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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2011

Open Access 01-12-2011 | Research

Compound Kushen Injection suppresses human breast cancer stem-like cells by down-regulating the canonical Wnt/β-catenin pathway

Authors: Weiru Xu, Hongsheng Lin, Ying Zhang, Xinyi Chen, Baojin Hua, Wei Hou, Xin Qi, Yingxia Pei, Xiaoyun Zhu, Zhizheng Zhao, Liangliang Yang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2011

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Abstract

Background

Cancer stem cells (CSCs) play an important role in cancer initiation, relapse and metastasis. To date, no specific medicine has been found to target CSCs as they are resistant to most conventional therapies and proliferate indefinitely. Compound Kushen Injection (CKI) has been widely used for cancer patients with remarkable therapeutic effects in Chinese clinical settings for many years. This study focused on whether CKI could inhibit MCF-7 SP cells in vitro and in vivo.

Methods

The analysis of CKI on SP population and the main genes of Wnt signaling pathway were studied first. Then we studied the tumorigenicity of SP cells and the effects of CKI on SP cells in vivo. The mice inoculated with 10,000 SP cells were randomly divided into three groups (6 in each group) and treated with CKI, cisplatin and saline (as a control) respectively for 7 weeks. The tumor formation rates of each group were compared. The main genes and proteins of the Wnt signaling pathway were analyzed by RT-PCR and western blot.

Results

CKI suppressed the size of SP population (approximately 90%), and down-regulated the main genes of Wnt signaling pathway. We also determined that MCF-7 SP cells were more tumorigenic than non-SP and unsorted cells. The Wnt signaling pathway was up-regulated in tumors derived from SP cells compared with that in tumors from non-SP cells. The tumor formation rate of the CKI Group was 33% (2/6, P < 0.05), and that of Cisplatin Group was 50%(3/6, P < 0.05), whereas that of the Control Group was 100% (6/6).The RT-PCR and western blot results indicated that CKI suppressed tumor growth by down-regulating the Wnt/β-catenin pathway, while cisplatin activated the Wnt/β-catenin pathway and might spare SP cells.

