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Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Research Article

A Truncated Snail1 Transcription Factor Alters the Expression of Essential EMT Markers and Suppresses Tumor Cell Migration in a Human Lung Cancer Cell Line

Author(s): Mohammad Davoodzadeh Gholami, Reza Falak*, Sahel Heidari, Majid Khoshmirsafa, Mohammad H. Kazemi, Amir-Hassan Zarnani, Elaheh Safari, Nader Tajik and Gholam A. Kardar*

Volume 14, Issue 2, 2019

Page: [158 - 169] Pages: 12

DOI: 10.2174/1574892814666190527111429

Price: $65

Abstract

Background: Epithelial-to-Mesenchymal Transition (EMT) is necessary for metastasis. Zinc- finger domain-containing transcription factors, especially Snail1, bind to E-box motifs and play a crucial role in the induction and regulation of EMT.

Objective: We hypothesized if C-terminal region of Snail1 (CSnail1) may competitively bind to E-box and block cancer metastasis.

Methods: The CSnail1 gene coding sequence was inserted into the pIRES2-EGFP vector. Following transfection of A549 cells with the designed construct, EMT was induced with TGF-β1 and the expression of essential EMT markers was evaluated by real-time PCR and immunoblotting. We also monitored cell migration.

Results: CSnail1 inhibited TGF-β1-induced N-cadherin and vimentin mRNA expression and increased β-catenin expression in transfected TGF-β1-treated A549 cells. A similar finding was obtained in western blotting. CSnail1 also blocked the migration of transfected cells in the scratch test.

Conclusion: Transfection of A549 cells with CSnail1 alters the expression of essential EMT markers and consequently suppresses tumor cell migration. These findings confirm the capability of CSnail1 in EMT blocking and in parallel to current patents could be applied as a novel strategy in the prevention of metastasis.

Keywords: E-box motif, Epithelial-to-Mesenchymal Transition (EMT), metastasis, Snail, transcription factor, Zinc finger domain.

