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Current Topics in Medicinal Chemistry

Author(s): Yu-hang Guo, Revathimadhubala Kuruganti and Ying Gao*

DOI: 10.2174/1568026619666191018100848

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Recent Advances in Ginsenosides as Potential Therapeutics Against Breast Cancer

Page: [2334 - 2347] Pages: 14

  • * (Excluding Mailing and Handling)

Abstract

The dried root of ginseng (Panax ginseng C. A. Meyer or Panax quinquefolius L.) is a traditional Chinese medicine widely used to manage cancer symptoms and chemotherapy side effects in Asia. The anti-cancer efficacy of ginseng is attributed mainly to the presence of saponins, which are commonly known as ginsenosides. Ginsenosides were first identified as key active ingredients in Panax ginseng and subsequently found in Panax quinquefolius, both of the same genus. To review the recent advances on anti-cancer effects of ginsenosides against breast cancer, we conducted a literature study of scientific articles published from 2010 through 2018 to date by searching the major databases including Pubmed, SciFinder, Science Direct, Springer, Google Scholar, and CNKI. A total of 50 articles authored in either English or Chinese related to the anti-breast cancer activity of ginsenosides have been reviewed, and the in vitro, in vivo, and clinical studies on ginsenosides are summarized. This review focuses on how ginsenosides exert their anti-breast cancer activities through various mechanisms of action such as modulation of cell growth, modulation of the cell cycle, modulation of cell death, inhibition of angiogenesis, inhibition of metastasis, inhibition of multidrug resistance, and cancer immunemodulation. In summary, recent advances in the evaluation of ginsenosides as therapeutic agents against breast cancer support further pre-clinical and clinical studies to treat primary and metastatic breast tumors.

Keywords: Panax ginseng, Panax quinquefolius, Panax notoginseng, Ginsenosides, Breast Cancer, Mechanism.

Graphical Abstract

[1]
American Cancer Society. Cancer facts & figures. Canc. J. Clin.,, 2018.
[2]
Sak, K. Chemotherapy and dietary phytochemical agents. Chemother. Res. Pract., 2012, 2012282570
[http://dx.doi.org/10.1155/2012/282570] [PMID: 23320169]
[3]
Lee, C.H.; Kim, J.H. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J. Ginseng Res., 2014, 38(3), 161-166.
[http://dx.doi.org/10.1016/j.jgr.2014.03.001] [PMID: 25378989]
[4]
Ong, W.Y.; Farooqui, T.; Koh, H.L.; Farooqui, A.A.; Ling, E.A. Protective effects of ginseng on neurological disorders. Front. Aging Neurosci., 2015, 7, 129.
[http://dx.doi.org/10.3389/fnagi.2015.00129] [PMID: 26236231]
[5]
Wang, L.D. The original history and species characteristics of Panax quinquefolius. Zhongchengyao, 1999, 21(2), 95-96.
[6]
Yun, T.K. Panax ginseng--a non-organ-specific cancer preventive? Lancet Oncol., 2001, 2(1), 49-55.
[http://dx.doi.org/10.1016/S1470-2045(00)00196-0] [PMID: 11905620]
[7]
Nag, S.A.; Qin, J.J.; Wang, W.; Wang, M.H.; Wang, H.; Zhang, R. Ginsenosides as anticancer agents: in vitro and in vivo activities, structure-activity relationships, and molecular mechanisms of action. Front. Pharmacol., 2012, 3, 25.
[http://dx.doi.org/10.3389/fphar.2012.00025] [PMID: 22403544]
[8]
Wu, J.; Zhong, J.J. Production of ginseng and its bioactive components in plant cell culture: current technological and applied aspects. J. Biotechnol., 1999, 68(2-3), 89-99.
[http://dx.doi.org/10.1016/S0168-1656(98)00195-3] [PMID: 10194851]
[9]
Hwang, C.R.; Lee, S.H.; Jang, G.Y.; Hwang, I.G.; Kim, H.Y.; Woo, K.S.; Lee, J.; Jeong, H.S. Changes in ginsenoside compositions and antioxidant activities of hydroponic-cultured ginseng roots and leaves with heating temperature. J. Ginseng Res., 2014, 38(3), 180-186.
[http://dx.doi.org/10.1016/j.jgr.2014.02.002] [PMID: 25378992]
[10]
Majeed, F.; Malik, F.Z.; Ahmed, Z.; Afreen, A.; Afzal, M.N.; Khalid, N. Ginseng phytochemicals as therapeutics in oncology: Recent perspectives. Biomed. Pharmacother., 2018, 100, 52-63.
[http://dx.doi.org/10.1016/j.biopha.2018.01.155] [PMID: 29421582]
[11]
Helms, S. Cancer prevention and therapeutics: Panax ginseng. Altern. Med. Rev., 2004, 9(3), 259-274.
[PMID: 15387718]
[12]
Li, B.; Wang, C.Z.; He, T.C.; Yuan, C.S.; Du, W. Antioxidants potentiate American ginseng-induced killing of colorectal cancer cells. Cancer Lett., 2010, 289(1), 62-70.
[http://dx.doi.org/10.1016/j.canlet.2009.08.002] [PMID: 19716228]
[13]
Chen, L.; Huang, T.; Zhang, J.; Zheng, M.Y.; Feng, K.Y.; Cai, Y.D.; Chou, K.C. Predicting drugs side effects based on chemical-chemical interactions and protein-chemical interactions. BioMed Res. Int., 2013, 2013485034
[http://dx.doi.org/10.1155/2013/485034] [PMID: 24078917]
[14]
Chou, K.C.; Elrod, D.W. Bioinformatical analysis of G-protein-coupled receptors. J. Proteome Res., 2002, 1(5), 429-433.
