Polyphenols Interfering with Breast Cancer Metastasis

molecules

Review Molecular Mechanisms and Metabolomics of Natural Polyphenols Interfering with Breast Cancer Metastasis

Yingqian Ci, Jinping Qiao * and Mei Han *

Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing100875, China; [email protected] * Correspondence: [email protected] (J.Q.); [email protected] (M.H.); Tel.: +86-10-6220-7786 (J.Q. & M.H.)

Academic Editor: Derek J. McPhee Received: 31 August 2016; Accepted: 21 November 2016; Published: 17 December 2016

Abstract: Metastatic cancers are the main cause of cancer-related death. In breast primary cancer, the five-year survival rate is close to 100%; however, for metastatic breast cancer, that rate drops to a mere 25%, due in part to the paucity of effective therapeutic options for treating metastases. Several in vitro and in vivo studies have indicated that consumption of natural polyphenols significantly reduces the risk of cancer metastasis. Therefore, this review summarizes the research findings involving the molecular mechanisms and metabolomics of natural polyphenols and how they may be blocking breast cancer metastasis. Most natural polyphenols are thought to impair breast cancer metastasis through downregulation of MMPs expression, interference with the VEGF signaling pathway, modulation of EMT regulator, inhibition of NF-κB and mTOR expression, and other related mechanisms. Intake of natural polyphenols has been shown to impact endogenous metabolites and complex biological metabolic pathways in vivo. Breast cancer metastasis is a complicated process in which each step is modulated by a complex network of signaling pathways. We hope that by detailing the reported interactions between breast cancer metastasis and natural polyphenols, more attention will be directed to these promising candidates as effective adjunct therapies against metastatic breast cancer in the clinic.

Keywords: natural polyphenols; breast cancer metastasis; metabolomics

1. Introduction Catechins, generally known as tea polyphenols and comprising approximately 1/3 of the constituents of green tea), are one of the most attractive natural compounds because of their bioavailability [1]. Natural polyphenols show a very broad spectrum of biological activities, including antioxidant-related activity [2]. Catechins contain characteristic polyphenolic compounds, (−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), and (−)-epicatechin (EC), shown in Figure1[ 1,3]. Other natural polyphenols such as kaempferol, quercetin, myricetin, and their glycosides (mono-, di-, and tri-) are also present in tea (Figure1)[ 4], and tea also includes other natural polyphenols, such as baicalein, resveratrol, curcumin and so on. The analogues of catechins exhibit health beneﬁts that protect against many life-threatening diseases, including cardiovascular diseases, chronic inﬂammation, and cancer [5], through regulation of various signaling pathways [6]. There is evidence that natural polyphenols can inhibit cancer cell proliferation and metastases, induce apoptosis, and exert chemopreventive activities [7,8].

Molecules 2016, 21, 1634; doi:10.3390/molecules21121634 www.mdpi.com/journal/molecules Molecules 2016, 21, 1634 2 of 27 Molecules 2016, 21, 1634 2 of 26

Molecules 2016, 21, 1634 2 of 26

Figure 1. Structures of the major catechins andand naturalnatural polyphenols.polyphenols. Figure 1. Structures of the major catechins and natural polyphenols. Cancer metastases are the major cause of cancer mortality. Metastatic breast cancer is one of the Cancer metastases are the major cause of cancer mortality. Metastatic breast cancer is one of the deadliest types of cancers worldwide in women with a mortality rate greater than 2.1 per million cases deadliestCancer types metastases of cancers are worldwide the major cause in women of cancer with mo artality. mortality Metastatic rate greater breast cancer than2.1 is one per of million the annually [9]. We use published cancer statistics in the US in the SEER 18 areas from 2004 to 2010 as an casesdeadliest annually types [9 of]. cancers We use worldwide published in cancer women statistics with a mortality in the US rate in greater the SEER than 182.1 areasper million from cases 2004 to example.annually Figure [9]. We 2 showsuse published the five-year cancer relative statistics surviv in theal US rates in the of allSEER malignant 18 areas tumorsfrom 2004 have to 2010significantly as an 2010 as an example. Figure2 shows the five-year relative survival rates of all malignant tumors have improved,example. especiallyFigure 2 shows when the focusing five-year on relative distant surviv metastalases rates (all of allmetastatic malignant cancers tumors had have a 5significantly year survival significantly improved, especially when focusing on distant metastases (all metastatic cancers had rateimproved, of less than especially 40%). when Although focusing the on survival distant ratemetast ofases primary (all metastatic breast cancer cancers is had now a 5close year tosurvival 100%, it a 5 year survival rate of less than 40%). Although the survival rate of primary breast cancer is now decreasesrate of less to onlythan 25%40%). once Although distant the metastasis survival rate has ofoccurred primary (Figure breast cancer2a). The is nowpresence close ofto metastases100%, it close to 100%, it decreases to only 25% once distant metastasis has occurred (Figure2a). The presence causesdecreases a sharp to droponly 25%in survival once distant rate among metastasis other has canc occurreders as well. (Figure Figure 2a). 2b The shows presence the difference of metastases in five- of metastases causes a sharp drop in survival rate among other cancers as well. Figure2b shows the yearcauses relative a sharp survival drop in rates survival between rate among regional other an cancd distanters as well. metastases Figure 2b (breast shows thecancer difference and colon in five- and difference in five-year relative survival rates between regional and distant metastases (breast cancer rectumyear relativecancer aresurvival both approximatelrates betweeny 60%).regional The an highestd distant increase metastases in mortality (breast duecancer to distantand colon metastasis and and colon and rectum cancer are both approximately 60%). The highest increase in mortality due to occursrectum in cancer breast are cancer. both approximatel Unfortunately,y 60%). the The only highest antimetastatic increase in mortality therapeutics due to indistant clinical metastasis practice, distant metastasis occurs in breast cancer. Unfortunately, the only antimetastatic therapeutics in clinical includingoccurs in anthracyclines, breast cancer. taxanes,Unfortunately, and trastuzumab, the only antimetastatic have little efficacy,therapeutics so it inis imperativeclinical practice, to find practice,including including anthracyclines, anthracyclines, taxanes, taxanes,and trastuzumab, and trastuzumab, have little have efficacy, little so efficacy, it is imperative so it is imperative to find effective drugs for cancer metastasis (data from American Cancer Society, Inc., Surveillance Research, toeffective find effective drugs drugsfor cancer for cancermetastasis metastasis (data from (data Amer fromican American Cancer Society, Cancer Inc., Society, Surveillance Inc., Surveillance Research, 2015 [10]). Research,2015 [10]). 2015 [10]).

