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Pharmaceuticals (Basel)
2019 Aug 01;123:. doi: 10.3390/ph12030117.
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Stereoselective Anti-Cancer Activities of Ginsenoside Rg3 on Triple Negative Breast Cancer Cell Models.
Nakhjavani M
,
Palethorpe HM
,
Tomita Y
,
Smith E
,
Price TJ
,
Yool AJ
,
Pei JV
,
Townsend AR
,
Hardingham JE
.
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Ginsenoside Rg3 (Rg3) has two epimers, 20(S)-ginsenoside Rg3 (SRg3) and 20(R)-ginsenoside Rg3 (RRg3), and while Rg3 itself has been reported to have anti-cancer properties, few studies have been reported on the anti-cancer effects of the different epimers. The aim was to investigate the stereoselective effects of the Rg3 epimers on triple negative breast cancer (TNBC) cell lines, tested using cell-based assays for proliferation, apoptosis, cell cycle arrest, migration and invasion. Molecular docking showed that Rg3 interacted with the aquaporin 1 (AQP1) water channel (binding score -9.4 kJ mol-1). The Xenopus laevis oocyte expression system was used to study the effect of Rg3 epimers on the AQP1 water permeability. The AQP1 expression in TNBC cell lines was compared with quantitative-polymerase chain reaction (PCR). The results showed that only SRg3 inhibited the AQP1 water flux and inhibited the proliferation of MDA-MB-231 (100 μM), due to cell cycle arrest at G0/G1. SRg3 inhibited the chemoattractant-induced migration of MDA-MB-231. The AQP1 expression in MDA-MB-231 was higher than in HCC1143 or DU4475 cell lines. These results suggest a role for AQP1 in the proliferation and chemoattractant-induced migration of this cell line. Compared to SRg3, RRg3 had more potency and efficacy, inhibiting the migration and invasion of MDA-MB-231. Rg3 has stereoselective anti-cancer effects in the AQP1 high-expressing cell line MDA-MB-231.
Figure 1. (A) The role of aquaporin 1 (AQP1) in cell migration and invasion (as reviewed in [39]). AQPs are redistributed to the leading edge of the migrating cell, leading water, ions and gases inside the cell; hence, along with changes in actin polymerisation, they play a role in the forward movement of the cell. AQP1 is a tetramer. Water passes through the pore of each monomer, and ions and gases pass through the central pore of the tetramer. (B) Top view of an AQP1 monomer, being blocked with Rg3, the black structure, (C) Side view of an AQP1 monomer, blocked with Rg3, and (D) H-bonding between Rg3 and Gly 65.
Figure 2. (A) Double swelling assay showing the swelling rates for the first and the second swelling on a single oocyte. Eight oocytes per treatment were measured for swelling in a hypotonic medium, before and 2 h after exposure to a vehicle or epimers of Rg3. The results were analysed and presented with a linear regression. (B) The AQP1 transcript expression in MDA-MB-231, HCC1143 and DU4475 cell lines. Each data point represents a mean ± SD value of 3 replicates, and comparisons were made with the vehicle control group (**** p < 0.0001).
Figure 3. Effect of SRg3 and RRg3 on the proliferation of MDA-MB-231, HCC1143 and DU4475 triple negative breast cancer cell lines, after 3 days, with (A) a crystal violet assay on the adherent cell lines and (B) an MTS assay. Only 100 μM of SRg3 showed an inhibition of proliferation of MDA-MB-231 in both assays, indicating the cell line selectivity and stereoselective effect of Rg3 for the inhibition of proliferation. Each data point represents a mean ± SD value of 6 replicates, and comparisons are made with the vehicle control group (**** p < 0.0001).
Figure 4. The effect of SRg3 on apoptosis and cell cycle arrest in the MDA-MB-231 cell line. (A) Total apoptotic cells (%) induced by vehicle or 100 μM SRg3 after 3 days of exposure; (B) Scatter plots of untreated cells or the cells treated with vehicle or SRg3. The left lower quadrant, right lower quadrant, right upper quadrant and left upper quadrant indicate viable cells, early apoptotic cells, late apoptotic cells and necrotic cells, respectively. (C) Cell population (%) in each of the G0/G1, S and G2/M phases of the cell cycle. (D) Histograms of the untreated, vehicle and SRG3-treated cells, following staining with PI. The violet, yellow and green curves represent events in the G0/G1, S and G2/M phases, respectively. The data presented is representative of 3 repeats.
