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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Review Article

The Anticancer Properties of Silibinin: Its Molecular Mechanism and Therapeutic Effect in Breast Cancer

Author(s): Agata Binienda, Sylwia Ziolkowska and Elzbieta Pluciennik*

Volume 20, Issue 15, 2020

Page: [1787 - 1796] Pages: 10

DOI: 10.2174/1871520620666191220142741

Price: $65

Abstract

Background: Silibinin (SB), the main component of Silymarin (SM), is a natural substance obtained from the seeds of the milk thistle. SM contains up to 70% of SB as two isoforms: A and B. It has an antioxidant and anti-inflammatory effect on hepatocytes and is known to inhibit cell proliferation, induce apoptosis, and curb angiogenesis. SB has demonstrated activity against many cancers, such as skin, liver, lung, bladder, and breast carcinomas.

Methods: This review presents current knowledge of the use of SM in breast cancer, this being one of the most common types of cancer in women. It describes selected molecular mechanisms of the action of SM; for example, although SB influences both Estrogen Receptors (ER), α and β, it has opposite effects on the two. Its action on ERα influences the PI3K/AKT/mTOR and RAS/ERK signaling pathways, while by up-regulating ERβ, it increases the numbers of apoptotic cells. In addition, ERα is involved in SB-induced autophagy, while ERβ is not. Interestingly, SB also inhibits metastasis by suppressing TGF-β2 expression, thus suppressing Epithelial to Mesenchymal Transition (EMT). It also influences migration and invasive potential via the Jak2/STAT3 pathway.

Results: SB may be a promising enhancement of BC treatment: when combined with chemotherapeutic drugs such as carboplatin, cisplatin, and doxorubicin, the combination exerts a synergistic effect against cancer cells. This may be of value when treating aggressive types of mammary carcinoma.

Conclusion: Summarizing, SB inhibits proliferation, induces apoptosis, and restrains metastasis via several mechanisms. It is possible to combine SB with different anticancer drugs, an approach that represents a promising therapeutic strategy for patients suffering from BC.

Keywords: Silibinin, estrogen, estrogen receptors, signaling pathways, breast cancer, metastasis.

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[1]
Karimi, G.; Vahabzadeh, M.; Lari, P.; Rashedinia, M.; Moshiri, M. “Silymarin”, a promising pharmacological agent for treatment of diseases. Iran. J. Basic Med. Sci., 2011, 14(4), 308-317.
[PMID: 23492971]
[2]
Kidd, P.M. Bioavailability and activity of phytosome complexes from botanical polyphenols: The silymarin, curcumin, green tea, and grape seed extracts. Altern. Med. Rev., 2009, 14(3), 226-246.
[PMID: 19803548]
[3]
Chambers, C.S.; Holečková, V.; Petrásková, L.; Biedermann, D.; Valentová, K.; Buchta, M.; Křen, V. The silymarin composition… and why does it matter??? Food Res. Int., 2017, 100(Pt 3), 339-353.
[http://dx.doi.org/10.1016/j.foodres.2017.07.017 ] [PMID: 28964357]
[4]
Romanucci, V.; Gravante, R.; Cimafonte, M.; Marino, C.D.; Mailhot, G.; Brigante, M.; Zarrelli, A.; Fabio, G.D. Phosphate-Linked Silibinin Dimers (PLSd): New promising modified metabolites. Molecules, 2017, 22(8), 1323.
[http://dx.doi.org/10.3390/molecules22081323 ] [PMID: 28800072]
[5]
Vaid, M.; Katiyar, S.K. Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.). Int. J. Oncol., 2010, 36(5), 1053-1060.
[PMID: 20372777]
[6]
Rajnochová Svobodová, A.; Gabrielová, E.; Michaelides, L.; Kosina, P.; Ryšavá, A.; Ulrichová, J.; Zálešák, B.; Vostálová, J. UVA-photoprotective potential of silymarin and silybin. Arch. Dermatol. Res., 2018, 310(5), 413-424.
[http://dx.doi.org/10.1007/s00403-018-1828-6 ] [PMID: 29564550]
[7]
Calani, L.; Brighenti, F.; Bruni, R.; Del Rio, D. Absorption and metabolism of milk thistle flavanolignans in humans. Phytomedicine, 2012, 20(1), 40-46.
