(−)-Epigallocatechin Gallate (EGCG)  | MCF-7 | In vitro: 30 μM | Suppressing the Heregulin β1-stimulated activation of epidermal growth factor receptor-related protein B2 (ErbB2)/ErbB3/protein kinase B. | [30] |
Mouse mammary cancer virus-Her-2/neu cell line NF639 | In vitro: 60 μg/mL | Up-regulation of the epithelial genes E-cadherin, γ-catenin, MTA3, and estrogen receptor α (ERα). Down-regulation of proinvasive snail gene. Activation of FOXO3a. | [31] |
Inflammatory Breast Cancer lines: SUM-149 and SUM-190 | In vitro: 5–160 μg/mL | Elevation of the levels of cleaved Caspase-3 and PARP. | [32] |
MCF-7 MDA-MB-231 | In vitro: 20 μM | Reducing EZH2 and class I HDAC protein levels, inducing TIMP-3 levels,suppressing invasiveness and activity of MMP-2 and MMP-9. | [26] |
(−)-Epigallocatechin (EGC)  | MDA-MB-231 human breast cancer cell line | In vitro: 50, 80 μg/mL | Inhibition of MMP-9 expression and AKT signaling pathway by inhibiting both at the RNA and protein level. | [33] |
MCF-7 | In vitro: 30 μM | Disruption of the Heregulin β1-stimulated activation of ErbB2/ErbB3/Akt. | [30] |
(−)-Epicatechin  | Murine mammacarcinoma cell line 4T1 | In vitro: 10 μM | Inhibiting cell shedding and invasion by their anti-oxidative capacity and down-regulation of MMP-9 expression. | [34] |
Kaempferol  | MDA-MB-231 human breast carcinoma cells | In vitro: 10, 20, 40 μM | Blocking the PKCδ/MAPK/AP-1 cascade and subsequentiy suppressing MMP-9 expression. | [35] |
Quercetin  | Metastatic MDA-MB-231 MDA-MB-435 Female severe combined immunodeficiency (SCID) mice | In vitro: 15 μM In vivo: 15 mg/kg 3X per week i.p. | Induction of mTOR activities through Akt inhibition and AMPK activation. | [36] |
Oroxylin A  | MDA-MB-435 | In vitro: 1, 10 and 100 μM | Inhibiting the expressions of MMP-2, MMP-9 and ERK1/2 | [37] |
Baicalein  | MDA-MB-231 | In vitro: 2, 10, 50 μM | Down-regulating the expression of MMP-2/9 involved MAPK signaling pathway. | [38] |
Genistein  | MDA-MB-435/HAL | In vivo: 750 μg/g | Reducing the percent metastatic burden in the lungs, and affect the outgrowth of seeded tumor cells by dietary intervention following cancer surgery. | [39] |
Resveratrol  | 4T1 Female BALB/c mice | In vitro: 0–30 μM In vivo: 100 mg/kg/day 200 mg/kg/day | Decreasing the activity and expression of MMP-9. | [40] |
MCF-7 | In vitro: 2, 5 and 10 μM | Inhibition of HRG-β1-mediated MMP-9 expression via down-regulation of the MAPK/ERK signaling pathway. | [41] |
MDA-MB-435 | In vitro: 10 and 20 μM | Suppressing insulin-like growth factor (IGF)-1-mediated cell migration and invasion and MMP-2 expression via inhibition of the PI3K/Akt signaling pathway. | [42] |
Female BALB/c mice (4T1) | In vivo: 50 mg/mouse/2day i.p. | Inactivating Stat3, preventing the generation and function of tBregs, including expression of TGF-β. | [43] |
Immunocompromised mice Green fluorescent protein (GFP) tagged-MDA-MB-231 (ERα(-), ERβ(+)) or a metastatic variant of GFP-MDA-MB-435 (ER (-)) cells | In vivo: 0.5, 5 and 50 mg/mouse 5 days/week i.g. | Increased expression of the Rac downstream effector PAK1, JNK and Akt. | [44] |
Piceatannol  | Female BALB/c mice (4T1) | In vivo: 10 and 20 mg/kg/day i.g. In vitro: 30 μM | Reducing the expression of MMP-9 in both cancer and lung tissues and increasing apoptotic cells and expression of both Bax and cleaved caspase-3 but reducing Bcl-2 expression in cancer tissues. | [28] |
Butein  | HER2-over-expressing breast cancer SKBr3 cells | In vitro: 10,25,50 μM | Inhibition of CXCR4 expression correlated with the suppression of CXCL12- induced migration and invasion, and inhibiting of NF-κB activation. | [45] |
Xanthohumol  | MCF-7 MDA-MB-231 | In vitro: MCF-7: 5 μmol/L MDA-MB-231: 50 μmol/L | Inhibiting the activity of CYP, SELE and NF-κB, affecting ICAM-1 expression and adherence to LECs, suppressing paxillin, MCL2 and S100A4. | [46] |