[1]
Gholami MD, Kardar GA, Saeedi Y, Heydari S, Garssen J, Falak R. Exhaustion of T lymphocytes in the tumor microenvironment: Significance and effective mechanisms. Cell Immunol 2017; 322: 1-14.
[http://dx.doi.org/10.1016/j.cellimm.2017.10.002] [PMID: 29079339]
[2]
Gupta GP, Massagué J. Cancer metastasis: Building a framework. Cell 2006; 127(4): 679-95.
[http://dx.doi.org/10.1016/j.cell.2006.11.001] [PMID: 17110329]
[3]
Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis Science (80- ) 2011;331(6024):1559-64.
[http://dx.doi.org/10.1126/science.1203543]
[4]
Meyer T, Hart IR. Mechanisms of tumour metastasis. Eur J Cancer 1998; 34(2): 214-21.
[http://dx.doi.org/10.1016/S0959-8049(97)10129-0] [PMID: 9741324]
[5]
Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139(5): 871-90.
[http://dx.doi.org/10.1016/j.cell.2009.11.007] [PMID: 19945376]
[6]
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119(6): 1420-8.
[http://dx.doi.org/10.1172/JCI39104] [PMID: 19487818]
[7]
De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression Nat Rev Cancer 2013; 13(2): 97- 110.
[http://dx.doi.org/10.1038/nrc3447] [PMID: 23344542]
[8]
Guttilla IK, Adams BD, White BA. ERα, microRNAs, and the epithelial-mesenchymal transition in breast cancer. Trends Endocrinol Metab 2012; 23(2): 73-82.
[http://dx.doi.org/10.1016/j.tem.2011.12.001] [PMID: 22257677]
[9]
Jianru X, Shuai H, Ting W, Xinghai Y, Wang Z, Zhipeng W, et al. Application of EMT (epithelial to meschymal transition) circulating tumor stem cells in lung cancer proliferation, drug resistance and transfer diseases. CN107299084 (2017).
[10]
Tse JC, Kalluri R. Mechanisms of metastasis: Epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 2007; 101(4): 816-29.
[http://dx.doi.org/10.1002/jcb.21215] [PMID: 17243120]
[11]
Chen J, Imanaka N, Griffin JD. Hypoxia potentiates notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer 2010; 102(2): 351-60.
[http://dx.doi.org/10.1038/sj.bjc.6605486] [PMID: 20010940]
[12]
Zavadil J, Böttinger EP. TGF-β and epithelial-to-mesenchymal transitions. Oncogene 2005; 24(37): 5764-74.
[http://dx.doi.org/10.1038/sj.onc.1208927] [PMID: 16123809]
[13]
Massagué J. TGFβ in cancer. Cell 2008; 134(2): 215-30.
[http://dx.doi.org/10.1016/j.cell.2008.07.001] [PMID: 18662538]
[14]
Sabbineni H, Verma A, Somanath PR. Isoform-specific effects of transforming growth factor β on endothelial-to-mesenchymal transition. J Cell Physiol 2018; 233(11): 8418-28.
[http://dx.doi.org/10.1002/jcp.26801] [PMID: 29856065]
[15]
Sánchez-Tilló E, Liu Y, de Barrios O, Siles L, Fanlo L, Cuatrecasas M, et al. EMT-activating transcription factors in cancer: Beyond EMT and tumor invasiveness. Cell Mol Life Sci 2012; 69(20): 3429-56.
[http://dx.doi.org/10.1007/s00018-012-1122-2] [PMID: 22945800]
[16]
Illam SP, Narayanankutty A, Mathew SE, Valsalakumari R, Jacob RM, Raghavamenon AC. Epithelial mesenchymal transition in cancer progression: Prev entive phytochemicals. Recent Patents Anticancer Drug Discov 2017; 12(3): 234-46.
[http://dx.doi.org/10.2174/1574892812666170424150407] [PMID: 28440207]
[17]
Foroni C, Broggini M, Generali D, Damia G. Epithelial-mesenchymal transition and breast cancer: Role, molecular mechanisms and clinical impact. Cancer Treat Rev 2012; 38(6): 689-97.
[http://dx.doi.org/10.1016/j.ctrv.2011.11.001] [PMID: 22118888]
[18]
Drasin DJ, Robin TP, Ford HL. Breast cancer epithelial-to-mesenchymal transition: Examining the functional consequences of plasticity. Breast Cancer Res 2011; 13(6): 226.
[http://dx.doi.org/10.1186/bcr3037] [PMID: 22078097]
[19]
Birchmeier W, Behrens J. Cadherin expression in carcinomas: Role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1994; 1198(1): 11-26.
[PMID: 8199193]
[20]
Peinado H, Cano A. new potential therapeutic targets to combat epithelial tumor invasion. Clin Transl Oncol 2006; 8(12): 851-7.
[http://dx.doi.org/10.1007/s12094-006-0148-z] [PMID: 17169758]
[21]
Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2(2): 84-9.
[http://dx.doi.org/10.1038/35000034] [PMID: 10655587]
[22]
Bolós V, Peinado H, Pérez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: A comparison with snail and E47 repressors. J Cell Sci 2003; 116(3): 499-511.