[http://dx.doi.org/10.1016/j.phymed.2012.09.004 ] [PMID: 23072776]
[8]
Bijak, M. Silybin, a major bioactive component of milk thistle (Silybum marianum L. Gaernt.)-chemistry, bioavailability, and metabolism. Molecules, 2017, 22(11), E1942
[http://dx.doi.org/10.3390/molecules22111942] [PMID: 29125572]
[9]
Javed, S.; Kohli, K.; Ali, M. Reassessing bioavailability of silymarin. Altern. Med. Rev.,, 2011 , 16(3), 239-249.
[PMID: 21951025]
[10]
Mahmoodi, N.; Motamed, N.; Paylakhi, S.H. The comparison of the effects of silybin and silybin-phosphatidylcholine on viability and ESR expression in human breast cancer T47D cell line. Cell J., 2014, 16(3), 299-308.
[PMID: 24611152]
[11]
Lazzeroni, M.; Guerrieri-Gonzaga, A.; Gandini, S.; Johansson, H.; Serrano, D.; Cazzaniga, M.; Aristarco, V.; Puccio, A.; Mora, S.; Caldarella, P.; Pagani, G.; Pruneri, G.; Riva, A.; Petrangolini, G.; Morazzoni, P.; DeCensi, A.; Bonanni, B. A presurgical study of oral silybin-phosphatidylcholine in patients with early breast cancer. Cancer Prev. Res. (Phila.), 2016, 9(1), 89-95.
[http://dx.doi.org/10.1158/1940-6207.CAPR-15-0123] [PMID: 26526990]
[12]
Méndez-Sánchez, N.; Dibildox-Martinez, M.; Sosa-Noguera, J.; Sánchez-Medal, R.; Flores-Murrieta, F.J. Superior silybin bioavailability of silybin-phosphatidylcholine complex in oily-medium soft-gel capsules versus conventional silymarin tablets in healthy volunteers. BMC Pharmacol. Toxicol., 2019, 20(1), 5.
[http://dx.doi.org/10.1186/s40360-018-0280-8 ] [PMID: 30635055]
[13]
Amiri, B.; Ebrahimi-Far, M.; Saffari, Z.; Akbarzadeh, A.; Soleimani, E.; Chiani, M. Preparation, characterization and cytotoxicity of silibinin- containing nanoniosomes in T47D human breast carcinoma cells. Asian Pac. J. Cancer Prev., 2016, 17(8), 3835-3838.
[PMID: 27644625]
[14]
Yazdi Rouholamini, S.E.; Moghassemi, S.; Maharat, Z.; Hakamivala, A.; Kashanian, S.; Omidfar, K.; Kashanian, S.; Omidfar, K. Effect of silibinin-loaded nano-niosomal coated with trimethyl chitosan on miRNAs expression in 2D and 3D models of T47D breast cancer cell line. Artif. Cells Nanomed. Biotechnol., 2018, 46(3), 524-535.
[http://dx.doi.org/10.1080/21691401.2017.1326928 ] [PMID: 28509572]
[15]
Federico, A.; Dallio, M.; Loguercio, C. Silymarin/silybin and chronic liver disease: A marriage of many years. Molecules, 2017, 22(2), E191
[http://dx.doi.org/10.3390/molecules22020191] [PMID: 28125040]
[16]
Wesołowska, O.; Łania-Pietrzak, B.; Kuzdzał, M.; Stanczak, K.; Mosiadz, D.; Dobryszycki, P.; Ozyhar, A.; Komorowska, M.; Hendrich, A.B.; Michalak, K. Influence of silybin on biophysical properties of phospholipid bilayers. Acta Pharmacol. Sin., 2007, 28(2), 296-306.
[http://dx.doi.org/10.1111/j.1745-7254.2007.00487.x ] [PMID: 17241534]
[17]
Bosch-Barrera, J.; Menendez, J.A. Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy. Cancer Treat. Rev., 2015, 41(6), 540-546.
[http://dx.doi.org/10.1016/j.ctrv.2015.04.008 ] [PMID: 25944486]
[18]
Bosch-Barrera, J.; Queralt, B.; Menendez, J.A. Targeting STAT3 with silibinin to improve cancer therapeutics. Cancer Treat. Rev., 2017, 58, 61-69.
[http://dx.doi.org/10.1016/j.ctrv.2017.06.003 ] [PMID: 28686955]
[19]
Shukla, S.K.; Dasgupta, A.; Mehla, K.; Gunda, V.; Vernucci, E.; Souchek, J.; Goode, G.; King, R.; Mishra, A.; Rai, I.; Nagarajan, S.; Chaika, N.V.; Yu, F.; Singh, P.K. Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth. Oncotarget, 2015, 6(38), 41146-41161.