Curcumin  | MCF-7 | In vitro: 30 μM | Suppression of the PKCα, MAPK and NF-κB/AP-1 pathway and TPA-induced MMP-9 expression | [47] |
4T1 BALB/c mice | In vitro: 5–20 μM In vivo: 40 mg/kg 80 mg/kg | Suppression of NF-κB expression by down-regulation of VEGF, COX-2, and MMP-9 expressions. | [48] |
MDA-MB-231 MDA-MB-231MOCK injecting into the left cardiac ventricle CD-1 Foxn1nu female mice. | In vitro: 25 μM | Up-regulation of miR181b and down-regulation of CXCL1 and 2. | [49] |
MDA-MB-231 MDA-MB-231MOCK injecting into the left cardiac ventricle CD-1 Foxn1nu female mice. | In vitro: 25 μM In vivo: feding with standard diet containing 1% curcumin | Reducing the expression of MMPs via down-regulation of NF-κB and AP-1 activity and transcriptional. | [50] |
MCF-10F; MDA-Mb-231; Tumor 2 | In vitro: 30 µM for 48 h | Decreasing E-cadherin, N-cadherin, β-catenin, Slug, AXL, Twist1, Vimentin and Fibronectin protein expression involved in EMT. | [51] |
Demethoxycurcumin  | MDA-MB-231 | In vitro: 1, 7.5, 15 μM | Inhibiting the DNA binding activity of NF-κB, decreasing the levels of ECM degradation-associated proteins including MMP-9, MT1-MMP, uPA , uPAR, ICAM-1 and CXCR4, up-regulating the level of PAI-1. | [52] |
Oleuropein  | MDA-cell line | In vitro: 200 μg/mL | Increasing the TIMPs, and then suppressing the MMPs expressions | [27] |
Ovariectomised nude mice MCF-7 | In vivo: 125 mg/kg diet | Possessing a potent in vivo anti-cancer activity inhibiting both the MCF-7 cells xenograft growth and their invasiveness into the lung. | [53] |
Amentoflavone  | MCF-7 | In vivo: 50 and 100 μM in 0.1% DMSO | Inhibiting NF-κB activation decreases expression and secretion of angiogenesis- and metastasis-related proteins. Amentoflavone may induce anti-angiogenic and anti-metastatic effects through suppression of NF-κB activation. | [54] |
Glabridin  | MDA-Mb-231 | In vitro: 8 μM for 24, 48, 72 h | Attenuating the angiogenic ability by the microRNA-520a (miR-520a)-mediated inhibition of the NF-κB/IL-6/STAT-3 signal pathway. | [55] |
A resveratrol tetramer | BJMC3879 Female BALB/c mice | In vitro: 8 μM In vivo: 22.9 mg/kg/day 44.7 mg/kg/day i.p. | Modulating the transcription level of mutant p53. Suppressing metastasis to both lymph nodes and lungs. | [56] |
Enterolactone, an active polyphenol metabolite of Lignan | MDA-MB-231 cells | In vitro: IC50 = 261.9 ± 10.5 μM | Down-regulating phosphorylation of the FAK/paxillin pathway, inhibiting migration and invasion of cells. | [57] |
Curcumin loaded polymeric micelles | Subcutaneous 4T1 breast cancer model | In vivo: 30 mg/kg/day | Inhibiting cancer growth and spontaneous pulmonary metastasis. | [58] |
Grape natural polyphenols: resveratrol,quercetin,catechin,(or combination with gefitinib) | Human metastatic breast cancer cell GFP-MDA-MB-231 (ERα(−), ERβ(+)) Immunocompromised mice | In vitro: 5 μM In vivo: 5 mg/kg/day respectively i.g. or 5 mg/kg/2days and 200 mg/kg/2days i.g. | Reducing Akt activity, inducing the activation of AMPK and inhibiting mTOR signaling pathway. | [59] |
ER(−) GFP-MDA-MB-435 Female athymic nu/nu mice | In vitro: 0.5 or 5 μM In vivo: 5 mg/kg/day together i.g | Up-regulating FOXO1 and NFKBIA (IκBα), activating apoptosis and inhibiting NF-κB activity, reducing metastasis. | [60] |
Mixed natural polyphenols resveratrol, baicalein, epicatechin, epigallocatechin polyphenon 60 | 4T1 multicellular cancer spheroids | In vitro: 100 μM | Suppressing invasion by down-regulation of MMP-9 expression and their anti-oxidative capacity. | [34] |
Natural polyphenols extract from Green tea | MCF-7 MDA-MB-231 | In vitro: 10 μg/mL | Reducing EZH2 and class I HDAC protein levels, inducing TIMP-3 mRNA and protein levels, suppressing invasiveness and activity of MMP-2 and MMP-9. | [26] |