[http://dx.doi.org/10.1021/pr025527k] [PMID: 12645914]
[15]
Min, J.L.; Xiao, X.; Chou, K.C. iEzy-drug: a web server for identifying the interaction between enzymes and drugs in cellular networking. BioMed Res. Int., 2013, 2013701317
[http://dx.doi.org/10.1155/2013/701317] [PMID: 24371828]
[16]
Xiao, X.; Min, J.L.; Wang, P.; Chou, K.C. iGPCR-drug: a web server for predicting interaction between GPCRs and drugs in cellular networking. PLoS One, 2013, 8(8)e72234
[http://dx.doi.org/10.1371/journal.pone.0072234] [PMID: 24015221]
[17]
Xiao, X.; Min, J.L.; Wang, P.; Chou, K.C. iCDI-PseFpt: identify the channel-drug interaction in cellular networking with PseAAC and molecular fingerprints. J. Theor. Biol., 2013, 337, 71-79.
[http://dx.doi.org/10.1016/j.jtbi.2013.08.013] [PMID: 23988798]
[18]
Fan, Y.N.; Xiao, X.; Min, J.L.; Chou, K.C. iNR-Drug: predicting the interaction of drugs with nuclear receptors in cellular networking. Int. J. Mol. Sci., 2014, 15(3), 4915-4937.
[http://dx.doi.org/10.3390/ijms15034915] [PMID: 24651462]
[19]
Xiao, X.; Min, J.L.; Lin, W.Z.; Liu, Z.; Cheng, X.; Chou, K.C. iDrug-Target: predicting the interactions between drug compounds and target proteins in cellular networking via benchmark dataset optimization approach. J. Biomol. Struct. Dyn., 2015, 33(10), 2221-2233.
[http://dx.doi.org/10.1080/07391102.2014.998710] [PMID: 25513722]
[20]
Cheng, X.; Xiao, X.; Chou, K.C. pLoc-mPlant: predict subcellular localization of multi-location plant proteins by incorporating the optimal GO information into general PseAAC. Mol. Biosyst., 2017, 13(9), 1722-1727.
[http://dx.doi.org/10.1039/C7MB00267J] [PMID: 28702580]
[21]
Cheng, X.; Xiao, X. pLoc-mVirus: predict subcellular localization of multi-location virus proteins via incorporating the optimal GO information into general PseAAC. Gene, 2017, 644(156), 315-321.
[22]
Cheng, X.; Zhao, S.G.; Lin, W.Z.; Xiao, X.; Chou, K.C. pLoc-mAnimal: predict subcellular localization of animal proteins with both single and multiple sites. Bioinformatics, 2017, 33(22), 3524-3531.
[http://dx.doi.org/10.1093/bioinformatics/btx476] [PMID: 29036535]
[23]
Cheng, X.; Xiao, X.; Chou, K.C. pLoc-mEuk: Predict subcellular localization of multi-label eukaryotic proteins by extracting the key GO information into general PseAAC. Genomics, 2018, 110(1), 50-58.
[http://dx.doi.org/10.1016/j.ygeno.2017.08.005] [PMID: 28818512]
[24]
Cheng, X.; Xiao, X.; Chou, K.C. pLoc-mHum: predict subcellular localization of multi-location human proteins via general PseAAC to winnow out the crucial GO information. Bioinformatics, 2018, 34(9), 1448-1456.
[http://dx.doi.org/10.1093/bioinformatics/btx711] [PMID: 29106451]
[25]
Chou, K.C. Some remarks on predicting multi-label attributes in molecular biosystems. Mol. Biosyst., 2013, 9(6), 1092-1100.
[http://dx.doi.org/10.1039/c3mb25555g] [PMID: 23536215]
[26]
Zhou, G.P.; Troy, F.A. II NMR study of the preferred membrane orientation of polyisoprenols (dolichol) and the impact of their complex with polyisoprenyl recognition sequence peptides on membrane structure. Glycobiology, 2005, 15(4), 347-359.
[http://dx.doi.org/10.1093/glycob/cwi016] [PMID: 15563715]
[27]
Zhou, G.P.; Chen, D.; Liao, S.; Huang, R.B. Recent Progresses in Studying Helix-Helix Interactions in Proteins by Incorporating the Wenxiang Diagram into the NMR Spectroscopy. Curr. Top. Med. Chem., 2016, 16(6), 581-590.
[http://dx.doi.org/10.2174/1568026615666150819104617] [PMID: 26286215]
[28]
Zhou, G.P. Impacts of computational biology to medicinal chemistry. Med. Chem., 2017, 13(6), 504-505.
[http://dx.doi.org/10.2174/157340641306170802111946] [PMID: 28874113]
[29]
Zhou, G.P. Impact of biological science to medicinal chemistry. Curr. Top. Med. Chem., 2017, 17(21), 2335-2336.
[http://dx.doi.org/10.2174/156802661721170721204409] [PMID: 28799500]
[30]
Huang, R.B.; Cheng, D.; Liao, S.M.; Lu, B.; Wang, Q.Y.; Xie, N.Z.; Troy Ii, F.A.; Zhou, G.P. The intrinsic relationship between structure and function of the sialyltransferase ST8Sia family members. Curr. Top. Med. Chem., 2017, 17(21), 2359-2369.
[http://dx.doi.org/10.2174/1568026617666170414150730] [PMID: 28413949]
[31]
Xie, N.Z.; Chen, X.R.; Wang, Q.Y.; Chen, D.; Du, Q.S.; Zhou, G.P.; Huang, R.B. Microbial Routes to (2R,3R)-2,3-Butanediol: Recent advances and future prospects. Curr. Top. Med. Chem., 2017, 17(21), 2433-2439.