[http://dx.doi.org/10.18632/oncotarget.5843 ] [PMID: 26510913]
[20]
Cancer.Net Editorial Board. National Cancer Institute’s Surveillance Epidemiology.,
[21]
Masoud, V.; Pagès, G. Targeted therapies in breast cancer: New challenges to fight against resistance. World J. Clin. Oncol., 2017, 8(2), 120-134.
[http://dx.doi.org/10.5306/wjco.v8.i2.120 ] [PMID: 28439493]
[22]
Cheung, C.W.Y.; Gibbons, N.; Johnson, D.W.; Nicol, D.L. Silibinin--a promising new treatment for cancer. Anticancer Agents Med. Chem.,, 2010, 10(3), 186-195.
[http://dx.doi.org/10.2174/1871520611009030186] [PMID: 20015009]
[23]
Deroo, B.J.; Korach, K.S. Estrogen receptors and human disease. J. Clin. Invest., 2006, 116(3), 561-570.
[http://dx.doi.org/10.1172/JCI27987 ] [PMID: 16511588]
[24]
Moerkens, M.; Zhang, Y.; Wester, L.; van de Water, B.; Meerman, J.H.N. Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation. BMC Cancer, 2014, 14, 283.
[http://dx.doi.org/10.1186/1471-2407-14-283 ] [PMID: 24758408]
[25]
Thomas, C.; Gustafsson, J-Å. Targeting PES1 for restoring the ERα/ERβ ratio in breast cancer. J. Clin. Invest., 2012, 122(8), 2771-2773.
[http://dx.doi.org/10.1172/JCI65133 ] [PMID: 22820293]
[26]
Ali, S.; Coombes, R.C. Estrogen receptor alpha in human breast cancer: occurrence and significance. J. Mammary Gland Biol. Neoplasia, 2000, 5(3), 271-281.
[http://dx.doi.org/10.1023/A:1009594727358 ] [PMID: 14973389]
[27]
Iwase, H.; Omoto, Y.; Toyama, T.; Hara, Y.; Iwata, H.; Kobayashi, S. Clinical significance of estrogen receptor in breast cancer. Breast Cancer, 1999, 6(4), 325-330.
[http://dx.doi.org/10.1007/BF02966448 ] [PMID: 11091738]
[28]
Williams, C.; Lin, C-Y. Oestrogen receptors in breast cancer: Basic mechanisms and clinical implications. Ecancermedicalscience, 2013, 7, 370.
[PMID: 24222786]
[29]
Roger, P.; Sahla, M.E.; Mäkelä, S.; Gustafsson, J.Å.; Baldet, P.; Rochefort, H. Decreased expression of estrogen receptor β protein in proliferative preinvasive mammary tumors. Cancer Res., 2001, 61(6), 2537-2541.
[PMID: 11289127]
[30]
Li, H.; Tu, Z.; An, L.; Qian, Z.; Achilefu, S.; Gu, Y. Inhibitory effects of ERβ on proliferation, invasion, and tumor formation of MCF-7 breast cancer cells--prognostication for the use of ERβ- selective therapy. Pharm. Biol.,, 2012, 50(7), 839-849.
[http://dx.doi.org/10.3109/13880209.2011.637506 ] [PMID: 22486657]
[31]
Yadegarynia, S.; Pham, A.; Ng, A.; Nguyen, D.; Lialiutska, T.; Bortolazzo, A.; Sivryuk, V.; Bremer, M.; White, J.B. Profiling flavonoid cytotoxicity in human breast cancer cell lines: Determination of structure-function relationships. Nat. Prod. Commun., 2012, 7(10), 1295-1304.
[http://dx.doi.org/10.1177/1934578X1200701011 ] [PMID: 23156993]
[32]
Plísková, M.; Vondrácek, J.; Kren, V.; Gazák, R.; Sedmera, P.; Walterová, D.; Psotová, J.; Simánek, V.; Machala, M. Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation. Toxicology, 2005, 215(1-2), 80-89.
[http://dx.doi.org/10.1016/j.tox.2005.06.020 ] [PMID: 16076518]
[33]
Martinez-Perez, C.; Ward, C.; Cook, G.; Mullen, P.; McPhail, D.; Harrison, D.J.; Langdon, S.P. Novel flavonoids as anti-cancer agents: Mechanisms of action and promise for their potential application in breast cancer. Biochem. Soc. Trans., 2014, 42(4), 1017-1023.