Figure 5. Migration assays on the MDA-MB-231 cell line following exposure to RRg3 and SRg3. (A) The percentage of wound closure following exposure of the MDA-MB-231 cell line to RRg3 and SRg3. Data is presented as mean ± SD of 6 repeats, and comparisons are made with the vehicle control group (** p = 0.001). (B) The transwell migration assay on the MDA-MB-231 cell line following exposure to RRg3 and SRg3. Data are presented as mean ± SD of 3 replicates, and comparisons are made with the vehicle control group (**** p < 0.0001).
Figure 6. Spheroid invasion assay on the MDA-MB-231 cell line following exposure to RRg3 and SRg3. (A) The percentage of increase in the area, as an indicator of invasion to the extracellular matrix,following exposure of the MDA-MB-231 spheroids to RRg3 and SRg3. Data are presented as mean ± SD of 3 replicates, and comparisons are made with the vehicle control group (***) p = 0.0001. (B) Representative images of the vehicle control and RRg3-treated spheroids after 7 days, indicating the inhibition of spheroid invasion in the RRg3-treated spheroids.
Chen,
Ginsenoside Rg3 inhibits CXCR4 expression and related migrations in a breast cancer cell line.
2011, Pubmed
Chen,
Ginsenoside Rg3 inhibits CXCR4 expression and related migrations in a breast cancer cell line.
2011,
Pubmed
Dai,
Breast Cancer Cell Line Classification and Its Relevance with Breast Tumor Subtyping.
2017,
Pubmed
De Ieso,
Mechanisms of Aquaporin-Facilitated Cancer Invasion and Metastasis.
2018,
Pubmed
Dorward,
Pharmacological blockade of aquaporin-1 water channel by AqB013 restricts migration and invasiveness of colon cancer cells and prevents endothelial tube formation in vitro.
2016,
Pubmed
Endo,
Water channel (aquaporin 1) expression and distribution in mammary carcinomas and glioblastomas.
1999,
Pubmed
Esteva-Font,
Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice.
2014,
Pubmed
Galán-Cobo,
Aquaporin-1 plays important role in proliferation by affecting cell cycle progression.
2016,
Pubmed
He,
Neuroprotective effect of 20(R)-ginsenoside Rg(3) against transient focal cerebral ischemia in rats.
2012,
Pubmed
Ismail-Khan,
A review of triple-negative breast cancer.
2010,
Pubmed
Jeong,
Stereospecificity of ginsenoside Rg3 action on ion channels.
2004,
Pubmed
,
Xenbase
Justus,
In vitro cell migration and invasion assays.
2014,
Pubmed
Kang,
Therapeutic potential of 20(S)-ginsenoside Rg(3) against streptozotocin-induced diabetic renal damage in rats.
2008,
Pubmed
Kao,
Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery.
2009,
Pubmed
Kee,
Ginsenoside Rg3 suppresses mast cell-mediated allergic inflammation via mitogen-activated protein kinase signaling pathway.
2019,
Pubmed
Kim,
Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance.
2014,
Pubmed
Kim,
Ginsenoside Rg3 Induces Apoptosis of Human Breast Cancer (MDA-MB-231) Cells.
2013,
Pubmed
Kim,
Ginsenoside Rg3 Inhibits Constitutive Activation of NF-κB Signaling in Human Breast Cancer (MDA-MB-231) Cells: ERK and Akt as Potential Upstream Targets.
2014,
Pubmed
Kourghi,
Bumetanide Derivatives AqB007 and AqB011 Selectively Block the Aquaporin-1 Ion Channel Conductance and Slow Cancer Cell Migration.
2016,
Pubmed
,
Xenbase
Lee,
Vascular smooth muscle dysfunction and remodeling induced by ginsenoside Rg3, a bioactive component of ginseng.
2010,
Pubmed
Liu,
Efficacy and Mechanism of Panax Ginseng in Experimental Stroke.
2019,
Pubmed
Liu,
Ginsenoside 20(S)-Rg3 targets HIF-1α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells.
2014,
Pubmed
Migliati,
Inhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding site.
2009,
Pubmed
,
Xenbase
Mobasheri,
Immunohistochemical localization of aquaporin 10 in the apical membranes of the human ileum: a potential pathway for luminal water and small solute absorption.
2004,
Pubmed
Nakhjavani,
Ginsenoside Rg3: Potential Molecular Targets and Therapeutic Indication in Metastatic Breast Cancer.
2019,
Pubmed
Otterbach,
Aquaporin 1 (AQP1) expression is a novel characteristic feature of a particularly aggressive subgroup of basal-like breast carcinomas.
2010,
Pubmed
Palethorpe,
Myofibroblast androgen receptor expression determines cell survival in co-cultures of myofibroblasts and prostate cancer cells in vitro.