[http://dx.doi.org/10.1242/jcs.00224] [PMID: 12508111]
[23]
Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2(2): 76-83.
[http://dx.doi.org/10.1038/35000025] [PMID: 10655586]
[24]
Hajra KM, Chen DYS, Fearon ER. The Slug zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 2002; 62(6): 1613-8.
[PMID: 11912130]
[25]
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178-96.
[http://dx.doi.org/10.1038/nrm3758] [PMID: 24556840]
[26]
Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7(6): 415-28.
[http://dx.doi.org/10.1038/nrc2131] [PMID: 17508028]
[27]
Stanisavljevic J, Porta-de-la-Riva M, Batlle R, de Herreros AG, Baulida J. The p65 subunit of NF-κB and PARP1 assist Snail1 in activating fibronectin transcription. J Cell Sci 2011; 124(24): 4161-71.
[http://dx.doi.org/10.1242/jcs.078824] [PMID: 22223884]
[28]
Peinado H, Ballestar E, Esteller M, Cano A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol 2004; 24(1): 306-19.
[http://dx.doi.org/10.1128/MCB.24.1.306-319.2004] [PMID: 14673164]
[29]
Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: A target for therapeutic intervention. J Exp Clin Cancer Res 2014; 33(1): 62.
[http://dx.doi.org/10.1186/s13046-014-0062-0] [PMID: 25084828]
[30]
Myung JK, Choi SA, Kim SK, Wang KC, Park SH. Snail plays an oncogenic role in glioblastoma by promoting epithelial mesenchymal transition. Int J Clin Exp Pathol 2014; 7(5): 1977-87.
[PMID: 24966907]
[31]
Osorio LA, Farfán NM, Castellón EA, Contreras HR. SNAIL transcription factor increases the motility and invasive capacity of prostate cancer cells. Mol Med Rep 2016; 13(1): 778-86.
[http://dx.doi.org/10.3892/mmr.2015.4585] [PMID: 26648419]
[32]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 2001; 25(4): 402-8.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[33]
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72(1-2): 248-54.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[34]
Grada A, Otero-Vinas M, Prieto-Castrillo F, Obagi Z, Falanga V. Research techniques made simple: Analysis of collective cell migration using the wound healing assay. J Invest Dermatol 2017; 137(2): e11-6.
[http://dx.doi.org/10.1016/j.jid.2016.11.020] [PMID: 28110712]
[35]
Liang CC, Park AY, Guan J-L. In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2007; 2(2): 329-33.
[http://dx.doi.org/10.1038/nprot.2007.30] [PMID: 17406593]
[36]
Wheelock MJ, Johnson KR. Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol 2003; 19(1): 207-35.
[http://dx.doi.org/10.1146/annurev.cellbio.19.011102.111135] [PMID: 14570569]
[37]
Ishiwata T. Cancer stem cells and epithelial-mesenchymal transition: Novel therapeutic targets for cancer. Pathol Int 2016; 66(11): 601-8.
[http://dx.doi.org/10.1111/pin.12447] [PMID: 27510923]
[38]
Liu X, Fan D. The epithelial-mesenchymal transition and cancer stem cells: Functional and mechanistic links. Curr Pharm Des 2015; 21(10): 1279-91.
[http://dx.doi.org/10.2174/1381612821666141211115611]
[39]
Zhang J, Niu Y, Huang C. Role of FoxM1 in the progression and epithelial to mesenchymal transition of gastrointestinal cancer. Recent Patents Anticancer Drug Discov 2017; 12(3): 247-59.
[http://dx.doi.org/10.2174/1574892812666170424144352] [PMID: 28440206]
[40]
Miao L, Yang L, Li R, Rodrigues DN, Crespo M, Hsieh J-T, et al. Disrupting androgen receptor signaling induces snail-mediated epithelial-mesenchymal plasticity in prostate cancer. Cancer Res 2017; 77(11): 3101-12.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2169] [PMID: 28302679]
[41]
Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: Implications in development and cancer. Development 2005; 132(14): 3151-61.
[http://dx.doi.org/10.1242/dev.01907] [PMID: 15983400]
[42]
Elloul S, Elstrand MB, Nesland JM, Tropé CG, Kvalheim G, Goldberg I, et al. Snail, slug, and smad‐interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005; 103(8): 1631-43.
[http://dx.doi.org/10.1002/cncr.20946] [PMID: 15742334]
[43]
Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, et al. Correlation of snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 2002; 21(20): 3241-6.
[http://dx.doi.org/10.1038/sj.onc.1205416] [PMID: 12082640]
[44]