(a) (b) (a) (b) FigureFigure 2.2. 2.((aa )()a Five-yearFive-year) Five-year RelativeRelative Relative Survival SurvivalSurvival Rates*Rates*Rates* (%)(%)(%) byby StageStage at atat Diagnosis, Diagnosis,Diagnosis, US, US,US, 2004–2010. 2004–2010.2004–2010. Local: Local:Local: an anan invasiveinvasiveinvasive malignantmalignant malignant tumortumor tumor conﬁnedconfined confined to toto primary primaryprimary organ.organ. Regional: Regional:Regional: a aa malignant malignantmalignant tumor tumortumor that thatthat has hashas extended extendedextended into surrounding organs or tissues and regional lymph nodes. Distant: a malignant tumor that has spread intointo surrounding organs organs or or tissues tissues and and regional regional lymph lymph nodes. nodes. Distan Distant: a malignantt: a malignant tumor tumor that has that spread has to parts of the body remote from the primary cancer, or via the lymphatic system to distant lymph nodes; spreadto parts toof partsthe body of the remote body from remote the primary from the cancer, primary or via cancer, the lymphatic or via the system lymphatic to distant system lymph to distant nodes; (b) The difference in relative survival rates between Regional and Distant metastases, and Value (%) = lymph(b) The nodes;difference (b) Thein relative difference survival in relative rates between survival Regional rates between and Distant Regional metastases, and Distant and Value metastases, (%) = Regional–Distant. Rates* are adjusted for normal life expectancy and are based on cases diagnosed in the andRegional–Distant. Value (%) = Regional–Distant. Rates* are adjusted Rates*for normal are adjusted life expectancy for normal and are life based expectancy on cases and diagnosed are based in the on SEER 18 areas from 2004 to 2010, all followed through 2011, and the data are from the American Cancer casesSEER diagnosed18 areas from in the2004 SEER to 2010, 18 areasall followed from 2004 thro tough 2010, 2011, all and followed the data through are from 2011, the American and the data Cancer are Society, Inc., Surveillance Research, 2015. fromSociety, the Inc., American Surveillance Cancer Research, Society, 2015. Inc., Surveillance Research, 2015. Molecules 2016, 21, 1634 3 of 27 Molecules 2016, 21, 1634 3 of 26

Cancer metastasis is is a very complicated process. Cancer Cancer cells cells can can enter enter the the circulatory circulatory system, system, becoming invasive invasive and and motile motile long long before before a tumor a tumor is found. is found. Only Only a small a small proportion proportion of cancer of cancer cells managecells manage to permeate to permeate regional regional and distant and organs, distant a organs,fundamental a fundamental step for eventual step for relapse. eventual Therefore, relapse. a primaryTherefore, cancer a primary might cancer have already might have seeded already regional seeded and regional distant organs and distant with organsthousands with of thousands cancer cells of [11].cancer Various cells [ studies11]. Various have studiesexplored have the processes explored of the cancer processes metastasis of cancer in animal metastasis models. in animal The metastatic models. cascadeThe metastatic begins cascade with the begins dissemination with the dissemination of metastasis-competent of metastasis-competent cells from cellsthe fromprimary the primarytumor, intravasationtumor, intravasation into the blood into the circulation, blood circulation, active or passive active ormigration passive toward migration the towardtarget organ, the target embedding organ, intoembedding a capillary into bed, a capillary attachment bed, to attachment the endotheliu to them, endothelium, and extravasation, and extravasation, which leads which to infiltration leads to intoinﬁltration the underlying into the underlyingtissue, and expansion tissue, and in expansion the target in microenvironment the target microenvironment (Figure 3) [12]. (Figure Generally,3)[ 12]. forGenerally, breast cancer for breast metastasis, cancer metastasis,an invasive antumor invasive often tumor metastasizes often metastasizes to lung, liver, to lung,bone, liver,and brain. bone, Metastasisand brain. Metastasisoccurs less occurscommonly less commonlyin pleura, lymph in pleura, node lymph and spleen node and[13]. spleen [13].

Figure 3. SimplifiedSimplified summarizes summarizes of of metastatic metastatic cascade cascade of of breast breast cancer cancer and and genes involving in the process of of metastasis. metastasis. Cancer-driven Cancer-driven events events in the in themetastatic metastatic cascade cascade are delineated are delineated in time in and time space and inspace a counter-clockwise in a counter-clockwise beginning beginning with with the theprimar primaryy cancer, cancer, and and then then intravasation intravasation into into the the blood blood circulation,circulation, active active or or passive passive migration migration toward toward th thee target target organ, organ, embedding embedding into into a a capillary capillary bed, bed, attachment toto thethe endothelium, endothelium, and an extravasation,d extravasation, which which leads leads to infiltration to infiltration into theinto underlying the underlying tissue, tissue,and expansion and expansion in the targetin the microenvironment.target microenvironme MMPs,nt. MMPs, matrix matrix metalloproteinases; metalloproteinases; ZEB1, ZEB1, zinc finger zinc fingerE-box-binding E-box-binding homeobox homeobox 1; SLUG, 1; SLUG, zinc zinc finger finger protein protein SNAI2; SNAI2; MTA3, MTA3, metastasis-associated metastasis-associated protein; MUC1: mucin 1, cell surface-associated; PSA, PSA, prostate-specific prostate-specific antigen; antigen; EMMPRIN: EMMPRIN: extracellular extracellular matrix matrix metalloproteinase inducer; inducer; uPA: uPA: urokinase plas plasminogenminogen activator; uPAR uPAR:: urokinase plasminogen activator receptor; PAI: PAI: plasminogenplasminogen activator inhibitor;inhibitor; RECK: reversion-inducing cysteine-rich protein with kazal motifs; motifs; PN-II: PN-II: protease protease nexin-II; nexin-II; alpha1-AT: alpha1-AT: alpha 1-antitrypsin; EPCAM, epithelial epithelial cellcell adhesion adhesion molecule; molecule; CK19, CK19, Cytokeratin Cytokeratin 19; 19; CEA, CEA, carcinoembryonic carcinoembryonic antigen; antigen; SAA, SAA, serum serum amyloid amyloid A; A; LOX, protein-lysine 6-oxidase; 6-oxidase; RAC1, RAC1, Ras-related C3 C3 botulinum toxin substrate1; cdc42, cell division controlcontrol protein protein 42 42 homolog; homolog; ST6GALNAC5, ST6GALNAC5, AGPTL4: AGPTL4: promoting promoting seeding; seeding; promoting promoting colonization: colonization: OPN, CXCR4;OPN, CXCR4; COX-, CXCL12/CXCR4: COX-, CXCL12/CXCR4: proinflammatory proinflammatory molecules and molecules chemokines/receptors; and chemokines/receptors; VCAM-1, TNC, OPN:VCAM-1, adhesion TNC, and OPN: extracellula adhesion andr matrix extracellular molecules; matrix SRC, molecules; NF-κB: intracellular SRC, NF-κB: signaling intracellular proteins. signaling The dataproteins. adapted The from data the adapted study from of Bos the and study Zhou of [8,14]. Bos and Zhou [8,14]. Molecules 2016, 21, 1634 4 of 27