[http://dx.doi.org/10.2174/1568026617666170504101646] [PMID: 28474550]
[32]
Chou, K.C. Insights from modelling the 3D structure of the extracellular domain of alpha7 nicotinic acetylcholine receptor. Biochem. Biophys. Res. Commun., 2004, 319(2), 433-438.
[http://dx.doi.org/10.1016/j.bbrc.2004.05.016] [PMID: 15178425]
[33]
Chou, K.C. Structural bioinformatics and its impact to biomedical science. Curr. Med. Chem., 2004, 11(16), 2105-2134.
[http://dx.doi.org/10.2174/0929867043364667] [PMID: 15279552]
[34]
Liu, Z.; Xiao, X.; Yu, D.J.; Jia, J.; Qiu, W.R.; Chou, K.C. pRNAm-PC: Predicting N(6)-methyladenosine sites in RNA sequences via physical-chemical properties. Anal. Biochem., 2016, 497, 60-67.
[http://dx.doi.org/10.1016/j.ab.2015.12.017] [PMID: 26748145]
[35]
Liu, Z.; Xiao, X.; Qiu, W.R.; Chou, K.C. iDNA-Methyl: identifying DNA methylation sites via pseudo trinucleotide composition. Anal. Biochem., 2015, 474, 69-77.
[http://dx.doi.org/10.1016/j.ab.2014.12.009] [PMID: 25596338]
[36]
Liu, Z.; Xiao, X.; Qiu, W.R.; Chou, K.C. Benchmark data for identifying DNA methylation sites via pseudo trinucleotide composition. Data Brief, 2015, 4, 87-89.
[http://dx.doi.org/10.1016/j.dib.2015.04.021] [PMID: 26217768]
[37]
Feng, P.; Ding, H.; Yang, H.; Chen, W.; Lin, H.; Chou, K.C. iRNA-PseColl: Identifying the occurrence sites of different RNA modifications by incorporating collective effects of nucleotides into PseKNC. Mol. Ther. Nucleic Acids, 2017, 7, 155-163.
[http://dx.doi.org/10.1016/j.omtn.2017.03.006] [PMID: 28624191]
[38]
Chou, K.C. Pseudo amino acid composition and its applications in bioinformatics, proteomics and system biology. Curr. Proteomics, 2009, 6, 262-274.
[http://dx.doi.org/10.2174/157016409789973707]
[39]
Chen, W.; Lei, T.Y.; Jin, D.C.; Lin, H.; Chou, K.C. PseKNC: a flexible web server for generating pseudo K-tuple nucleotide composition. Anal. Biochem., 2014, 456, 53-60.
[http://dx.doi.org/10.1016/j.ab.2014.04.001] [PMID: 24732113]
[40]
Chen, W.; Lin, H.; Chou, K.C. Pseudo nucleotide composition or PseKNC: an effective formulation for analyzing genomic sequences. Mol. Biosyst., 2015, 11(10), 2620-2634.
[http://dx.doi.org/10.1039/C5MB00155B] [PMID: 26099739]
[41]
Liu, B.; Liu, F.; Wang, X.; Chen, J.; Fang, L.; Chou, K.C. Pse-in-One: a web server for generating various modes of pseudo components of DNA, RNA, and protein sequences. Nucleic Acids Res., 2015, 43(W1)W65-71
[http://dx.doi.org/10.1093/nar/gkv458] [PMID: 25958395]
[42]
Liu, B.; Wu, H. Pse-in-One 2.0: An improved package of web servers for generating various modes of pseudo components of DNA, RNA, and protein Sequences. Nat. Sci., 2017, 9, 67-91.
[http://dx.doi.org/10.4236/ns.2017.94007]
[43]
Smith, R.G.; Caswell, D.; Carriere, A.; Zielke, B. Variation in the ginsenoside content of American ginseng, Panax quinquefolius L., roots. Can. J. Bot., 1996, 74(10), 1616-1620.
[http://dx.doi.org/10.1139/b96-195]
[44]
Jiang, H.P.; Qiu, Y.K.; Cheng, D.R.; Kang, T.G.; Dou, D.Q. Structure elucidation and complete NMR spectral assignments of two new dammarane-type tetraglycosides from Panax quinquefolium. Magn. Reson. Chem., 2008, 46(8), 786-790.
[http://dx.doi.org/10.1002/mrc.2247] [PMID: 18478623]
[45]
Fuzzati, N. Analysis methods of ginsenosides. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2004, 812(1-2), 119-133.
[http://dx.doi.org/10.1016/S1570-0232(04)00645-2] [PMID: 15556492]
[46]
Qi, L.W.; Wang, C.Z.; Yuan, C.S. Ginsenosides from American ginseng: chemical and pharmacological diversity. Phytochemistry, 2011, 72(8), 689-699.
[http://dx.doi.org/10.1016/j.phytochem.2011.02.012] [PMID: 21396670]
[47]
Sun, S.; Qi, L.W.; Du, G.J.; Mehendale, S.R.; Wang, C.Z.; Yuan, C.S. Red notoginseng: higher ginsenoside content and stronger anticancer potential than Asian and American ginseng. Food Chem., 2011, 125(4), 1299-1305.
[http://dx.doi.org/10.1016/j.foodchem.2010.10.049] [PMID: 21344064]
[48]
Foster, S. Asian Ginseng, Panax ginseng. American botanical Council, Botanical booklet series, 1991, 303
[49]
Cheng, C.C.; Yang, S.M.; Huang, C.Y.; Chen, J.C.; Chang, W.M.; Hsu, S.L. Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Cancer Chemother. Pharmacol., 2005, 55(6), 531-540.