2018,
Pubmed
Palethorpe,
The Aquaporin 1 Inhibitor Bacopaside II Reduces Endothelial Cell Migration and Tubulogenesis and Induces Apoptosis.
2018,
Pubmed
Palethorpe,
Androgen Signaling in Esophageal Adenocarcinoma Cell Lines In Vitro.
2017,
Pubmed
Pan,
Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells.
2012,
Pubmed
Papadopoulos,
Aquaporins and cell migration.
2008,
Pubmed
Park,
20(S)-ginsenoside Rg3 enhances glucose-stimulated insulin secretion and activates AMPK.
2008,
Pubmed
Park,
Rg3-enriched Korean Red Ginseng improves vascular function in spontaneously hypertensive rats.
2014,
Pubmed
Park,
Stereospecific anticancer effects of ginsenoside Rg3 epimers isolated from heat-processed American ginseng on human gastric cancer cell.
2014,
Pubmed
Pei,
Differential Inhibition of Water and Ion Channel Activities of Mammalian Aquaporin-1 by Two Structurally Related Bacopaside Compounds Derived from the Medicinal Plant Bacopa monnieri.
2016,
Pubmed
,
Xenbase
Pelagalli,
Inhibition of AQP1 Hampers Osteosarcoma and Hepatocellular Carcinoma Progression Mediated by Bone Marrow-Derived Mesenchymal Stem Cells.
2016,
Pubmed
Qin,
Expression of aquaporin1, a water channel protein, in cytoplasm is negatively correlated with prognosis of breast cancer patients.
2016,
Pubmed
Riaz,
miRNA expression profiling of 51 human breast cancer cell lines reveals subtype and driver mutation-specific miRNAs.
2013,
Pubmed
Saba,
Alleviation of diabetic complications by ginsenoside Rg3-enriched red ginseng extract in western diet-fed LDL-/- mice.
2018,
Pubmed
Shan,
Ginsenoside Rg3 inhibits melanoma cell proliferation through down-regulation of histone deacetylase 3 (HDAC3) and increase of p53 acetylation.
2014,
Pubmed
Shi,
Aquaporins in human breast cancer: identification and involvement in carcinogenesis of breast cancer.
2012,
Pubmed
Smith,
Reduced aquaporin-1 transcript expression in colorectal carcinoma is associated with promoter hypermethylation.
2019,
Pubmed
Smith,
The Purified Extract from the Medicinal Plant Bacopa monnieri, Bacopaside II, Inhibits Growth of Colon Cancer Cells In Vitro by Inducing Cell Cycle Arrest and Apoptosis.
2018,
Pubmed
Sun,
Ginsenoside Rg3 improves cardiac mitochondrial population quality: mimetic exercise training.
2013,
Pubmed
Szczuka,
American Ginseng (Panax quinquefolium L.) as a Source of Bioactive Phytochemicals with Pro-Health Properties.
2019,
Pubmed
Tian,
Neuroprotective effect of 20(S)-ginsenoside Rg3 on cerebral ischemia in rats.
2005,
Pubmed
Tian,
Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4.
2016,
Pubmed
Tomita,
Bumetanide-Derived Aquaporin 1 Inhibitors, AqB013 and AqB050 Inhibit Tube Formation of Endothelial Cells through Induction of Apoptosis and Impaired Migration In Vitro.
2019,
Pubmed
Tomita,
Role of Aquaporin 1 Signalling in Cancer Development and Progression.
2017,
Pubmed
Wang,
Chemopreventive effects of heat-processed Panax quinquefolius root on human breast cancer cells.
2008,
Pubmed
Wei,
Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice.
2012,
Pubmed
Wei,
Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice.
2012,
Pubmed
Wu,
Stereospecificity of ginsenoside Rg3 in the promotion of cellular immunity in hepatoma H22-bearing mice.
2014,
Pubmed
Yan,
Fucosyltransferase IV (FUT4) as an effective biomarker for the diagnosis of breast cancer.
2015,
Pubmed
Yang,
Ginsenoside Rg3 promotes beta-amyloid peptide degradation by enhancing gene expression of neprilysin.
2009,
Pubmed
Yi,
Roles of ginsenosides in inflammasome activation.
2019,
Pubmed
Yool,
Functional domains of aquaporin-1: keys to physiology, and targets for drug discovery.
2007,
Pubmed
Yool,
AqF026 is a pharmacologic agonist of the water channel aquaporin-1.
2013,
Pubmed
,
Xenbase
Yool,
Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer.
2010,
Pubmed
Zhao,
miR-493-5p attenuates the invasiveness and tumorigenicity in human breast cancer by targeting FUT4.
2016,
Pubmed
