Chen X, Zhang X, Liu J, Wang H (2009) The antitumoral effect of Paris Saponin I associated with the induction of apoptosis through the mitochondrial pathway. Mol Cancer Ther 8:1179–1188PubMedCrossRef

17.

Siu FM, Ma DL, Cheung YW, Lok CN, Yan K, Yang Z, Yang M, Xu S, Ko BC, He QY, Che CM (2008) Proteomic and transcriptomic study on the action of a cytotoxic saponin (Polyphyllin D): induction of endoplasmic reticulum stress and mitochondria-mediated apoptotic pathways. Proteomics 8:3105–3117PubMedCrossRef

18.

Yang YH, Dai LJ, He KH, Wei JR, Zhao TZ, Su B, Wang MH (2012) Relation between soil nutrient of artificially cultivated area and rhizome quality of Paris polyphylla var. yunnanensis. Zhong Yao Cai 35:1557–1561PubMed

19.

Chiang HC, Wang JJ, Wu RT (1992) Immunomodulating effects of the hydrolysis products of formosanin C and beta-ecdysone from Paris formosana Hayata. Anticancer Res 12:1475–1478PubMed

20.

Xiao X, Zou J, Bui-Nguyen TM, Bai P, Gao L, Liu J, Liu S, Xiao J, Chen X, Zhang X, Wang H (2012) Paris saponin II of Rhizoma Paridis: a novel inducer of apoptosis in human ovarian cancer cells. Biosci Trends 6:201–211PubMedCrossRef

21.

Finley SD, Popel AS (2013) Effect of tumor microenvironment on tumor VEGF during anti-VEGF treatment: systems biology predictions. J Natl Cancer Inst 105:802–811PubMedCrossRef

22.

Sun ZG, Zhang L, Li LJ, Tian JK (2007) Studies on the extraction process of total saponins from Paris polyphylla Smith. Zhong Yao Cai 30:726–729PubMed

23.

Nguyen TM, Subramanian IV, Kelekar A, Ramakrishnan S (2007) Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells. Blood 109:4793–4802PubMedCrossRef

24.

Nicosia RF, Ottinetti A (1990) Growth of microvessels in serum-free matrix culture of rat aorta. A quantitative assay of angiogenesis in vitro. Lab Invest 63:115–122PubMed

25.

Watanabe M, Fujioka-Kaneko Y, Kobayashi H, Kiniwa M, Kuwano M, Basaki Y (2005) Involvement of integrin-linked kinase in capillary/tube-like network formation of human vascular endothelial cells. Biol Proced Online 7:41–47PubMedCentralPubMedCrossRef

26.

Bentink S, Haibe-Kains B, Risch T, Fan JB, Hirsch MS, Holton K, Rubio R, April C, Chen J, Wickham-Garcia E, Liu J, Culhane A, Drapkin R, Quackenbush J, Matulonis UA (2012) Angiogenic mRNA and microRNA gene expression signature predicts a novel subtype of serous ovarian cancer. PLoS ONE 7:e30269PubMedCentralPubMedCrossRef

27.

Coultas L, Chawengsaksophak K, Rossant J (2005) Endothelial cells and VEGF in vascular development. Nature 438:937–945PubMedCrossRef

28.

Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, Hicklin DJ, Tateno M, Bohlen P, Moore MA, Rafii S (2001) Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA 98:10857–10862PubMedCentralPubMedCrossRef

29.

Sakai Y, Goodison S, Cao W, Urquidi V, Namiki K, Porvasnik S, Urbanek C, Rosser CJ (2009) VEGF induces expression of Bcl-2 and multiple signaling factors in microvascular endothelial cells in a prostate cancer model. World J Urol 27:659–666PubMedCentralPubMedCrossRef

30.

Markowska A, Lubin J, Madry R, Markowska J (2013) Development of antiangiogenic therapies for ovarian cancer. Eur J Gynaecol Oncol 34:303–306PubMed

31.

Sia D, Alsinet C, Newell P, Villanueva A (2013) VEGF signaling in cancer treatment. Curr Pharm Des [Epub ahead of print]

32.

Wei J (1998) Determination of steroidal saponins in Rhizoma Paridis by RP-HPLC. Yao Xue Xue Bao 33:465–468PubMed

33.

Huang Y, Cui LJ, Liu WN, Wang Q (2006) Quantitative analysis of steroidal saponins in Chinese material medica Rhizoma Paridis by HPLC-ELSD. Zhongguo Zhong Yao Za Zhi 31:1230–1233PubMed

34.

Li ZH, Wan JY, Wang GQ, Zhao FG, Wen JH (2013) Identification of compounds from Paris polyphylla (ChongLou) active against Dactylogyrus intermedius. Parasitology 140:952–958PubMedCrossRef

35.

Wen F, Yin H, Chen C, Liu X, Xue D, Chen T, He J, Zhang H (2012) Chemical characteristics of saponins from Paris fargesii var. brevipetala and cytotoxic activity of its main ingredient, paris saponin H. Fitoterapia 83:627–635PubMedCrossRef

36.

Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63PubMedCrossRef

37.

Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C (1995) A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods 184:39–51PubMedCrossRef

38.

Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501PubMedCrossRef

39.

Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556PubMedCrossRef

40.

Namiki A, Brogi E, Kearney M, Kim EA, Wu T, Couffinhal T, Varticovski L, Isner JM (1995) Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem 270:31189–31195PubMedCrossRef

41.

Bertin S, Mohsen-Kanson T, Baque P, Gavelli A, Momier D, Anjuere F, Carle GF, Pierrefite-Carle V (2010) Tumor microenvironment modifications induced by soluble VEGF receptor expression in a rat liver metastasis model. Cancer Lett 298:264–272PubMedCrossRef

42.

Shuli M, Wenyuan G, Yanjun Z, Chaoyi M, Liu Y, Yiwen L (2011) Paridis saponins inhibiting carcinoma growth and metastasis in vitro and in vivo. Arch Pharm Res 34:43–50PubMedCrossRef

43.

Xiao X, Yang M, Bai P, Chen XL, Liu SL, Zou J, Wang H (2012) Observation on anticancer function of PS II isolated from Rhizoma Paridis. Sichuan Da Xue Xue Bao Yi Xue Ban 43:651–656PubMed

44.

Cosgrove D, Lassau N (2009) Assessment of tumour angiogenesis using contrast-enhanced ultrasound. J Radiol 90:156–164PubMedCrossRef

Titel: Paris Saponin II suppresses the growth of human ovarian cancer xenografts via modulating VEGF-mediated angiogenesis and tumor cell migration
verfasst von: Xue Xiao
Mei Yang
Jianguo Xiao
Juan Zou
Qin Huang
Kaixuan Yang
Bo Zhang
Fan Yang
Shanling Liu
He Wang
Peng Bai
Publikationsdatum: 01.04.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2014
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2408-x

Springer Medizin

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