[http://dx.doi.org/10.1007/s00280-004-0919-6] [PMID: 15739095]
[50]
Wang, A.; Wang, C.Z.; Wu, J.A.; Osinski, J.; Yuan, C.S. Determination of major ginsenosides in Panax quinquefolius (American ginseng) using high-performance liquid chromatography. Phytochem. Anal., 2005, 16(4), 272-277.
[http://dx.doi.org/10.1002/pca.838] [PMID: 16042154]
[51]
Li, W.; Gu, C.; Zhang, H.; Awang, D.V.; Fitzloff, J.F.; Fong, H.H.; van Breemen, R.B. Use of high-performance liquid chromatography-tandem mass spectrometry to distinguish Panax ginseng C. A. Meyer (Asian ginseng) and Panax quinquefolius L. (North American ginseng). Anal. Chem., 2000, 72(21), 5417-5422.
[http://dx.doi.org/10.1021/ac000650l] [PMID: 11080895]
[52]
Assinewe, V.A.; Baum, B.R.; Gagnon, D.; Arnason, J.T. Phytochemistry of wild populations of Panax quinquefolius L. (North American ginseng). J. Agric. Food Chem., 2003, 51(16), 4549-4553.
[http://dx.doi.org/10.1021/jf030042h] [PMID: 14705875]
[53]
Sanada, S.; Kondo, N. SHOJI, J.; TANAKA, O.; Shibata, S. Studies on the saponins of ginseng. I. Structures of ginsenoside-Ro,-Rb1,-Rb2,-Rc and-Rd. Chem. Pharm. Bull. (Tokyo), 1974, 22(2), 421-428.
[http://dx.doi.org/10.1248/cpb.22.421]
[54]
Kasai, R.; Besso, H.; Tanaka, O.; Saruwatari, Y.; Fuma, T. Saponins of red ginseng. Chem. Pharm. Bull., 2018, 31(6), 2120-2125.
[http://dx.doi.org/10.1248/cpb.31.2120]
[55]
Popovich, D.G.; Yeo, C.R.; Zhang, W. Ginsenosides derived from Asian (Panax ginseng), American ginseng (Panax quinquefolius) and potential cytoactivity. Int. J. Pharm., 2012, 6(1), 56-62.
[56]
Dharmananda, S. The nature of ginseng: Traditional use, modern research, and the question of dosage. Herbal Gram., 2002, 54, 34-51.
[57]
Shin, B.K.; Kwon, S.W.; Park, J.H. Chemical diversity of ginseng saponins from Panax ginseng. J. Ginseng Res., 2015, 39(4), 287-298.
[http://dx.doi.org/10.1016/j.jgr.2014.12.005] [PMID: 26869820]
[58]
Nakamura, S.; Sugimoto, S.; Matsuda, H.; Yoshikawa, M. Medicinal flowers. XVII. New dammarane-type triterpene glycosides from flower buds of American ginseng, Panax quinquefolium L. Chem. Pharm. Bull. (Tokyo), 2007, 55(9), 1342-1348.
[http://dx.doi.org/10.1248/cpb.55.1342] [PMID: 17827759]
[59]
Park, H.W. In, G.; Han, S.T.; Lee, M.W.; Kim, S.Y.; Kim, K.T.; Cho, B.G.; Han, G.H.; Chang, I.M. Simultaneous determination of 30 ginsenosides in Panax ginseng preparations using ultra performance liquid chromatography. J. Ginseng Res., 2013, 37(4), 457-467.
[http://dx.doi.org/10.5142/jgr.2013.37.457] [PMID: 24235860]
[60]
Wang, W.; Zhao, Y.Q.; Rayburn, E.R.; Hill, D.L.; Wang, H.; Zhang, R.W. Novel ginsenosides 25-OH-PPD and 25-OCH3-PPD as experimental therapy for pancreatic cancer: Anticancer activity and mechanisms of action. Cancer Chemoth. Pharm., 2007, 589-601.
[61]
Wan, J.B.; Li, S.P.; Chen, J.M.; Wang, Y.T. Chemical characteristics of three medicinal plants of the Panax genus determined by HPLC-ELSD. J. Sep. Sci., 2007, 30(6), 825-832.
[http://dx.doi.org/10.1002/jssc.200600359] [PMID: 17536727]
[62]
Qiu, Y.K.; Dou, D.Q.; Cai, L.P.; Jiang, H.P.; Kang, T.G.; Yang, B.Y.; Kuang, H.X.; Li, M.Z.C. Dammarane-type saponins from Panax quinquefolium and their inhibition activity on human breast cancer MCF-7 cells. Fitoterapia, 2009, 80(4), 219-222.
[http://dx.doi.org/10.1016/j.fitote.2009.01.011] [PMID: 19535014]
[63]
Besso, H.; Kasai, R.; Saruwatari, Y.; Fuwa, T.; Tanaka, O. Ginsenoside-Ra1 and ginsenoside-Ra2 new dammarane-saponins of ginseng roots. Chem. Pharm. Bull. (Tokyo), 1982, 30(7), 2380-2385.
[http://dx.doi.org/10.1248/cpb.30.2380]
[64]
Ruan, C.C.; Liu, Z.; Li, X.; Liu, X.; Wang, L.J.; Pan, H.Y.; Zheng, Y.N.; Sun, G.Z.; Zhang, Y.S.; Zhang, L.X. Isolation and characterization of a new ginsenoside from the fresh root of Panax Ginseng. Molecules, 2010, 15(4), 2319-2325.