Based on the complicated process of breast cancer metastasis, which involves multiple targets and organs, and the interventional effect of natural polyphenols in vivo, more scientiﬁc and advanced technologies, such as metabolomics, should be used to address this delicate process. Metabolomics, involving the comprehensive characterization of metabolism and metabolites in biological systems, is an emerging ‘omics’ science technology. Recent developments in metabolomics technologies are increasingly being utilized to discover molecular mechanisms of disease, customize drug treatments, identify novel drug targets and monitor therapeutic outcomes [15]. In this review, we discuss how natural polyphenols can modulate signaling pathways that are necessary for invasive behavior and metastasis of breast cancer in vitro and in vivo, and then, we brieﬂy summarize the studies of tea catechin on endogenous metabolites using metabolomics technologies.

2. The Molecular Mechanism of Natural Polyphenols on Breast Cancer Metastasis In Vitro Over the past two decades, it has been demonstrated that natural polyphenols are beneﬁcial for both chemoprevention and chemosensitization [16]. Large numbers of studies have concentrated on the ability of natural polyphenols to inhibit cancer cell proliferation and related mechanisms. Increasingly, more and more research has illustrated that natural polyphenols can suppress cancer cell invasion and migration, revealing the therapeutic potential of natural polyphenols against cancer metastases [8]. The tumorigenesis and metastasis need the participation of many molecular pathways that are important in the treatment of every step of cancer progression. Some proteins and enzymes exert effects only on the metastasis ability, and many of these are correlated with metastatic colonization [17]. This review pays special attention to the increasing evidence that natural polyphenols can block migration and invasion of breast cancer cells through a series of molecular mechanisms, including the down-regulation of matrix metalloproteinases (MMPs) expression [18], the regulatory effects of epithelial-to-mesenchymal transition (EMT), the suppression of vascular endothelial growth factor (VEGF) signalling and cancer angiogenesis, the inhibition of nuclear factor-kappa B (NF-κB), and the mammalian targeting function of rapamycin (mTOR), as well as other signalling pathways. The results of those studies are summarized in Table1.

2.1. MMPs MMPs are a family of the metzincin group of enzymes that share the conserved zinc-binding motif in their catalytic active site [19]. MMPs participate in crucial pathological processes such as cancer, cardiovascular disease and neurological disorders. MMPs play an important role in tissue reconstruction near proliferating cells of malignant neoplasms during cancer metastasis [20]. In particular, MMPs facilitate angiogenesis, cancer cell invasion and metastasis [21]. Large studies have investigated the prognostic value of MMPs in breast cancer metastasis [22–24].

2.1.1. MMPs Involving Tissue Inhibitor of Matrix Metalloproteinase Signiﬁcantly, low levels of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) protein expression in breast cancer has been reported to be correlated with an aggressive cancer phenotype [25]. EGCG and Green tea polyphenols (GTP) mediate epigenetic activation of TIMP-3 levels, resulting in suppression of invasiveness and gelatinolytic activity of MMP-2 and MMP-9 in MDA-MB-231 and MCF-7 breast cancer cells [26]. Oleuropein, the main polyphenol in olive oil, has anti-metastatic effects. Studies have found that TIMP-1, -3, and -4 were over-expressed in MDA-cells after incubation with oleuropein (200 µg/mL), while MMP-2 and MMP-9 genes were down-regulated [27]. Piceatannol, a polyphenol that is found in grapes, berries and red wine, exhibits anti-metastatic activities. Similar to EGCG and GTP, the anti-metastatic effect of piceatannol involved increased protein levels of TIMP-2, which decreases MMP-9 activity [28]. Japanese quince fruit juice is used as a food additive, and its polyphenol extract also decreased MMP-9 activity through the stimulation of TIMP-1 expression [29]. Table 1. Mechanisms of natural polyphenols interfering in breast cancer metastasis.