[http://dx.doi.org/10.1042/BST20140073] [PMID: 25109996]
[34]
Kuiper, G.G.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van der Saag, P.T.; van der Burg, B.; Gustafsson, J.A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology, 1998, 139(10), 4252-4263.
[http://dx.doi.org/10.1210/endo.139.10.6216 ] [PMID: 9751507]
[35]
Javan Moghaddam, S.; Keyomarsi, K. Cell cycle regulatory roles of ER-Alpha in breast cancer. Cancer Res., 2005, 65(9)(Supplement), LP-296
[36]
Madhu Krishna, B.; Chaudhary, S.; Mishra, D.R.; Naik, S.K.; Suklabaidya, S.; Adhya, A.K.; Mishra, S.K. Estrogen receptor α dependent regulation of estrogen related receptor β and its role in cell cycle in breast cancer. BMC Cancer, 2018, 18(1), 607.
[http://dx.doi.org/10.1186/s12885-018-4528-x ] [PMID: 29843638]
[37]
Zheng, N.; Zhang, P.; Huang, H.; Liu, W.; Hayashi, T.; Zang, L.; Zhang, Y.; Liu, L.; Xia, M.; Tashiro, S.; Onodera, S.; Ikejima, T. ERα down-regulation plays a key role in silibinin-induced autophagy and apoptosis in human breast cancer MCF-7 cells. J. Pharmacol. Sci., 2015, 128(3), 97-107.
[http://dx.doi.org/10.1016/j.jphs.2015.05.001 ] [PMID: 26117209]
[38]
Wang, H.J.; Jiang, Y.Y.; Wei, X.F.; Huang, H.; Tashiro, S.; Onodera, S.; Ikejima, T. Silibinin induces protective superoxide generation in human breast cancer MCF-7 cells. Free Radic. Res., 2010, 44(1), 90-100.
[http://dx.doi.org/10.3109/10715760903300717 ] [PMID: 19968587]
[39]
Wang, H.J.; Wei, X.F.; Jiang, Y.Y.; Huang, H.; Yang, Y.; Fan, S.M.; Zang, L.H.; Tashiro, S.; Onodera, S.; Ikejima, T. Silibinin induces the generation of nitric oxide in human breast cancer MCF-7 cells. Free Radic. Res., 2010, 44(5), 577-584.
[http://dx.doi.org/10.3109/10715761003692495 ] [PMID: 20370556]
[40]
Zheng, N.; Liu, L.; Liu, W-W.; Li, F.; Hayashi, T.; Tashiro, S-I.; Onodera, S.; Ikejima, T. Crosstalk of ROS/RNS and autophagy in silibinin-induced apoptosis of MCF-7 human breast cancer cells in vitro. Acta Pharmacol. Sin., 2017, 38(2), 277-289.
[http://dx.doi.org/10.1038/aps.2016.117 ] [PMID: 27867187]
[41]
Cheng, P-H.; Lian, S.; Zhao, R.; Rao, X-M.; McMasters, K.M.; Zhou, H.S. Combination of autophagy inducer rapamycin and oncolytic adenovirus improves antitumor effect in cancer cells. Virol. J., 2013, 10, 293.
[http://dx.doi.org/10.1186/1743-422X-10-293 ] [PMID: 24059864]
[42]
Kim, T.H.; Woo, J.S.; Kim, Y.K.; Kim, K.H. Silibinin induces cell death through reactive oxygen species-dependent downregulation of notch-1/ERK/Akt signaling in human breast cancer cells. J. Pharmacol. Exp. Ther., 2014, 349(2), 268-278.
[http://dx.doi.org/10.1124/jpet.113.207563 ] [PMID: 24472723]
[43]
Ciruelos Gil, E.M. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat. Rev., 2014, 40(7), 862-871.
[http://dx.doi.org/10.1016/j.ctrv.2014.03.004 ] [PMID: 24774538]
[44]
Li, L.; Zhao, G-D.; Shi, Z.; Qi, L-L.; Zhou, L-Y.; Fu, Z-X. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncol. Lett., 2016, 12(5), 3045-3050.
[http://dx.doi.org/10.3892/ol.2016.5110 ] [PMID: 27899961]
[45]
Kim, S.; Choi, J.H.; Lim, H.I.; Lee, S.K.; Kim, W.W.; Kim, J.S.; Kim, J.H.; Choe, J.H.; Yang, J.H.; Nam, S.J.; Lee, J.E. Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf/MEK/ERK pathway in MCF-7 human breast cancer cells. Phytomedicine, 2009, 16(6-7), 573-580.