[http://dx.doi.org/10.3390/molecules15042319] [PMID: 20428044]
[65]
Hwang, Y.P.; Jeong, H.G. Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K/Akt/Nrf2-dependent pathway in human dopaminergic cells. Toxicol. Appl. Pharmacol., 2010, 242(1), 18-28.
[http://dx.doi.org/10.1016/j.taap.2009.09.009] [PMID: 19781563]
[66]
Xu, T.M.; Cui, M.H.; Xin, Y.; Gu, L.P.; Jiang, X.; Su, M.M.; Wang, D.D.; Wang, W.J. Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin. Med. J. (Engl.), 2008, 121(15), 1394-1397.
[http://dx.doi.org/10.1097/00029330-200808010-00012] [PMID: 18959116]
[67]
Xie, J.T.; Wang, C.Z.; Zhang, B.; Mehendale, S.R.; Li, X.L.; Sun, S.; Han, A.H.; Du, W.; He, T.C.; Yuan, C.S. In vitro and in vivo anticancer effects of American ginseng berry: exploring representative compounds. Biol. Pharm. Bull., 2009, 32(9), 1552-1558.
[http://dx.doi.org/10.1248/bpb.32.1552] [PMID: 19721231]
[68]
Christensen, L.P.; Jensen, M.; Kidmose, U. Simultaneous determination of ginsenosides and polyacetylenes in American ginseng root (Panax quinquefolium L.) by HPLC. J. Agric. Food Chem., 2006, 54(24), 8995-9003.
[http://dx.doi.org/10.1021/jf062068p] [PMID: 17117783]
[69]
Wang, C.Z.; Aung, H.H.; Ni, M.; Wu, J.A.; Tong, R.; Wicks, S.; He, T.C.; Yuan, C.S. Red American ginseng: ginsenoside constituents and antiproliferative activities of heat-processed Panax quinquefolius roots. Planta Med., 2007, 73(7), 669-674.
[http://dx.doi.org/10.1055/s-2007-981524] [PMID: 17538869]
[70]
Lee, K.Y.; Lee, Y.H.; Kim, S.I.; Park, J.H.; Lee, S.K. Ginsenoside-Rg5 suppresses cyclin E-dependent protein kinase activity via up-regulating p21Cip/WAF1 and down-regulating cyclin E in SK-HEP-1 cells. Anticancer Res., 1997, 17(2A), 1067-1072.
[PMID: 9137450]
[71]
Dou, D.; Li, W.; Guo, N.; Fu, R.; Pei, Y.; Koike, K.; Nikaido, T. Ginsenoside Rg8, a new dammarane-type triterpenoid saponin from roots of Panax quinquefolium. Chem. Pharm. Bull. (Tokyo), 2006, 54(5), 751-753.
[http://dx.doi.org/10.1248/cpb.54.751] [PMID: 16651785]
[72]
Jung, J.S.; Shin, J.A.; Park, E.M.; Lee, J.E.; Kang, Y.S.; Min, S.W.; Kim, D.H.; Hyun, J.W.; Shin, C.Y.; Kim, H.S. Anti-inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide-stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase-1 expression. J. Neurochem., 2010, 115(6), 1668-1680.
[http://dx.doi.org/10.1111/j.1471-4159.2010.07075.x] [PMID: 20969575]
[73]
Kim, J.H.; Yi, Y.S.; Kim, M.Y.; Cho, J.Y. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J. Ginseng Res., 2017, 41(4), 435-443.
[http://dx.doi.org/10.1016/j.jgr.2016.08.004] [PMID: 29021688]
[74]
Tang, M.H.; Jiang, Z.H.; Zhao, Z.Z.; Zhang, J.S. Isolation and Determination of 20(S)-ginsenoside Rg3 and 20(R)-ginsenoside Rg3 with HPLC. Chin. Tradit. Herbal Drugs, 2004, 35(3), 280-282.
[75]
Zhao, Y. Advance in studies on anticarcinogenic effects of 20 (R)-ginsenoside Rg3. Linchuang Zhongliuxue Zazhi, 2001, 6(1), 81-82.
[76]
Qi, X.D.; Zhang, C.J.; Yu, H.T.; Shi, Y.; Sun, Y.; Lu, C.F.; Chen, G. S-and R-ginsenoside Rh2 indudcing the apoptosis of human lung cancer A549 cells. Guide Chin. Med., 2011, 9(21), 8-10.
[77]
Chen, Y.; Zhang, B.; Yu, Y.; Jin, Y. Effect of ginsenoside Rg3 on cell proliferation and invasion of breast cancer MCF-7 cell line. Chinese J. Mod. App. Pharm., 2013, 30(7), 722-725.
[78]
Kim, B.M.; Kim, D.H.; Park, J.H.; Na, H.K.; Surh, Y.J. Ginsenoside Rg3 induces apoptosis of human breast cancer (MDA-MB-231) cells. J. Cancer Prev., 2013, 18(2), 177-185.
[http://dx.doi.org/10.15430/JCP.2013.18.2.177] [PMID: 25337544]
[79]
Kim, B.M.; Kim, D.H.; Park, J.H.; Surh, Y.J.; Na, H.K. Ginsenoside Rg3 inhibits constitutive activation of NF-κB signaling in human breast cancer (MDA-MB-231) cells: ERK and Akt as potential upstream targets. J. Cancer Prev., 2014, 19(1), 23-30.
[http://dx.doi.org/10.15430/JCP.2014.19.1.23] [PMID: 25337569]
[80]
Peng, M.; Zhai, H.; Feng, Y.; Xin, L.; Sun, D. Studies on mechanisms of Rg3 inducing apoptosis through PI3K/Akt mediating MGBA in breast cancer cells. J. Lia. Med. Uni., 2016, 37(3), 1-3.