Effective Cancer Type or Natural Polyphenols Concentrations Result Ref. Animal Type or Doses Suppressing the Heregulin β1-stimulated activation of epidermal Table 1. Mechanisms of natural polyphenolsMCF-7 interfering inIn breast vitro: cancer 30 μM metastasis. growth factor receptor- [30] related protein B2 Effective Cancer Type or Natural Polyphenols Concentrations Result(ErbB2)/ErbB3/protein Ref. Animal Type kinase B. (−)-Epigallocatechin or Doses Suppressing theUp-regulation of the Gallate (EGCG)Table 1. Mechanisms of natural polyphenols interfering in breast cancer metastasis. Heregulin β1-stimulatedepithelial genes E- activation of epidermal Molecules 2016, 21, 1634OH Mouse mammary Effective cadherin, 5 of 27 MCF-7Cancer Type or In vitro: 30 μM growth factor receptor- [30] Natural Polyphenols OH cancer ConcentrationsIn vitro: 60 Resultγ-catenin, MTA3Ref., and Animal Type related protein B2 [31] virus-Her-2/neu or Dosesμg/mL estrogen receptor α (ERα). Suppressing(ErbB2)/ErbB3/protein the O HO cell line NF639 kinase B. Down-regulation of (−)-Epigallocatechin OH Heregulin β1-stimulated Table 1. MechanismsUp-regulationproinvasive of the natural snail polyphenols gene. interfering in breast cancer metastasis. Gallate (EGCG) activation of epidermal epithelial genesActivation E- of FOXO3a. O MCF-7 In vitro: 30 μM growth factor receptor- [30] OH MouseInflammatory mammary relatedcadherin, protein B2 OH Natural PolyphenolsOH Cancer Type or AnimalElevation Type of the levels of Effective Concentrations or Doses Result Ref. O OH cancer Breast Cancer lines:In vitro: 60In vitro: 5–160(ErbB2)/ErbB3/proteinγ-catenin, MTA3, and cleaved [31] [32] virus-Her-2/neuSUM-149 and SUM-μg/mL μg/mL kinaseestrogen B. receptor α (ERα). Suppressing the Heregulin β1-stimulated activation (−)-EpigallocatechinO OH cell line NF639 Down-regulationCaspase-3 of and PARP. (HO−)-Epigallocatechin OH 190 MCF-7Up-regulation of the In vitro: 30 µM of epidermal growth factor receptor-related protein [30] Gallate (EGCG) proinvasive snail gene. Gallate (EGCG) OH epithelial genes E- B2 (ErbB2)/ErbB3/protein kinase B. Activation ofReducing FOXO3a. EZH2 and O OH Mouse mammary cadherin, class I HDAC protein cancerInflammatory In vitro: 60 γ-catenin, MTA3, and Up-regulation of the epithelial genes E-cadherin, OH OH OH Elevation of the levels of [31] O Breast Cancer lines: In vitro:Mouse 5–160 mammary cancerlevels, inducing TIMP-3 -catenin MTA3 estrogen receptor (ER ) virus-Her-2/neuMCF-7 μg/mL estrogencleaved receptor α (ERα). [32] µ γ , , and α α . SUM-149 and SUM- μg/mL In vitro: 60 g/mL [31] O OH cell line NF639 virus-Her-2/neuIn vitro: 20Down-regulation μM cell linelevels,suppressing NF639of [26] Down-regulation of proinvasive snail gene. HO OH MDA-MB-231 Caspase-3 and PARP. 190 proinvasive snailinvasiveness gene. and Activation of FOXO3a. OH ActivationReducing EZH2 of FOXO3a. and O Inﬂammatory Breast Canceractivity lines:of MMP-2 and Elevation of the levels of cleaved Inflammatory class I HDAC protein In vitro: 5–160 µg/mL [32] OH OH SUM-149 andElevation SUM-190 of theMMP-9. levels of Caspase-3 and PARP. O Breast Cancer lines: In vitro: 5–160 levels, inducing TIMP-3 MCF-7 cleaved Inhibition of MMP-9[32] SUM-149 and SUM- μIng/mL vitro: 20 μM levels,suppressing [26] Reducing EZH2 and class I HDAC protein levels, OH MDA-MB-231 MCF-7 Caspase-3 andexpression PARP. and AKT 190 MDA-MB-231 invasiveness and In vitro: 20 µM inducing TIMP-3 levels,suppressing invasiveness [26] (−)-Epigallocatechin (EGC)OH MDA-MB-231In vitro: 50,activity 80 of MMP-2signaling and pathway by human breast Reducing EZH2 and [33] and activity of MMP-2 and MMP-9. μg/mL classMMP-9. I HDAC inhibiting protein both at the OH cancer cell line levels,Inhibition inducing of RNAMMP-9 TIMP-3 and MCF-7 In vitro: 20 μM levels,suppressingexpression and AKT [26] OH MDA-MB-231 protein level. Inhibition of MMP-9 expression and AKT signaling (−)-Epigallocatechin (EGC) In vitro:MDA-MB-231 50, 80 invasivenesssignaling human pathway and breast by (−)-Epigallocatechin (EGC) human breast [33] In vitro: 50, 80 µg/mL pathway by inhibiting both at the RNA [33] μg/mLcancer cell lineactivityinhibiting of bothMMP-2 at the and OH cancer cell line and protein level. OH MMP-9.RNA and HO O OH Inhibitionprotein level. of DisruptionMMP-9 of the expression andHeregulin AKT β1-stimulated MDA-MB-231MCF-7 In vitro: 30 μM [30] (−)-Epigallocatechin (EGC) OH In vitro: 50, 80 signaling pathway by OH human breast activation of [33] HO O μg/mL inhibitingDisruption both of the at the OH cancer cell line ErbB2/ErbB3/Akt. OH RNAHeregulin and β1-stimulated Disruption of the Heregulin β1-stimulated MCF-7 In vitro:MCF-7 30 μM [30] In vitro: 30 µM [30] OH OH proteinactivation level. of activation of ErbB2/ErbB3/Akt. ErbB2/ErbB3/Akt. OH OH HO(−)-EpicatechinO (−)-Epicatechin Disruption of the Heregulin β1-stimulated (−)-Epicatechin OH MCF-7 In vitro: 30 μM [30] OH activation of ErbB2/ErbB3/Akt. OHOH OH Inhibiting cell shedding Murine and invasion by their OH Inhibiting cell shedding mammacarcinoma In vitro: 10 μM anti-oxidative capacity [34] Inhibiting cell shedding and invasion by their HO O Murine Murine mammacarcinomaand invasion by their cell line 4T1 In vitro: 10 µM anti-oxidative capacity and down-regulation of [34] (−)-Epicatechin mammacarcinomacell line 4T1 In vitro: 10 μM anti-oxidativeand capacity down-regulation [34] of HO O H MMP-9 expression. cell line 4T1 and down-regulationMMP-9 ofexpression. OH H MMP-9 expression. OH OH OH Inhibiting cell shedding Murine and invasion by their OH mammacarcinoma In vitro: 10 μM anti-oxidative capacity [34] HO OH O cell line 4T1 and down-regulation of H MMP-9 expression.

1 1

Table 1. Cont.