[http://dx.doi.org/10.1016/j.phymed.2008.11.006 ] [PMID: 19181503]
[46]
Oh, S.J.; Jung, S.P.; Han, J.; Kim, S.; Kim, J.S.; Nam, S.J.; Lee, J.E.; Kim, J.H. Silibinin inhibits TPA-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. Oncol. Rep., 2013, 29(4), 1343-1348.
[http://dx.doi.org/10.3892/or.2013.2252 ] [PMID: 23353996]
[47]
Karimi, M.; Babaahmadi-Rezaei, H.; Mohammadzadeh, G.; Ghaffari, M-A. Effect of silibinin on maspin and ERα gene expression in MCF-7 human breast cancer cell line. Iran. J. Pathol. , 2017, 12(2), 135-143.
[PMID: 29515635]
[48]
Iorio, M.V.; Ferracin, M.; Liu, C.G.; Veronese, A.; Spizzo, R.; Sabbioni, S.; Magri, E.; Pedriali, M.; Fabbri, M.; Campiglio, M.; Ménard, S.; Palazzo, J.P.; Rosenberg, A.; Musiani, P.; Volinia, S.; Nenci, I.; Calin, G.A.; Querzoli, P.; Negrini, M.; Croce, C.M. MicroRNA gene expression deregulation in human breast cancer. Cancer Res., 2005, 65(16), 7065-7070.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1783 ] [PMID: 16103053]
[49]
Mandujano-Tinoco, E.A.; García-Venzor, A.; Melendez-Zajgla, J.; Maldonado, V.; Zajgla, M.; Maldonado, V. New emerging roles of microRNAs in breast cancer. Breast Cancer Res. Treat., 2018, 171(2), 247-259.
[http://dx.doi.org/10.1007/s10549-018-4850-7 ] [PMID: 29948402]
[50]
Zadeh, M.M.; Motamed, N.; Ranji, N.; Majidi, M.; Falahi, F. Breast cancer silibinin-induced apoptosis and downregulation of MicroRNA-21 and MicroRNA-155 in MCF-7 human breast. Cancer Cells, 2016, 19(1), 45-52.
[http://dx.doi.org/10.4048/jbc.2016.19.1.45 ] [PMID: 27066095]
[51]
Muhammad, N.; Bhattacharya, S.; Steele, R.; Ray, R.B. Anti-miR-203 suppresses ER-positive breast cancer growth and stemness by targeting SOCS3. Oncotarget, 2016, 7(36), 58595-58605.
[http://dx.doi.org/10.18632/oncotarget.11193 ] [PMID: 27517632]
[52]
Zheng, N.; Liu, L.; Liu, W.; Zhang, P.; Huang, H.; Zang, L.; Hayashi, T.; Tashiro, S.; Onodera, S.; Xia, M.; Ikejima, T. ERβ up-regulation was involved in silibinin-induced growth inhibition of human breast cancer MCF-7 cells. Arch. Biochem. Biophys., 2016, 591, 141-149.
[http://dx.doi.org/10.1016/j.abb.2016.01.002 ] [PMID: 26767948]
[53]
Nejati-Koshki, K.; Zarghami, N.; Pourhassan-Moghaddam, M.; Rahmati-Yamchi, M.; Mollazade, M.; Nasiri, M.; Esfahlan, R.J.; Barkhordari, A.; Tayefi-Nasrabadi, H. Inhibition of leptin gene expression and secretion by silibinin: Possible role of estrogen receptors. Cytotechnology, 2012, 64(6), 719-726.
[http://dx.doi.org/10.1007/s10616-012-9452-3 ] [PMID: 22526491]
[54]
Vona-Davis, L.; Rose, D.P. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr. Relat. Cancer, 2007, 14(2), 189-206.
[http://dx.doi.org/10.1677/ERC-06-0068 ] [PMID: 17639037]
[55]
Garofalo, C.; Surmacz, E. Leptin and cancer. J. Cell. Physiol., 2006, 207(1), 12-22.
[http://dx.doi.org/10.1002/jcp.20472 ] [PMID: 16110483]
[56]
Rene Gonzalez, R.; Watters, A.; Xu, Y.; Singh, U.P.; Mann, D.R.; Rueda, B.R.; Penichet, M.L. Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res., 2009, 11(3), R36-R36.