Côme C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, et al. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res 2006; 12(18): 5395-402.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0478] [PMID: 17000672]
[45]
Elloul S, Silins I, Tropé CG, Benshushan A, Davidson B, Reich R. Expression of E-cadherin transcriptional regulators in ovarian carcinoma. Virchows Arch 2006; 449(5): 520-8.
[http://dx.doi.org/10.1007/s00428-006-0274-6] [PMID: 17024425]
[46]
Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T, et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of snail in ovarian carcinoma cells. Am J Pathol 2003; 163(4): 1437-47.
[http://dx.doi.org/10.1016/S0002-9440(10)63501-8] [PMID: 14507651]
[47]
Miyoshi A, Kitajima Y, Kido S, Shimonishi T, Matsuyama S, Kitahara K, et al. Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer 2005; 92(2): 252.
[http://dx.doi.org/10.1038/sj.bjc.6602266] [PMID: 15668718]
[48]
Li T, Zhu Y, Ren W, Xu S, Yang Z, Fang A, et al. High co-expression of vascular endothelial growth factor receptor-1 and snail is associated with poor prognosis after curative resection of hepatocellular carcinoma. Med Oncol 2012; 29(4): 2750-61.
[http://dx.doi.org/10.1007/s12032-012-0160-9] [PMID: 22246525]
[49]
Pena C, García JM, Silva J, García V, Rodríguez R, Alonso I, et al. E-Cadherin and vitamin D receptor regulation by snail and zeb1 in colon cancer: Clinicopathological correlations. Hum Mol Genet 2005; 14(22): 3361-70.
[http://dx.doi.org/10.1093/hmg/ddi366] [PMID: 16203744]
[50]
Kahlert C, Lahes S, Radhakrishnan P, Dutta S, Mogler C, Herpel E, et al. Overexpression of zeb2 at the invasion front of colorectal cancer is an independent prognostic marker and regulates tumor invasion in vitro. Clin Cancer Res 2011; 17(24): 7654-63.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2816] [PMID: 22042972]
[51]
Yook. J.I., Kim, H.S., Kim, N.H., No, K.T., Choi, J.W., Cha, I.H., et al. Pharmaceutical composition for treating oral precancer and method for predicting or diagnosing oral precancer or oral cancer. WO2018128516 (2018).
[52]
Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. Cancer metastasis is accelerated through immunosuppression during snail-induced EMT of cancer cells. Cancer Cell 2009; 15(3): 195-206.
[http://dx.doi.org/10.1016/j.ccr.2009.01.023] [PMID: 19249678]
[53]
Vistain LF, Yamamoto N, Rathore R, Cha P, Meade TJ. Targeted inhibition of snail activity in breast cancer cells by using a coiii‐ebox conjugate. ChemBioChem 2015; 16(14): 2065-72.
[http://dx.doi.org/10.1002/cbic.201500289] [PMID: 26305708]
[54]
Harney AS, Lee J, Manus LM, Wang P, Ballweg DM, LaBonne C, et al. Targeted inhibition of snail family zinc finger transcription factors by oligonucleotide- Co (III) schiff base conjugate. Proc Natl Acad Sci 2009; 106(33): 13667-72.
[http://dx.doi.org/10.1073/pnas.0906423106] [PMID: 19666616]
[55]
Baritaki S, Chapman A, Yeung K, Spandidos DA, Palladino M, Bonavida B. Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: Pivotal roles of snail repression and RKIP induction. Oncogene 2009; 28(40): 3573-85.
[http://dx.doi.org/10.1038/onc.2009.214] [PMID: 19633685]
[56]
Hsu HY, Lin TY, Hwang PA, Tseng LM, Chen RH, Tsao SM, et al. Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGFβ receptor degradation in breast cancer. Carcinogenesis 2012; 34(4): 874-84.
[http://dx.doi.org/10.1093/carcin/bgs396] [PMID: 23275155]
[57]
Zhang X, Li Y, Zhang Y, Song J, Wang Q, Zheng L, et al. Beta-elemene blocks epithelial-mesenchymal transition in human breast cancer cell line MCF-7 through Smad3-mediated down-regulation of nuclear transcription factors. PLoS One 2013; 8(3)e58719
[http://dx.doi.org/10.1371/journal.pone.0058719] [PMID: 23516540]
[58]
Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-β1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005; 6(1): 56.
[http://dx.doi.org/10.1186/1465-9921-6-56] [PMID: 15946381]
[59]
Gurzu S, Banias L, Bara T, Bara Jr T., Jung I. The Epithelial-mesenchymal transition pathway in two cases with gastric metastasis originating from breast carcinoma, one with a metachronous primary gastric cancer. Recent Patents Anticancer Drug Discov 2018; 13(1): 118-24.
[http://dx.doi.org/10.2174/2212798409666171101121108] [PMID: 29090670]