Effective CancerTable Type 1. Cont. or Molecules 2016Natural, 21, Polyphenols 1634 Concentrations Result Ref. 6 of 27 AnimalTable Type1. Cont. Effective Cancer Type or or Doses Natural Polyphenols Table 1. Cont. Concentrations Result Ref. Animal Type Effective Kaempferol Cancer Type or or Doses Natural Polyphenols Concentrations Result Ref. Effective CancerAnimal Type Type or Table 1. Cont. Kaempferol Natural Polyphenols OH Concentrationsor Doses Result Ref. Animal Type Blocking the or Doses Kaempferol PKCδ/MAPK/AP-1 Natural PolyphenolsOH MDA-MB-231 Cancer Type or Animal Type Effective Concentrations or Doses Result Ref. In vitro: 10, 20, 40 cascadeBlocking and the HOKaempferol O human breast [35] Kaempferol OH μM subsequentiyPKCδ/MAPK/AP-1 carcinomaMDA-MB-231 cells Blocking the OH In vitro: 10, 20, 40 cascade and HO O human breast suppressingPKCδ/MAPK/AP-1 MMP-9 [35] MDA-MB-231 μM subsequentiyBlocking the carcinoma cells In vitro: 10, 20, 40 expression.cascade and HO O human breast suppressingPKCδ/MAPK/AP-1 MMP-9 [35] OH MDA-MB-231 μM subsequentiy carcinoma cells In vitro: 10, 20, 40 expression.cascade and HO O human breast MDA-MB-231 human breastsuppressing MMP-9 [35] Blocking the PKCδ/MAPK/AP-1 cascade and OH O μM subsequentiy In vitro: 10, 20, 40 µM [35] OH carcinoma cells carcinoma cells subsequentiy suppressing MMP-9 expression. expression.suppressing MMP-9 O Quercetin OH OH expression. OH O OH Quercetin OH Metastatic OH O MDA-MB-231 Induction of mTOR Quercetin OH MDA-MB-435Metastatic In vitro: 15 μM QuercetinHO O activities through Akt Quercetin FemaleMDA-MB-231 severe In vivo: 15 mg/kg [36] OH Metastatic inhibitionInduction ofand mTOR AMPK combinedMDA-MB-435 3InX vitro: per week 15 μ Mi.p. HO O MDA-MB-231Metastatic activation.activities through Akt OH immunodeficiencyFemale severe In vivo: 15 mg/kg Induction of mTOR [36] OH MDA-MB-435MDA-MB-231 MetastaticIn vitro: 15 μM inhibition and AMPK HO O OH (SCID)combined mice 3X per week i.p. activities through Akt In vitro: 15 µM Female severe MDA-MB-231In vivo: 15 mg/kg activation.Induction of mTOR [36] Induction of mTOR activities through Akt inhibition OH immunodeficiencyMDA-MB-435 MDA-MB-435 In vitro: 15 μM inhibition and AMPK In vivo: 15 mg/kg HO O combined 3X per week i.p. activities through Akt [36] OH O Female severe FemaleIn vivo: severe 15 combined mg/kg [36] and AMPK activation. OH OH (SCID) mice activation.inhibition and AMPK 3X per week i.p. immunodeficiencycombined immunodeﬁciency 3X per week i.p. (SCID) mice activation. OH O OH (SCID) mice Oroxylin A immunodeficiency OH (SCID) mice OH O Oroxylin A OH O Oroxylin AOH O Inhibiting the OroxylinO A OH O In vitro: 1, 10 and expressions of MMP- Oroxylin A MDA-MB-435 Inhibiting the [37] O OH O 100 μM 2, In vitro: 1, 10 and expressions of MMP- OH O MDA-MB-435 MMP-9Inhibiting and the ERK1/2 [37] Inhibiting the expressions of MMP-2, HOO O MDA-MB-435100 μM 2, In vitro: 1, 10 and 100 µM [37] In vitro: 1, 10 and expressionsInhibiting the of MMP- MMP-9 and ERK1/2 O MDA-MB-435 MMP-9 and ERK1/2 [37] HO O 100In vitro: μM 1, 10 and 2,expressions of MMP- MDA-MB-435 [37] 100 μM MMP-92, and ERK1/2 HO O MMP-9 and ERK1/2

BaicaleinHO O Baicalein Baicalein

Baicalein Down-regulating the HO O In vitro: 2, 10, 50 expression of MMP- Baicalein MDA-MB-231 [38] μM 2/9Down-regulating involved MAPK the µ Down-regulating the expression of MMP-2/9 MDA-MB-231 In vitro: 2, 10, 50 M [38] HO O In vitro: 2, 10, 50 expression of MMP- involved MAPK signaling pathway. MDA-MB-231 signalingDown-regulating pathway. the [38] μM 2/9 involved MAPK HO O In vitro: 2, 10, 50 expression of MMP- HO MDA-MB-231 signalingDown-regulating pathway. the [38] μM 2/9 involved MAPK HO O In vitro: 2, 10, 50 expression of MMP- OH O MDA-MB-231 [38] HO μM signaling2/9 involved pathway. MAPK signaling pathway. HO OH O HO OH O OH O

2 2 2

Table 1. Cont.

Effective Cancer Type or Natural Polyphenols Concentrations Result Ref. Animal Type or Doses Reducing the Genistein percent metastatic burden in the