[http://dx.doi.org/10.1186/bcr2321 ] [PMID: 19531256]
[57]
Putti, T.C.; El-Rehim, D.M.A.; Rakha, E.A.; Paish, C.E.; Lee, A.H.S.; Pinder, S.E.; Ellis, I.O. Estrogen receptor-negative breast carcinomas: A review of morphology and immunophenotypical analysis. Mod. Pathol., 2005, 18(1), 26-35.
[http://dx.doi.org/10.1038/modpathol.3800255 ] [PMID: 15332092]
[58]
Yousefi, M.; Ghaffari, S.H.; Zekri, A.; Hassani, S.; Alimoghaddam, K.; Ghavamzadeh, A. Silibinin induces apoptosis and inhibits proliferation of Estrogen Receptor (ER)-negative breast carcinoma cells through suppression of nuclear factor kappa B activation. 2014, 17(5), 366-371.
[59]
Scully, O.J.; Bay, B-H.; Yip, G.; Yu, Y. Breast cancer metastasis. Cancer Genomics Proteomics, 2012, 9(5), 311-320.
[PMID: 22990110]
[60]
Feng, Y.; Spezia, M.; Huang, S.; Yuan, C.; Zeng, Z.; Zhang, L.; Ji, X.; Liu, W.; Huang, B.; Luo, W.; Liu, B.; Lei, Y.; Du, S.; Vuppalapati, A.; Luu, H.H.; Haydon, R.C.; He, T.C.; Ren, G. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis., 2018, 5(2), 77-106.
[http://dx.doi.org/10.1016/j.gendis.2018.05.001 ] [PMID: 30258937]
[61]
Ha, N.H.; Faraji, F.; Hunter, K.W. Mechanisms of metastasis; Cancer Target. Drug Deliv. Elus. Dream, 2013, pp. 435-458.
[62]
van Zijl, F.; Krupitza, G.; Mikulits, W. Initial steps of metastasis: Cell invasion and endothelial transmigration. Mutat. Res., 2011, 728(1-2), 23-34.
[http://dx.doi.org/10.1016/j.mrrev.2011.05.002 ] [PMID: 21605699]
[63]
Roche, J. The epithelial-to-mesenchymal transition in cancer. Cancers (Basel), 2018, 10(2), 10-13.
[http://dx.doi.org/10.3390/cancers10020052 ] [PMID: 29462906]
[64]
Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Invest., 2009, 119(6), 1420-1428.
[http://dx.doi.org/10.1172/JCI39104 ] [PMID: 19487818]
[65]
Xu, J.; Lamouille, S.; Derynck, R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res., 2009, 19(2), 156-172.
[http://dx.doi.org/10.1038/cr.2009.5 ] [PMID: 19153598]
[66]
Kim, S.; Han, J.; Jeon, M.; You, D.; Lee, J.; Kim, H.J.; Bae, S.; Nam, S.J.; Lee, J.E. Silibinin inhibits triple negative breast cancer cell motility by suppressing TGF-β2 expression. Tumour Biol., 2016, 37(8), 11397-11407.
[http://dx.doi.org/10.1007/s13277-016-5000-7 ] [PMID: 26984157]
[67]
Kumar, P.; Aggarwal, R. An overview of triple-negative breast cancer Arch. Gynecol. Obstet., 2016, 293(2), 247-269.
[http://dx.doi.org/10.1007/s00404-015-3859-y] [PMID: 26341644]
[68]
Akshata Desai, K.A. Triple negative breast cancer - an overview. Hered. Genet., 2012, 60(1), 79-87.
[69]
Lebert, J.M.; Lester, R.; Powell, E.; Seal, M.; McCarthy, J. Advances in the systemic treatment of triple-negative breast cancer. Curr. Oncol., 2018, 25(Suppl. 1), S142-S150.
[http://dx.doi.org/10.3747/co.25.3954 ] [PMID: 29910657]
[70]
Colak, S.; Ten Dijke, P. Targeting TGF-β signaling in cancer. Trends Cancer, 2017, 3(1), 56-71.
[http://dx.doi.org/10.1016/j.trecan.2016.11.008 ] [PMID: 28718426]
[71]
Padua, D.; Zhang, X.H.F.; Wang, Q.; Nadal, C.; Gerald, W.L.; Gomis, R.R.; Massagué, J. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell, 2008, 133(1), 66-77.