[60]
Zhang K, Yang G, Wu W, Zhang J, Xia X, Jiang T, et al. Decreased expression of caveolin-1 and E-cadherin correlates with the clinicopathologic features of gastric cancer and the EMT process. Recent Patents Anticancer Drug Discov 2016; 11(2): 236-44.
[http://dx.doi.org/10.2174/1574892811666160128151437] [PMID: 26817615]
[61]
Todaro GJ, Lazar GK, Green H. The initiation of cell division in a contact‐inhibited mammalian cell line. J Cell Comp Physiol 1965; 66(3): 325-33.
[http://dx.doi.org/10.1002/jcp.1030660310] [PMID: 5884360]
[62]
Ren L, Yan M, Zhiyuan H, Zewen W. Microfluidic chip for study of tumor single cell invasion and epithelial-mesenchymal transition. CN107497503 (2017).
[63]
Yang R, Lu L, Yang X, Yidong P. CRISPR-Cas9 targeted gene knock sanil1 human cells and their specific sgRNA addition. CN108410877 (2018).
[64]
Haraguchi M, Sato M, Ozawa M. CRISPR/Cas9n-mediated deletion of the snail 1gene (snai1) reveals its role in regulating cell morphology, cell-cell interactions, and gene expression in ovarian Cancer (RMG-1) cells. PLoS One 2015; 10(7)e0132260
[http://dx.doi.org/10.1371/journal.pone.0132260] [PMID: 26161782]
[65]
Soon-Shiong P. Modulation of tumor cell susceptibility. WO2018136659 (2018).
[66]
Gao W, Zhu H, Cheng Y. An ion pump inhibitor for inhibiting tumor metastasis and anti-mesenchymal transition between epithelium. CN108113987 (2018).
[67]
Shih JC, Chung L, Zhau HE, Wu BJ, Olenyuk BZ. Monoamine oxidase inhibitors and methods for treatment and diagnosis of prostate cancer. US2018185303 (2018).
[68]
Bradleay LJ, Robert MD, Lars AA. Methods using axl as a biomarker of epithelial-to-mesenchymal transition. US2018024680 (2018).
[69]
Zhu S, Qian W, Xiaoyun Z, Cai M, Kai S. Application of soluble E-cadherin serving as cancer epithelium mesenchymal transition marker. CN108196060 (2018).
[70]
Hellesoy M, Hodneland NL, Micklem RD. Biomarkers for cancer. US20180208989 (2018).
[71]
Rebbaa A, Comesse S, Daich A, Lawson M, Pintaala C. Compounds and methods for inhibiting EMT pathways to treat cancer, organ fibrosis and metabolic disorders. WO2018156459 (2018).
[72]
Scheffer T, Ek KT, Hua H. Compositions and methods for preventing the proliferation and epithelial-mesenchymal transition of epithelial cells. WO2016187555 (2016).
[73]
Byung SY, Joon HK, Han SK, Ho SY, Ik HK. Novel compound and composition for prevention, improvement or treatment of fibrosis or non-alcoholic steatohepatitis comprising the same. KR101871166 (2018).
[74]
Laurin P, Gagnon L. Methods and compositions for preventing or minimizing epithelial-mesenchymal transition. WO2018115953 (2018).
[75]
Guifu D, Haiwei X, Yake W, Xiaopei Z, Wei Y, Jian W, et al. 15-Idene-14-deoxy-11,12-dehydroandrographolide derivative and application thereof in preparing anti-fibrosis drugs. WO2018177301 (2018).
[76]
Khew-Goodall Y, Goodall G. Methods of modulating epithelialmesenchymal transition and mesenchymal-epithelial transition in cells and agents useful for the same. US20100088775 (2010).
[77]
Plasslick-Deetjen J, Buechel J, Sonja S, Lopez-Cabrera M, Aguilera A, Selgas R. Method and kit for diagnosing Epithelial- To-Mesenchymal Transition (EMT) of the peritoneum. US2018246098 (2018).
[78]
Barthomeuf C, Chollet P, Bayet-Robert M. Curcuminoids in combination docetaxel for the treatment of cancer and tumour metastasis. US20140128337 (2014).
[79]
Cornblatt B, Cornblatt G, Bzhelyansky A, Henderson R. Compositions comprising sulforaphane or a sulforaphane precursor and ursolic acid. WO2014008353 (2014).
[80]
Martins-Green MWL. Specific pomegranate juice compoments and inhibition of prostate cancer progression/metastasis. WO2014165714 (2014).
[81]
S. F. Black garlic extract and application thereof in preventing and curing breast cancer. CN105596674 (2016).
[82]
Xu H, Shen K, Lao Y, Tan H, Chen K, Bian Z, et al. Usage of guttiferone k for treating high metastatic cancer. US20150231090 (2015).
[83]
Xu H, Lao Y, Tan H, Chen K, Bian Z, Yang D, et al. Usage of guttiferone k, a natural compound from garcinia yunnanensis hu on treating high metastatic esophageal cancer. US20150011646 (2015).

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