CH2 OH OH O OH lungs, and affect MDA-MB-435/HAL In vivo: 750 μg/g the outgrowth [39] HO O of seeded tumor HO O cells by dietary O intervention OH following cancer surgery. In vitro: 0–30 μM Decreasing the 4T1 In vivo: 100 activity and [40] Female BALB/c mice mg/kg/day expression of 200 mg/kg/day MMP-9. Inhibition of Molecules 2016, 21, 1634 Table 1. Cont. HRG-β1- 7 of 27 mediated MMP- Effective Cancer Type or 9 Natural Polyphenols Concentrations Result Ref. Animal Type In vitro: 2, 5 and expression via MCF-7 or Doses Table 1. Cont. [41] 10Reducing μM the down- Genistein percent regulation of the Natural Polyphenols Cancer Type or Animal Typemetastatic Effective Concentrations or Doses Result Ref. MAPK/ERK Genistein burden in the CH2 OH OH O OH lungs, and affect signaling MDA-MB-435/HAL In vivo: 750 μg/g the outgrowth [39] pathway. Reducing the percent metastatic burden in the lungs, HO O MDA-MB-435/HALof seeded tumor In vivo:Suppressing 750 µg/g and affect the outgrowth of seeded tumor cells by [39] HO O cells by dietary dietary intervention following cancer surgery. O insulin-like intervention OH following cancer growth factor surgery. Resveratrol In vitro:(IGF)-1- 0–30 µM 4T1 Resveratrol In vitro: 0–30 μM Decreasing the In vivo:mediated 100 mg/kg/day cell Decreasing the activity and expression of MMP-9. [40] 4T1 Female BALB/cIn vivo:mice 100 activity and OH 200[40] mg/kg/day migration and Female BALB/c mice mg/kg/day expression of In vitro: 10 and 20 Inhibition of HRG-β1-mediated MMP-9 expression MDA-MB-435200 mg/kg/day MMP-9. invasion and [42] MCF-7 μM In vitro: 2, 5 and 10 µM via down-regulation of the MAPK/ERK [41] HO Inhibition of MMP-2 signaling pathway. HRG-β1- expression via mediated MMP- Suppressing insulin-like growth factor inhibition of the (IGF)-1-mediated cell migration and invasion and MDA-MB-435 9 In vitro: 10 and 20 µM [42] MMP-2 expression via inhibition of the PI3K/Akt In vitro: 2, 5 and expression via PI3K/Akt MCF-7 [41] signaling pathway. 10 μM down- signaling regulation of the Inactivating Stat3, preventing the generation and OH Female BALB/c mice (4T1) In vivo:pathway. 50 mg/mouse/2day i.p. [43] MAPK/ERK function of tBregs, including expression of TGF-β. Inactivating Immunocompromised mice signaling Green ﬂuorescent protein (GFP)pathway. Stat3, In vivo: 0.5, 5 and 50 mg/mouse Increased expression of the Rac downstream effector tagged-MDA-MB-231 (ERα(-),Suppressing ERβ(+)) [44] 5 days/weekpreventing i.g. the PAK1, JNK and Akt. or a metastatic variant of Ininsulin-likeReducing vivo: 50 the generation and FemaleGFP-MDA-MB-435 BALB/c mice (ER (-)) cells Piceatannol mg/mouse/2daygrowthexpression factor of function of [43] PiceatannolResveratrol (4T1) (IGF)-1-MMP-9 in both OH i.p.mediatedcancer and cell lung tBregs, OH migrationtissues and and including In vitro: 10 and 20 MDA-MB-435 invasionincreasing and [42] μInM vivo: 10 and 20 expression of HO Female BALB/c mice MMP-2apoptotic cells Reducing the expression of MMP-9 in both cancer mg/kg/day i.g. In vivo:[28] TGF- 10 andβ. 20 mg/kg/day i.g. and lung tissues and increasing apoptotic cells and (4T1) Female BALB/c mice (4T1) expressionand expression via [28] In vitro: 30 μM In vitro: 30 µM HO Table 1. ImmunocompromisedCont. inhibitionof both Bax of and the expression of both Bax and cleaved caspase-3 but reducing Bcl-2 expression in cancer tissues. mice PI3K/Aktcleaved caspase- Increased Cancer Type Effective signaling3 but reducing Natural Polyphenols OH or AnimalGreen Concentrations fluorescent or Result Ref. expression of OH Inpathway.Bcl-2 vivo: expression 0.5, 5 and Type protein (GFP)Doses tagged- the Rac OH 50Inactivatingin mg/mouse cancer [44] Butein MDA-MB-231 (ERα(-), InhibitionStat3,tissues. of CXCR4 downstream 5 days/week i.g. Butein ERβ(+)) or a metastatic expressionpreventing correlated the effector PAK1, OH O HER2-over- variant of GFP-MDA-In vivo: 50 with thegeneration suppression and JNK and Akt. Female BALB/c mice Inhibition of CXCR4 expression correlated with the expressing HER2-over-expressingIn vitro:mg/mouse/2day 10,25,50 breastof CXCL12-function cancer induced of [43] (4T1) MB-435 (ER (-)) cells In vitro:[45] 10,25,50 µM suppression of CXCL12- induced migration and [45] breast cancer SKBr3μM cellsi.p. migrationtBregs, and invasion, and inhibiting of NF-κB activation. OH SKBr3 cells invasion,including and HO inhibitingexpression of NF-κ ofB OH activation.TGF- β. Immunocompromised Xanthohumol Inhibiting the activity mice Increased of CYP, SELE and NF- O OH CH3 Green fluorescent In vitro: MCF-7: 5 expression of In vivo: 0.5, 5 andκB, affecting ICAM-1 proteinMCF-7 (GFP) tagged-μmol/L the Rac CH3 50 mg/mouse expression and [46][44] MDA-MB-231MDA-MB-231 (ERαMDA-MB-231:(-), 50 downstream 5 days/week i.g.adherence to LECs, HO O OH ERβ(+)) or a metastaticμmol/L 3 effector PAK1, suppressing paxillin, CH3 variant of GFP-MDA- JNK and Akt. MCL2 and S100A4. MB-435 (ER (-)) cells Suppression of the PKCα, MAPK and NF- MCF-7 In vitro: 30 μM κB/AP-1 pathway and [47] TPA-induced MMP-9 expression Suppression of NF-κB In vitro: 5–20 μM expression by down- 4T1 3 In vivo: 40 mg/kg regulation of VEGF, [48] BALB/c mice 80 mg/kg COX-2, and MMP-9 expressions. MDA-MB-231 MDA-MB- Curcumin 231MOCK Up-regulation of injecting into miR181b and down- In vitro: 25 μM [49] O O the left cardiac regulation of CXCL1 ventricle CD-1 and 2. Foxn1nu female mice. H3CO OCH3 MDA-MB-231 OH OH MDA-MB- Reducing the In vitro: 25 μM 231MOCK expression of MMPs In vivo: feding injecting into via down-regulation with standard diet [50] the left cardiac of NF-κB and AP-1 containing 1% ventricle CD-1 activity and curcumin Foxn1nu transcriptional. female mice. Decreasing E- cadherin, N-cadherin, MCF-10F; β-catenin, Slug, AXL, In vitro: 30 μM for MDA-Mb-231; Twist1, Vimentin and [51] 48 h Tumor 2 Fibronectin protein expression involved in EMT. Inhibiting the DNA Demethoxycurcumin binding activity of NF-

O O κB, decreasing the levels of ECM degradation- 4 In vitro: 1, 7.5, 15 MDA-MB-231 associated proteins [52] μM H including MMP-9, OCH3 MT1-MMP, uPA , OH OH uPAR, ICAM-1 and

CXCR4, up-regulating

the level of PAI-1.

Table 1. Cont.