[http://dx.doi.org/10.1016/j.cell.2008.01.046 ] [PMID: 18394990]
[72]
Ehata, S.; Hanyu, A.; Fujime, M.; Katsuno, Y.; Fukunaga, E.; Goto, K.; Ishikawa, Y.; Nomura, K.; Yokoo, H.; Shimizu, T. β Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci., 2007, 98(1), 127-133.
[PMID: 17129361]
[73]
Lv, Z.D.; Na, D.; Liu, F.N.; Du, Z.M.; Sun, Z.; Li, Z.; Ma, X.Y.; Wang, Z.N.; Xu, H.M. Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis. J. Exp. Clin. Cancer Res., 2010, 29(1), 139.
[http://dx.doi.org/10.1186/1756-9966-29-139 ] [PMID: 21034459]
[74]
Byun, H.J.; Darvin, P.; Kang, D.Y.; Sp, N.; Joung, Y.H.; Park, J.H.; Kim, S.J.; Yang, Y.M. Silibinin downregulates MMP2 expression via Jak2/STAT3 pathway and inhibits the migration and invasive potential in MDA-MB-231 cells. Oncol. Rep., 2017, 37(6), 3270-3278.
[http://dx.doi.org/10.3892/or.2017.5588 ] [PMID: 28440514]
[75]
Sivaraman, K.; Sikka, S.; Surana, R.; Dai, X.; Zhang, J.; Prem, A.; Tan, B.K.H.; Sethi, G.; Bishayee, A. Targeting the STAT3 signaling pathway in cancer : Role of synthetic and natural inhibitors. Rev. Can., 2014, 1845(2), 136-154.
[76]
Kim, S.; Jeon, M.; Lee, J.; Han, J.; Oh, S.J.; Jung, T.; Nam, S.J.; Kil, W.H.; Lee, J.E. Induction of fibronectin in response to epidermal growth factor is suppressed by silibinin through the inhibition of STAT3 in triple negative breast cancer cells. Oncol. Rep., 2014, 32(5), 2230-2236.
[http://dx.doi.org/10.3892/or.2014.3450 ] [PMID: 25175149]
[77]
Klarmann, G.J.; Decker, A.; Farrar, W.L. Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics, 2008, 3(2), 59-63.
[http://dx.doi.org/10.4161/epi.3.2.5899 ] [PMID: 18398311]
[78]
Lu, W.; Lin, C.; King, T.D.; Chen, H.; Reynolds, R.C.; Li, Y. Silibinin inhibits Wnt/β-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. Cell. Signal., 2012, 24(12), 2291-2296.
[http://dx.doi.org/10.1016/j.cellsig.2012.07.009 ] [PMID: 22820499]
[79]
Dastpeyman, M.; Motamed, N.; Azadmanesh, K.; Mostafavi, E.; Kia, V.; Jahanian-Najafabadi, A.; Shokrgozar, M.A. Inhibition of silibinin on migration and adhesion capacity of human highly metastatic breast cancer cell line, MDA-MB-231, by evaluation of β1-integrin and downstream molecules, Cdc42, Raf-1 and D4GDI. Med. Oncol., 2012, 29(4), 2512-2518.
[http://dx.doi.org/10.1007/s12032-011-0113-8 ] [PMID: 22101790]
[80]
Tyagi, A.K.; Agarwal, C.; Chan, D.C.F.; Agarwal, R. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol. Rep., 2004, 11(2), 493-499.
[http://dx.doi.org/10.3892/or.11.2.493 ] [PMID: 14719089]
[81]
Mittal, S.; Verma, Y.; Kamboj, K. Silibinin in human breast cancer: Scope beyond placebo! J. Gynecol. Women’s Health., 2017, 5, 1-5.
[http://dx.doi.org/10.19080/JGWH.2017.05.555669]
[82]
Ho, B.Y.; Lin, C.H.; Apaya, M.K.; Chao, W.W.; Shyur, L.F. Silibinin and paclitaxel cotreatment significantly suppress the activity and lung metastasis of triple negative 4T1 mammary tumor cell in mice. J. Tradit. Complement. Med., 2012, 2(4), 301-311.
[http://dx.doi.org/10.1016/S2225-4110(16)30116-X] [PMID: 24716145]
[83]
Chatran, M.; Pilehvar-Soltanahmadi, Y.; Dadashpour, M.; Faramarzi, L.; Rasouli, S.; Jafari-Gharabaghlou, D.; Asbaghi, N.; Zarghami, N.; Zarghami, N.; Street, G. Synergistic anti-proliferative effects of metformin and silibinin combination on T47D breast cancer cells via hTERT and cyclin D1 inhibition. Drug Res. (Stuttg.), 2018, 68(12), 710-716.