Conclusions

It suggested that CKI may serve as a novel drug targeting cancer stem-like cells, though further studies are recommended.
Appendix
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Literature
1.
Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 2001, 414: 105-111. 10.1038/35102167.CrossRefPubMed
2.
Gottesman MM: Mechanisms of cancer drug resistance. Annu Rev Med. 2002, 53: 615-627. 10.1146/annurev.med.53.082901.103929.CrossRefPubMed
3.
Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP: The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001, 7: 1028-1034. 10.1038/nm0901-1028.CrossRefPubMed
4.
Bao S, Wu Q, Mclendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006, 444: 756-760. 10.1038/nature05236.CrossRefPubMed
5.
Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL: Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002, 99: 319-325. 10.1182/blood.V99.1.319.CrossRefPubMed
6.
Reim F, Dombrowski Y, Ritter C, Buttmann M, Hausler S, Ossadnik M, Krockenberger M, Beier D, Beier CP, Dietl J, Becker JC, Honig A, Wischhusen J: Immunoselection of breast and ovarian cancer cells with trastuzumab and natural killer cells: selective escape of CD44high/CD24low/HER2low breast cancer stem cells. Cancer Res. 2009, 69: 8058-8066. 10.1158/0008-5472.CAN-09-0834.CrossRefPubMed
7.
Bonnet D, Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997, 3: 730-737. 10.1038/nm0797-730.CrossRefPubMed
8.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003, 100: 3983-3988. 10.1073/pnas.0530291100.PubMedCentralCrossRefPubMed
9.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB: Identification of human brain tumour initiating cells. Nature. 2004, 432: 396-401. 10.1038/nature03128.CrossRefPubMed
10.
Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT: CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci. 2004, 117: 3539-3545. 10.1242/jcs.01222.CrossRefPubMed
11.
Haraguchi N, Inoue H, Tanaka F, Mimori K, Utsunomiya T, Sasaki A, Mori M: Cancer stem cells in human gastrointestinal cancers. Hum Cell. 2006, 19: 24-29. 10.1111/j.1749-0774.2005.00004.x.CrossRefPubMed
12.
Kondo T, Setoguchi T, Taga T: Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA. 2004, 101: 781-786. 10.1073/pnas.0307618100.PubMedCentralCrossRefPubMed
13.
Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M: Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006, 24: 506-513. 10.1634/stemcells.2005-0282.CrossRefPubMed
14.
Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG: Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res. 2005, 65: 6207-6219. 10.1158/0008-5472.CAN-05-0592.CrossRefPubMed
15.
Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH: Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res. 2007, 67: 3716-3724. 10.1158/0008-5472.CAN-06-4343.CrossRefPubMed
16.
Brown MD, Gilmore PE, Hart CA, Samuel JD, Ramani VA, George NJ, Clarke NW: Characterization of benign and malignant prostate epithelial Hoechst 33342 side populations. Prostate. 2007, 67: 1384-1396. 10.1002/pros.20620.CrossRefPubMed
17.
Seigel GM, Campbell LM, Narayan M, Gonzalez-Fernandez F: Cancer stem cell characteristics in retinoblastoma. Mol Vis. 2005, 11: 729-737.PubMed
18.
Tian J, Wang WH, Gao HM, Wang ZM: [Determination of matrine, sophoridine and oxymatrine in Compound Kushen Injection by HPLC]. Zhongguo Zhong Yao Za Zhi. 2007, 32: 222-224.PubMed
19.
Wang ZY, Li GS, Huang HX: [Clinical observation on treatment of 75 mid-late stage cancer patients with yanshu Injection]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006, 26: 681-684.PubMed
20.
Chen J, Mei Q, Xu YC, Du J, Wei Y, Xu ZM: [Effects of Matrine Injection on T-lymphocyte subsets of patients with malignant tumor after gamma knife radiosurgery]. Zhong Xi Yi Jie He Xue Bao. 2006, 4: 78-79. 10.3736/jcim20060121.CrossRefPubMed
21.
Dai ZJ, Gao J, Wang XJ, Ji ZZ, Wu WY, Liu XX, Kang HF, Guan HT, Ren HT: [Apoptotic mechanism of gastric carcinoma cells induced by matrine injection]. Zhonghua Wei Chang Wai Ke Za Zhi. 2008, 11: 261-265.PubMed
22.
Dai ZJ, Gao J, Wu WY, Wang XJ, Li ZF, Kang HF, Liu XX, Ma XB: [Effect of matrine injections on invasion and metastasis of gastric carcinoma SGC-7901 cells in vitro]. Zhong Yao Cai. 2007, 30: 815-819.PubMed
23.
24.
Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, Huang DD, Tang L, Kong XN, Chen C, Liu SQ, Wu MC, Wang HY: Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008, 68: 4287-4295. 10.1158/0008-5472.CAN-07-6691.CrossRefPubMed
25.
Ysebaert L, Chicanne G, Demur C, De Toni F, Prade-Houdellier N, Ruidavets JB, Mansat-De Mas V, Rigal-Huguet F, Laurent G, Payrastre B, Manenti S, Racaud-Sultan C: Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia. 2006, 20: 1211-1216. 10.1038/sj.leu.2404239.CrossRefPubMed
26.
Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, Huber M, Hohl D, Cano A, Birchmeier W, Huelsken J: Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature. 2008, 452: 650-653. 10.1038/nature06835.CrossRefPubMed
27.
Li X, Ren J: [Isolation of CD44+/CD24 -/low and side population cells from MDA-MB-453 cells and the analysis of their activation of Wnt and Notch pathway]. Beijing Da Xue Xue Bao. 2008, 40: 471-475.PubMed
28.
Zhang Y, Piao B, Hua B, Hou W, Xu W, Qi X, Zhu X, Pei Y, Lin H: Oxymatrine diminishes the side population and inhibits the expression of beta-catenin in MCF-7 breast cancer cells. Med Oncol. 2010,
29.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996, 183: 1797-1806. 10.1084/jem.183.4.1797.CrossRefPubMed
30.
Hardman WE, Moyer MP, Cameron IL: Efficacy of treatment of colon, lung and breast human carcinoma xenografts with: doxorubicin, cisplatin, irinotecan or topotecan. Anticancer Res. 1999, 19: 2269-2274.PubMed
31.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
32.
He B, You L, Uematsu K, Xu Z, Lee AY, Matsangou M, Mccormick F, Jablons DM: A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia. 2004, 6: 7-14.PubMedCentralCrossRefPubMed
33.
Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR, Nusse R: Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003, 423: 448-452. 10.1038/nature01611.CrossRefPubMed
34.
Behrens J, Von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W: Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996, 382: 638-642. 10.1038/382638a0.CrossRefPubMed
35.
Cadigan KM, Nusse R: Wnt signaling: a common theme in animal development. Genes Dev. 1997, 11: 3286-3305. 10.1101/gad.11.24.3286.CrossRefPubMed
36.
Khan NI, Bradstock KF, Bendall LJ: Activation of Wnt/beta-catenin pathway mediates growth and survival in B-cell progenitor acute lymphoblastic leukaemia. Br J Haematol. 2007, 138: 338-348. 10.1111/j.1365-2141.2007.06667.x.CrossRefPubMed
37.
Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM: WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA. 2007, 104: 618-623. 10.1073/pnas.0606599104.PubMedCentralCrossRefPubMed
38.
Schulenburg A, Cech P, Herbacek I, Marian B, Wrba F, Valent P, Ulrich-Pur H: CD44-positive colorectal adenoma cells express the potential stem cell markers musashi antigen (msi1) and ephrin B2 receptor (EphB2). J Pathol. 2007, 213: 152-160. 10.1002/path.2220.CrossRefPubMed
39.
Peifer M, Polakis P: Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus. Science. 2000, 287: 1606-1609. 10.1126/science.287.5458.1606.CrossRefPubMed
40.
Bienz M, Clevers H: Linking colorectal cancer to Wnt signaling. Cell. 2000, 103: 311-320. 10.1016/S0092-8674(00)00122-7.CrossRefPubMed
41.
Polakis P: Wnt signaling and cancer. Genes Dev. 2000, 14: 1837-1851.PubMed
42.
43.
Morrison SJ, Kimble J: Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006, 441: 1068-1074. 10.1038/nature04956.CrossRefPubMed
44.
Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S, Roz E, Caserini R, Lo Vullo S, Camerini T, Mariani L, Delia D, Calabro E, Pastorino U, Sozzi G: Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA. 2009, 106: 16281-16286. 10.1073/pnas.0905653106.PubMedCentralCrossRefPubMed
45.
Cortes-Dericks L, Carboni GL, Schmid RA, Karoubi G: Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed. Int J Oncol. 2010, 37: 437-444.PubMed
46.
Honoki K, Fujii H, Kubo A, Kido A, Mori T, Tanaka Y, Tsujiuchi T: Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance. Oncol Rep. 2010, 24: 501-505.CrossRefPubMed
Metadata
Title
Compound Kushen Injection suppresses human breast cancer stem-like cells by down-regulating the canonical Wnt/β-catenin pathway
Authors
Weiru Xu
Hongsheng Lin
Ying Zhang
Xinyi Chen
Baojin Hua
Wei Hou
Xin Qi
Yingxia Pei
Xiaoyun Zhu
Zhizheng Zhao
Liangliang Yang
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2011
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-30-103

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