Cancer Type Effective Natural Polyphenols Table 1. Cont.or Animal Concentrations or Result Ref. Type Doses Cancer Type Effective Butein Natural Polyphenols or Animal Concentrations or Result InhibitionRef. of CXCR4 Type Doses expression correlated Butein OH O HER2-over- Inhibition of CXCR4 with the suppression expression correlated OH O expressing In vitro: 10,25,50 of CXCL12- induced HER2-over- with the suppression [45] expressing breastIn vitro:cancer 10,25,50 μM of CXCL12- induced migration and [45] breast cancer μM migration and OH SKBr3 cells invasion, and HO OH SKBr3 cells invasion, and HO inhibiting of NF-κB OH inhibiting of NF-κB OH activation. activation. Xanthohumol Inhibiting the activity Inhibiting the activity of CYP, SELE and NF- O OH CH3 In vitro: MCF-7: 5 of CYP, SELE and NF- O OH CH3 In vitro:κB, affecting MCF-7: ICAM-1 5 MCF-7 μmol/L κB, affecting ICAM-1 CH3 MCF-7 μmol/Lexpression and [46] CH MDA-MB-231 MDA-MB-231: 50 3 adherence to LECs, expression and [46] HO O OH MDA-MB-231μmol/L MDA-MB-231: 50 Table 1. Cont. suppressing paxillin, adherence to LECs, HO CH3 O OH μmol/LMCL2 and S100A4. Cancer Type Effective suppressing paxillin, CH3 Suppression of the Natural Polyphenols or Animal Concentrations or Result MCL2Ref. and S100A4. Type Doses PKCα, MAPK and NF- MCF-7 In vitro: 30 μM κB/AP-1 pathway and Suppression[47] of the Butein Inhibition of CXCR4 TPA-induced MMP-9 PKCα, MAPK and NF- expression correlated MoleculesOH2016O, 21, 1634 expression 8 of 27 HER2-over- MCF-7 In vitro:with the30 suppressionμM κB/AP-1 pathway and [47] Suppression of NF-κB expressing In vitro: 10,25,50 of CXCL12- induced TPA-induced MMP-9 In vitro: 5–20 μM expression by down- [45] breast4T1 cancer μM migration and In vivo: 40 mg/kg regulation of VEGF, expression[48] OH SKBr3BALB/c cells mice invasion, and HO 80 mg/kg COX-2, and MMP-9Table 1. Cont. inhibiting of NF-κB Suppression of NF-κB OH expressions. In vitro:activation. 5–20 μM expression by down- MDA-MB-2314T1 Natural Polyphenols Cancer Type or AnimalIn vivo: Type 40 mg/kg regulation Effective Concentrations of VEGF, or Doses[48] Result Ref. Xanthohumol MDA-MB- BALB/c mice Inhibiting the activity Xanthohumol MOCK 80 mg/kgof CYP, SELE and NF- COX-2, and MMP-9 Curcumin O OH CH 231 Up-regulation of 3 In vitro: MCF-7: 5 injecting into κmiR181bB, affecting and ICAM-1 down- expressions. MCF-7 μInmol/L vitro: 25 μM [49] Inhibiting the activity of CYP, SELE and NF-κB, O O CH3 MCF-7 In vitro: MCF-7: 5 µmol/L the left cardiac expressionregulation ofand CXCL1 [46] affecting ICAM-1 expression and adherence to LECs, [46] MDA-MB-231MDA-MB-231 MDA-MB-231MDA-MB-231: 50 MDA-MB-231: 50 µmol/L ventricle CD-1 adherenceand 2. to LECs, suppressing paxillin, MCL2 and S100A4. HO O OH μmol/L Foxn1nu MDA-MB- suppressing paxillin, CH3 MOCK Curcumin female mice. 231 MCL2 and S100A4. Up-regulation of H3CO OCH3 Suppression of the PKCα, MAPK and NF-κB/AP-1 Curcumin MDA-MB-231injecting MCF-7 into Suppression of the miR181b In vitro: 30 andµM down- [47] OH O O OH MDA-MB- In vitro:Reducing 25 μ theM [49] pathway and TPA-induced MMP-9 expression the leftIn vitro: cardiac 25 μM PKCα, MAPK and NF-regulation of CXCL1 MOCK MCF-7231 In vitro: 30 μM κexpressionB/AP-1 pathway of MMPs and In vitro:[47] 5–20 µM Suppression of NF-κB expression by ventricle4T1In vivo: CD-1 feding and 2. injecting into via down-regulation In vivo: 40 mg/kg down-regulation of VEGF, COX-2, [48] BALB/cwith standard mice diet TPA-induced MMP-9 [50] the left cardiacFoxn1nu of NF-κB and AP-1 80 mg/kg and MMP-9 expressions. containing 1% expression ventricle CD-1female mice. activity and MDA-MB-231curcumin Suppression of NF-κB H3CO Foxn1nuOCH3 MDA-MB-231In vitro: 5–20MOCK μM injectingexpressiontranscriptional. into by the down- left Up-regulation of miR181b and down-regulation of 4T1 MDA-MB-231 In vitro: 25 µM [49] female mice. cardiacIn vivo: ventricle 40 mg/kg CD-1 Foxn1nuregulation female of VEGF, [48] CXCL1 and 2. OH OH BALB/c miceMDA-MB- Reducing the mice.80 mg/kg In vitro:COX-2,Decreasing 25 and μM E-MMP-9 MOCK 231 expressions.cadherin, N-cadherin, expression of MMPs MDA-MB-231 In vivo: feding µ Reducing the expression of MMPs via MCF-10F; injectingMDA-MB-231 into MOCK injectingβ-catenin, into Slug, the left AXL, viaIn vitro: down-regulation 25 M MDA-MB-231 In vitro: 30 μM for In vivo: feding with standard diet down-regulation of NF-κB and AP-1 activity [50] MDA-Mb-231; cardiac ventricle CD-1with Foxn1nuTwist1, standard Vimentin diet and [51] [50] MDA-MB- the left48 h cardiac ofcontaining NF-κB and 1% curcumin AP-1 and transcriptional. TumorMOCK 2 female mice. containingFibronectin 1% protein Curcumin 231 ventricle CD-1 Up-regulation of activity and injecting into curcuminmiR181bexpression and involved down- in Decreasing E-cadherin, N-cadherin, β-catenin, Slug, MCF-10F;In vitro: 25 MDA-Mb-231; μM [49] O O Foxn1nu EMT. transcriptional.In vitro: 30 µM for 48 h AXL, Twist1, Vimentin and Fibronectin protein [51] the left cardiac Tumor 2 regulation of CXCL1 female mice. Inhibiting the DNA expression involved in EMT. Demethoxycurcumin ventricle CD-1 and 2. binding activity of NF- Demethoxycurcumin Foxn1nu Decreasing E- O O female mice. κB, decreasing the cadherin, N-cadherin, Inhibiting the DNA binding activity of NF-κB, H3CO OCH3 MDA-MB-231 levels of ECM MCF-10F; β-catenin, Slug, AXL, decreasing the levels of ECM OH OH MDA-MB- Reducingdegradation- the MDA-MB-231In vitro: 251, 7.5,μM 15 In vitro: 30 μM for In vitro: 1, 7.5, 15 µM degradation-associated proteins including MMP-9, [52] 231MDA-MB-231MOCK MDA-Mb-231; expressionassociated proteinsof MMPs Twist1,[52] Vimentin and [51] InμM vivo: feding 48 h MT1-MMP, uPA , uPAR, ICAM-1 and CXCR4, H including MMP-9, OCH3 injecting intoTumor 2 via down-regulation Fibronectin protein with standard diet [50] up-regulating the level of PAI-1. theTable left cardiac 1. Cont. ofMT1-MMP, NF-κB and uPA AP-1 , OH OH expression involved in containing 1% uPAR, ICAM-1 and ventricle CD-1 activity and curcuminEffective CXCR4, up-regulating EMT. CancerFoxn1nu Type or transcriptional. Natural Polyphenols Concentrations or the level Resultof PAI-1. Ref. femaleAnimal mice. Type Inhibiting the DNA Demethoxycurcumin Doses Decreasing E- binding activity of NF- Oleuropein Increasing the TIMPs, 5 cadherin, N-cadherin, Increasing the TIMPs, and then suppressing the Oleuropein O O MDA-cellIn vitro: line 200 and then suppressing κ InB, vitro: decreasing 200 µg/mL the [27] OH MDA-cellMCF-10F; line β-catenin, Slug, AXL, [27] MMPs expressions Inμ vitro:g/mL 30 μM for the MMPs levels of ECM O MDA-Mb-231; Twist1, Vimentin and [51] 48 h expressions HO Tumor 2 Fibronectin protein degradation- O O In vitro: 1, 7.5, 15 O MDA-MB-231 expression involved in associated proteins [52] μM HO O EMT. H Possessing a potent in including MMP-9, OCH3 Inhibiting the DNA DemethoxycurcuminOH vivo anti-cancer MT1-MMP, uPA , O O binding activity of NF- OH OH activity inhibiting uPAR, ICAM-1 and O O Ovariectomised In vivo: 125 mg/kg κB, decreasing the Possessing a potent in vivo anti-cancer activity Ovariectomised both the MCF-7 cells [53] nude mice MCF-7 diet levels of ECM CXCR4,In vivo: 125 up-regulating mg/kg diet inhibiting both the MCF-7 cells xenograft growth [53] nude mice MCF-7 xenograft growth and degradation- and their invasiveness into the lung. In vitro: 1, 7.5, 15 their invasiveness the level of PAI-1. MDA-MB-231 associated proteins [52] OH μM into the lung. H OCH including MMP-9, OH 3 MT1-MMP, uPA , 5 OH OH uPAR, ICAM-1 and Amentoflavone CXCR4, up-regulating Inhibiting NF-κB OH theactivation level of decreasesPAI-1. expression and 5 secretion of angiogenesis- and O OH metastasis-related In vivo: 50 and 100 proteins. O MCF-7 μM in [54] Amentoflavone may HO 0.1% DMSO HO induce anti- angiogenic and anti- O OH metastatic effects through suppression of O OH NF-κB activation.