[81]
Sun, D.; Gu, L.; Li, C.; Zhang, F. Ginsenoside Rg3 promotes the apoptosis of breast cancer MDA-MB-231 cells via regulation of mammaglobin-A expression. Zhongguo Zhongliu Shengwu Zhiliao Zazhi, 2017, 24(6), 615-619.
[82]
Guo, Q.; Yuan, M.; Gguo, Y. The influence of ginsenoside Rg3 on the growth and invasion of MDA-MB-231 human breast cancer cell. J. Prac. Gyne. Endo., 2018, 5(12), 8-10.
[83]
Zou, M.; Wang, J.; Gao, J.; Han, H.; Fang, Y. Phosphoproteomic analysis of the antitumor effects of ginsenoside Rg3 in human breast cancer cells. Oncol. Lett., 2018, 15(3), 2889-2898.
[PMID: 29435015]
[84]
Oh, J.; Yoon, H.J.; Jang, J.H.; Kim, D.H.; Surh, Y.J. The Korean red ginseng extract and its ingredient ginsenoside Rg3 inhibit manifestation of breast cancer stem cell-like properties through modulation of self-renewal signaling. J. Ginseng Res., •••, 43(3), 421-430.
[PMID: 31308814]
[85]
Zhang, Y.; Liu, Q.Z.; Xing, S.P.; Zhang, J.L. Inhibiting effect of Endostar combined with ginsenoside Rg3 on breast cancer tumor growth in tumor-bearing mice. Asian Pac. J. Trop. Med., 2016, 9(2), 180-183.
[http://dx.doi.org/10.1016/j.apjtm.2016.01.010] [PMID: 26919952]
[86]
Chen, K.; He, J.; Liang, W. Autophagy of MCF-7 cell induced by 20(R)-Ginsenoside Rg3. Contemp. Med., 2016, 22(23), 1-3.
[87]
Sun, X.; Wang, F. The effect of ginsenoside Rg3 on breast cancer MCF-7 mitochondrial pathway of Apoptosis. China Med. Pharm., 2011, 1(6), 9-11.
[88]
Kim, S.J.; Kim, A.K. Anti-breast cancer activity of Fine Black ginseng (Panax ginseng Meyer) and ginsenoside Rg5. J. Ginseng Res., 2015, 39(2), 125-134.
[http://dx.doi.org/10.1016/j.jgr.2014.09.003] [PMID: 26045685]
[89]
Kim, B.J. Involvement of melastatin type transient receptor potential 7 channels in ginsenoside Rd-induced apoptosis in gastric and breast cancer cells. J. Ginseng Res., 2013, 37(2), 201-209.
[http://dx.doi.org/10.5142/jgr.2013.37.201] [PMID: 23717173]
[90]
Mai, T.T.; Moon, J.; Song, Y.; Viet, P.Q.; Phuc, P.V.; Lee, J.M.; Yi, T.H.; Cho, M.; Cho, S.K. Ginsenoside F2 induces apoptosis accompanied by protective autophagy in breast cancer stem cells. Cancer Lett., 2012, 321(2), 144-153.
[http://dx.doi.org/10.1016/j.canlet.2012.01.045] [PMID: 22326284]
[91]
Choi, S.; Oh, J.Y.; Kim, S.J. Ginsenoside Rh2 induces Bcl-2 family proteins-mediated apoptosis in vitro and in xenografts in vivo models. J. Cell. Biochem., 2011, 112(1), 330-340.
[http://dx.doi.org/10.1002/jcb.22932] [PMID: 21080338]
[92]
Duan, Z.; Wei, B.; Deng, J.; Mi, Y.; Dong, Y.; Zhu, C.; Fu, R.; Qu, L.; Fan, D. The anti-tumor effect of ginsenoside Rh4 in MCF-7 breast cancer cells in vitro and in vivo. Biochem. Biophys. Res. Commun., 2018, 499(3), 482-487.
[http://dx.doi.org/10.1016/j.bbrc.2018.03.174] [PMID: 29596831]
[93]
Kang, J.H.; Song, K.H.; Woo, J.K.; Park, M.H.; Rhee, M.H.; Choi, C.; Oh, S.H. Ginsenoside Rp1 from Panax ginseng exhibits anti-cancer activity by down-regulation of the IGF-1R/Akt pathway in breast cancer cells. Plant Foods Hum. Nutr., 2011, 66(3), 298-305.
[http://dx.doi.org/10.1007/s11130-011-0242-4] [PMID: 21748437]
[94]
Sun, S.; Du, J.; Sun, X. Experimental Study on the Inhibition of Migration and Invasion in Cell Breast Cancer Cells MCF- 7 by Ginsenoside CK. Lishizhen Med. and Mat. Med. Res., 2018, 29(5), 1068-1070.
[95]
Zhang, K.; Li, Y. Effects of ginsenoside compound K combined with cisplatin on the proliferation, apoptosis and epithelial mesenchymal transition in MCF-7 cells of human breast cancer. Pharm. Biol., 2016, 54(4), 561-568.
[http://dx.doi.org/10.3109/13880209.2015.1101142] [PMID: 26511312]
[96]
Kwak, C.W.; Son, Y.M.; Gu, M.J.; Kim, G.; Lee, I.K.; Kye, Y.C.; Kim, H.W.; Song, K.D.; Chu, H.; Park, B.C.; Lee, H.K.; Yang, D.C.; Sprent, J.; Yun, C.H. A bacterial metabolite, compound K, induces programmed necrosis in MCF-7 cells via GSK3β. J. Microbiol. Biotechnol., 2015, 25(7), 1170-1176.