[http://dx.doi.org/10.1055/a-0631-8046 ] [PMID: 29920623]
[84]
Manouchehri, J.M.; Kalafatis, M. Sensitization of rhTRAIL-resistant triple-negative breast carcinoma through silibinin co-treatment. Anticancer Res., 2017, 37(12), 6593-6599.
[PMID: 29187434]
[85]
Sun, H.P.; Su, J.H.; Meng, Q.S.; Yin, Q.; Zhang, Z.W.; Yu, H.J.; Zhang, P.C.; Wang, S.L.; Li, Y.P. Silibinin and indocyanine green-loaded nanoparticles inhibit the growth and metastasis of mammalian breast cancer cells in vitro. Acta Pharmacol. Sin., 2016, 37(7), 941-949.
[http://dx.doi.org/10.1038/aps.2016.20 ] [PMID: 27133295]
[86]
Xu, P.; Yin, Q.; Shen, J.; Chen, L.; Yu, H.; Zhang, Z.; Li, Y. Synergistic inhibition of breast cancer metastasis by silibinin-loaded lipid nanoparticles containing TPGS. Int. J. Pharm., 2013, 454(1), 21-30.
[http://dx.doi.org/10.1016/j.ijpharm.2013.06.053] [PMID: 23830941]
[87]
Russo, J.; Russo, I.H. The role of estrogen in the initiation of breast cancer. J. Steroid Biochem. Mol. Biol., 2006, 102(1-5), 89-96.
[http://dx.doi.org/10.1016/j.jsbmb.2006.09.004 ] [PMID: 17113977]
[88]
Yaghjyan, L.; Colditz, G.A. Estrogens in the breast tissue: A systematic review. Cancer Causes Control, 2011, 22(4), 529-540.
[http://dx.doi.org/10.1007/s10552-011-9729-4 ] [PMID: 21286801]
[89]
Ray, R.B.; Raychoudhuri, A.; Steele, R.; Nerurkar, P. Bitter melon (Momordica charantia) extract inhibits breast cancer cell proliferation by modulating cell cycle regulatory genes and promotes apoptosis. Cancer Res., 2010, 70(5), 1925-1931.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3438 ] [PMID: 20179194]
[90]
Muhammad, N.; Steele, R.; Isbell, T.S.; Philips, N.; Ray, R.B. Bitter melon extract inhibits breast cancer growth in preclinical model by inducing autophagic cell death. Oncotarget, 2017, 8(39), 66226-66236.
[http://dx.doi.org/10.18632/oncotarget.19887 ] [PMID: 29029506]
[91]
Ramasamy, K.; Agarwal, R. Multitargeted therapy of cancer by silymarin. Cancer Lett., 2008, 269(2), 352-362.
[http://dx.doi.org/10.1016/j.canlet.2008.03.053 ] [PMID: 18472213]
[92]
Malewicz, B.; Wang, Z.; Jiang, C.; Guo, J.; Cleary, M.P.; Grande, J.P.; Lü, J. Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements. Carcinogenesis, 2006, 27(9), 1739-1747.
[http://dx.doi.org/10.1093/carcin/bgl032 ] [PMID: 16597642]
[93]
Verschoyle, R.D.; Brown, K.; Steward, W.P.; Gescher, A.J. Consumption of silibinin, a flavonolignan from milk thistle, and mammary cancer development in the C3(1) SV40 T,t antigen transgenic multiple mammary adenocarcinoma (TAg) mouse. Cancer Chemother. Pharmacol., 2008, 62(2), 369-372.
[http://dx.doi.org/10.1007/s00280-007-0611-8 ] [PMID: 17909802]
[94]
Bosch-barrera, J.; Corominas-Faja, B.; Cuyàs, E.; Martin-Castillo, B.; Brunet, J.; Menendez, J.A. Silibinin administration improves hepatic failure due to extensive liver infiltration in a breast cancer patient. Anticancer Res., 2014, 34(8), 4323-4327.
[95]
Kaur, M.; Agarwal, R. Silymarin and epithelial cancer chemoprevention: How close we are to bedside? Toxicol. Appl. Pharmacol., 2007, 224(3), 350-359.
[http://dx.doi.org/10.1016/j.taap.2006.11.011] [PMID: 17184801]

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