Mouse mammary carcinoma 4T1 cells Female BALB/c mice | In vitro: 0.06–0.125 mg/mL In vivo: 0.6 g/kg/day i.g. | Increasing the expression of Bax-to-Bcl-2 ratio, activating caspase-8 and caspase-3, decreasing lung and liver metastasis, protecting the bone from breast cancer-induced bone destruction. | [61] |
Mouse mammary carcinoma 4T1 cells Female BALB/c mice | In vivo: 0.2% and 0.5% w/v in drinking water and was started 7 days before cancer cells inoculation | Decreasing the protein expression of Bcl-2 concomitantly increase in Bax, cytochrome c release, Apaf-1, and cleavage of caspase 3 and PARP proteins,inhibiting lungs metastasis. | [62] |
Natural polyphenols extract from Green tea | MDA-MB-231 human breast cancer cell line | In vitro: 40, 60 μg/mL | Inhibition of MMP-9 expression and AKT signaling pathway by inhibiting both at the RNA and protein level. | [33] |
Natural polyphenols extract from Soy isoflavones | Female BALB/c mice (4T1) | In vivo: 750 mg/kg/day diet genistein equivalent | Increasing Ki-67 protein expression amd stimulating metastatic cancer formation in lungs. | [63] |
Natural polyphenols extract from Japanese quince fruit | MDA-MB-231 | In vitro: 25, 50, 75, 100 μM catechin equivalents | Decreasing the MMP-9 activity and stimulating the TIMP-1 expression. | [29] |
Natural polyphenols extract from Nelumbo nucifera Gaertn leaves | MDA-MB-231 | In vitro: 0.5~2.0 mg/mL | Blocking vascular-like structure formation, suppressing CTGF expression reducing the MMP2 and VEGF expression, and attenuating PI3K-AKT-ERK activation. | [64] |
Natural polyphenols extract from Leucobryum bowringii Mitt. | MCF-7 | In vitro: 10, 25 and 50 μg/mL | Inhibition of MMP-2 and MMP-9 activities. | [65] |
Natural polyphenols extract from Peach phenolics | MDA-MB-435 | In vivo: 0.8–1.6 mg chlorogenic acid equivalent /day i.g. | Down-regulating the gene expression of MMPs, and up-regulating hβ2G gene expression in the lungs. | [66] |
Natural polyphenols extract from Artichoke | MDA-MB-231 | In vitro: 200 μM | Decreasing of proteolytic activity of MMP-2, involved in degrading components of the extracellular matrix. | [67] |
Natural polyphenols extract from Grape skin | 4T1 cells Balb/c mice implanting 4T1 subcutaneously | In vitro: 0.5 and 1.0 mg/ml in drinking water | Blocking the PI3k/Akt and MAPK pathways. | [68] |
Natural polyphenols extract from Evening primrose | MDA-MB-231 | In vitro: IC50 = 58 μM (gallic acid equivalents) | Decreasing the activity of MMP-9 through reducing the expression levels of the following proteins: VEGF, c-Fos, c-Jun. | [69] |
Natural polyphenols extract from Murraya koenigii | MDA-MB-231 Left mammary fat pad subcutaneously 4T1 | In vitro: MDA-MB-231 (IC50 = 2.40 ± 0.26) 4T1 (IC50 = 1.50 ± 0.90) In vivo: 50 mg/kg 200 mg/kg | Decreasing the level of nitric oxide and inflammation-related cytokines and genes, including iNOS, iCAM, NF-κB and c-MYC and reducing lung metastasis. | [70] |
Natural polyphenols extract from Grape seed proanthocyanidins | 4T1 cells were implanted subcutaneously in Balb/c mice | In vivo: 0.2% and 0.5%, w/w in a diet | Increasing the ratio of Bax:Bcl-2 proteins, cytochrome c release, induction of Apaf-1 and activation of caspase 3, inhibiting the metastasis of cancer cells to the lungs. | [71] |
Natural polyphenols extract from biotransformation of blueberry juice by Serratia vaccinii | murine 4T1 human MCF7 and MDA-MB-231 BALB/c mouse model | In vitro: 100 μM (gallic acid equivalent) In vivo: 2.9 mL/day | Decreasing lung metastasis by controlling PI3K/AKT, MAPK/ERK. | [72] |
Natural polyphenols extract from Korean A. annua L. | MDA-MB-231 | In vitro: 1, 10, 30 ug/mL | Inhibiting the cancer cell adhesion to ECs through suppression of vascular cell adhesion molecule-1 and invasion through suppression of EMT, MMP-2 and MMP-9. | [73] |