[http://dx.doi.org/10.4014/jmb.1505.05057] [PMID: 26032359]
[97]
Tong, C.; Zheng, J. Animal study of rh-endostatin combinationed with ginsenoside Rg3 on inhibiting growth of breast cancer xenografts. Hainan Yixueyuan Xuebao, 2012, 22(6), 531-534.
[98]
Li, G.; Chen, W.; Liang, H.; Wang, Y. Experimental study of artificial saponin rg3 combined with rh-ES treatment for breast cancer tumor-bearing mice. Chin. J. Gen. Surg., 2017, 26(11), 1493-1497.
[99]
Feng, X.; Jiang, G.; Li, Q. Ginsenoside Rh2 sensitized 5-fluorouracil which induced human breast cancer MCF-7 apoptosis. J. Shenyang Pharm. Univ., 2012, 29(5), 383-389.
[100]
Zhang, L.; Chen, Y. Inhibition effect of ginsenoside Rg3 on the growth of anoikis-resistant breast cancer cell MCF-7. Central South Pharmacy., 2014, 12(2), 128-131.
[101]
Zhang, L. Effect of ginsenoside Rg3 on the induction of MCF7/ADR cells apoptosis of breast cancer and its possible molecular mechanisms. Medical Recapitulate, 2015, 21(18), 3391-3393.
[102]
Pan, X.; Wang, M.; Cui, X. Research on the effect of ginsenoside Rg3 on proliferation of breast cancer cell line. Shand. Medicine , 2011, 26(51), 20-22.
[103]
Kwak, J.H.; Park, J.Y.; Lee, D.; Kwak, J.Y.; Park, E.H.; Kim, K.H.; Park, H.J.; Kim, H.Y.; Jang, H.J.; Ham, J.; Hwang, G.S.; Yamabe, N.; Kang, K.S. Inhibitory effects of ginseng sapogenins on the proliferation of triple negative breast cancer MDA-MB-231 cells. Bioorg. Med. Chem. Lett., 2014, 24(23), 5409-5412.
[http://dx.doi.org/10.1016/j.bmcl.2014.10.041] [PMID: 25453798]
[104]
Zhang, H.; Xu, H.L.; Fu, W.W.; Xin, Y.; Li, M.W.; Wang, S.J.; Yu, X.F.; Sui, D.Y. 20(S)-Protopanaxadiol induces human breast cancer MCF-7 apoptosis through a caspase-mediated pathway. Asian Pac. J. Cancer Prev., 2014, 15(18), 7919-7923.
[http://dx.doi.org/10.7314/APJCP.2014.15.18.7919] [PMID: 25292087]
[105]
Fan, F.; Schimming, A.; Jaeger, D.; Podar, K. Targeting the tumor microenvironment: focus on angiogenesis. J. Oncol., 2012, •••2012281261
[http://dx.doi.org/10.1155/2012/281261] [PMID: 21876693]
[106]
Li, G.; Yang, H.; Lu, Y. Effects of ginsenoside Rg3 on vasculogenic mimicry of breast cancer MCF-7 cell line. Tianjin Yi Yao, 2016, 44(9), 1069-1072.
[107]
Zhang, W.; Lu, Y.; Deng, L. Inhibitory effect of ginsenoside Rg3 combined with arsenictrioxide on tumor growth and neoangiogenesis in transplanted breast carcinoma. Chin. J. Oncol. Prev. and Treat., 2011, 3(2), 99-102.
[108]
Piao, L.; Zhang, M.; Jin, X.; Han, L.; Jiang, J.; Cai, Y.; Jin, Z. Inhibition effects and its mechanisms of ginsenoside Rg3 on the proliferation of human breast cancer. Med. J. Yanbian Uni., 2017, 40(1), 20-23.
[109]
Jiao, D.; Meng, Y.; Qiao, M.; Shan, J. Effects of ginsenoside Rg3 combined with neoadjuvant chemotherapy on advanced breast cancer and VEGF level. Prac. Clin. Med., 2017, 18(9), 27-29.
[110]
Zhang, E.; Shi, H.; Yang, L.; Wu, X.; Wang, Z. Ginsenoside Rd regulates the Akt/mTOR/p70S6K signaling cascade and suppresses angiogenesis and breast tumor growth. Oncol. Rep., 2017, 38(1), 359-367.
[http://dx.doi.org/10.3892/or.2017.5652] [PMID: 28534996]
[111]
Chen, X.P.; Qian, L.L.; Jiang, H.; Chen, J.H. Ginsenoside Rg3 inhibits CXCR4 expression and related migrations in a breast cancer cell line. Int. J. Clin. Oncol., 2011, 16(5), 519-523.
[http://dx.doi.org/10.1007/s10147-011-0222-6] [PMID: 21455623]
[112]
Wang, J.; Yu, F. Inhibitory Effect of ginsenoside Rg3 on breast cancer cell metastasis. J. Hubei Uni. Chinese Med., 2017, 19(6), 12-14.
[113]
Wang, W.; Zhang, X.; Qin, J.J.; Voruganti, S.; Nag, S.A.; Wang, M.H.; Wang, H.; Zhang, R. Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2. PLoS One, 2012, 7(7)e41586
[http://dx.doi.org/10.1371/journal.pone.0041586] [PMID: 22911819]
[114]
Wang, P.; Du, X.; Xiong, M.; Cui, J.; Yang, Q.; Wang, W.; Chen, Y.; Zhang, T. Ginsenoside Rd attenuates breast cancer metastasis implicating derepressing microRNA-18a-regulated Smad2 expression. Sci. Rep., 2016, 6, 33709.
[http://dx.doi.org/10.1038/srep33709] [PMID: 27641158]
[115]
Li, L.; Wang, Y.; Qi, B.; Yuan, D.; Dong, S.; Guo, D.; Zhang, C.; Yu, M. Suppression of PMA-induced tumor cell invasion and migration by ginsenoside Rg1 via the inhibition of NF-κB-dependent MMP-9 expression. Oncol. Rep., 2014, 32(5), 1779-1786.
[http://dx.doi.org/10.3892/or.2014.3422] [PMID: 25174454]
[116]
Piao, L.; Cai, Y.; Zhang, M. Effects of ginsenoside Rh2 combined with PI3K/AKT pathway inhibitor LY294002 on invasion and migration of breast cancer cells. China Pharmacy, 2013, 24(43), 4050-4052.
[117]
Piao, Y.; Li, S.; Zhang, Q. Effect of ginsenoside Rg3 combined with delaying tamoxifen resistance in breast cancer. Practical Oncology., 2013, 27(6), 481-484.
[118]
Pokharel, Y.R.; Kim, N.D.; Han, H.K.; Oh, W.K.; Kang, K.W. Increased ubiquitination of multidrug resistance 1 by ginsenoside Rd. Nutr. Cancer, 2010, 62(2), 252-259.
[http://dx.doi.org/10.1080/01635580903407171] [PMID: 20099200]
[119]
Zhou, B.; Xiao, X.; Xu, L.; Zhu, L.; Tan, L.; Tang, H.; Zhang, Y.; Xie, Q.; Yao, S. A dynamic study on reversal of multidrug resistance by ginsenoside Rh2 in adriamycin-resistant human breast cancer MCF-7 cells. Talanta, 2012, 88, 345-351.
[http://dx.doi.org/10.1016/j.talanta.2011.10.051] [PMID: 22265509]
[120]
Li, P.; Chen, S. Study of the ginsenoside Rh2 reversal MCF-7/ADM multidrug resistance. Guide of China Med., 2013, 11(21), 8-10.
[121]
Wen, X.; Zhang, H.D.; Zhao, L.; Yao, Y.F.; Zhao, J.H.; Tang, J.H. Ginsenoside Rh2 differentially mediates microRNA expression to prevent chemoresistance of breast cancer. Asian Pac. J. Cancer Prev., 2015, 16(3), 1105-1109.
[http://dx.doi.org/10.7314/APJCP.2015.16.3.1105] [PMID: 25735339]
[122]
Zhang, J.; Zhou, F.; Wu, X.; Zhang, X.; Chen, Y.; Zha, B.S.; Niu, F.; Lu, M.; Hao, G.; Sun, Y.; Sun, J.; Peng, Y.; Wang, G. Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells. Br. J. Pharmacol., 2012, 165(1), 120-134.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01505.x] [PMID: 21615726]
[123]
Zhang, J.; Lu, M.; Zhou, F.; Sun, H.; Hao, G.; Wu, X.; Wang, G. Key role of nuclear factor-κB in the cellular pharmacokinetics of adriamycin in MCF-7/Adr cells: the potential mechanism for synergy with 20(S)-ginsenoside Rh2. Drug Metab. Dispos., 2012, 40(10), 1900-1908.
[http://dx.doi.org/10.1124/dmd.112.045187] [PMID: 22745335]
[124]
Qu, D.; Wang, L.; Liu, M.; Shen, S.; Li, T.; Liu, Y.; Huang, M.; Liu, C.; Chen, Y.; Mo, R. Oral nanomedicine based on multicomponent microemulsions for drug-resistant breast cancer treatment. Biomacromolecules, 2017, 18(4), 1268-1280.
[http://dx.doi.org/10.1021/acs.biomac.7b00011] [PMID: 28350158]
[125]
Lu, P.; Su, W.; Miao, Z.H.; Niu, H.R.; Liu, J.; Hua, Q.L. Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer. Chin. J. Integr. Med., 2008, 14(1), 33-36.
[http://dx.doi.org/10.1007/s11655-007-9002-6] [PMID: 18219455]
[126]
Zhang, X.; Wang, X.; Tang, D. Clinical effect and life quality study of Shenyi capsule combined with docetaxel and cisplatin in treatment of advanced breast cancer. China J. Biochem. Med., 2015, 35(11), 97-99.
[127]
Xiao, L. Clinical observation on ginsenoside Rg3 combined with capecitabine in the treatment of advanced triple-negative breast cancer. Hebei Med. J., 2015, 37(16), 2445-2447.
[128]
Lee, H.; Lee, S.; Jeong, D. Kim. S. J. Ginsenoside Rh2 epigenetically regulates cell-mediated immune pathway to inhibit proliferation of MCF-7 breast cancer cells. J. Ginseng Res., 2017, 42(4), 455-462.
[129]
Pathania, S.; Ramakrishnan, S.M.; Bagler, G. Phytochemica: a platform to explore phytochemicals of medicinal plants. Database (Oxford), 2015, 2015bav075
[http://dx.doi.org/10.1093/database/bav075] [PMID: 26255307]
[130]
Mangal, M.; Sagar, P.; Singh, H.; Raghava, G.P.; Agarwal, S.M. NPACT: naturally occurring plant-based anti-cancer compound-activity-target database. Nucleic Acids Res., 2013, 41(Database issue), D1124-D1129.
[http://dx.doi.org/10.1093/nar/gks1047] [PMID: 23203877]
[131]
Ye, H.; Ye, L.; Kang, H.; Zhang, D.; Tao, L.; Tang, K.; Liu, X.; Zhu, R.; Liu, Q.; Chen, Y.Z.; Li, Y.; Cao, Z. HIT: linking herbal active ingredients to targets. Nucleic Acids Res., 2011, 39(Database issue), D1055-D1059.
[http://dx.doi.org/10.1093/nar/gkq1165] [PMID: 21097881]