Glabridin

Attenuating the angiogenic ability by the O O In vitro: 8 μM for microRNA-520a MDA-Mb-231 [55] H 24, 48, 72 h (miR-520a)-mediated inhibition of the NF- κB/IL-6/STAT-3 signal pathway. HO OH

Modulating the In vitro: 8 μM transcription level of BJMC3879 In vivo: 22.9 mutant p53. A resveratrol tetramer Female BALB/c mg/kg/day Suppressing [56] mice 44.7 mg/kg/day metastasis to both i.p. lymph nodes and lungs.

Table 1. Cont. Table 1. Cont. Effective Cancer Type or Natural Polyphenols ConcentrationsEffective or Result Ref. CancerAnimal Type Type or Natural Polyphenols ConcentrationsDoses or Result Ref. Animal Type Oleuropein Doses Increasing the TIMPs, Oleuropein In vitro: 200 andIncreasing then suppressing the TIMPs, OH MDA-cell line [27] μg/mL the MMPs O In vitro: 200 and then suppressing OH MDA-cell line [27] HO μg/mL expressionsthe MMPs O O O O HO expressions O O O HO O Possessing a potent in HO OH O vivoPossessing anti-cancer a potent in O O OH activityvivo anti-cancer inhibiting O O Ovariectomised In vivo: 125 mg/kg Molecules 2016, 21, 1634 bothactivity the inhibiting MCF-7 cells [53] 9 of 27 nudeOvariectomised mice MCF-7 dietIn vivo: 125 mg/kg xenograftboth the MCF-7 growth cells and [53] nude mice MCF-7 diet theirxenograft invasiveness growth and OH intotheir the invasiveness lung. OH OH into the lung. Table 1. Cont.

OH Amentoflavone Natural Polyphenols Cancer Type or Animal Type Effective Concentrations or Doses Result Ref. Amentoflavone Inhibiting NF-κB OH Amentoﬂavone activationInhibiting decreasesNF-κB OH expressionactivation decreases and secretionexpression of and angiogenesis-secretion of and O OH metastasis-relatedangiogenesis- and O OH In vivo: 50 and 100 proteins.metastasis-related Inhibiting NF-κB activation decreases expression O MCF-7 μInM vivo: in 50 and 100 [54] Amentoflavoneproteins. may and secretion of angiogenesis- and HO O MCF-7 MCF-70.1%μM in DMSO In vivo:[54] 50 and 100 µM in 0.1% DMSO metastasis-related proteins. Amentoﬂavone may [54] HO induceAmentoflavone anti- may HO 0.1% DMSO induce anti-angiogenic and anti-metastatic effects angiogenicinduce anti- and anti- HOO OH through suppression of NF-κB activation. metastaticangiogenic effects and anti- O OH throughmetastatic suppression effects ofthrough suppression O OH NF-of κB activation.

O OH NF-κB activation. Glabridin Glabridin Glabridin Attenuating the

angiogenicAttenuating ability the by theangiogenic ability by Attenuating the angiogenic ability by the O O In vitro: 8 μM for microRNA-520athe MDA-Mb-231 MDA-Mb-231 In vitro:[55] 8 µM for 24, 48, 72 h microRNA-520a (miR-520a)-mediated inhibition of [55] O O H 24,In vitro: 48, 72 8 h μ M for (miR-520a)-mediatedmicroRNA-520a MDA-Mb-231 [55] the NF-κB/IL-6/STAT-3 signal pathway. H 24, 48, 72 h inhibition(miR-520a)-mediated of the NF- κinhibitionB/IL-6/STAT-3 of the NF- signalκB/IL-6/STAT-3 pathway. HO OH signal pathway. HO OH In vitro: 8 µM Modulating the transcription level of mutant p53. BJMC3879 Modulating the A resveratrol tetramer In vivo: 22.9 mg/kg/day Suppressing metastasis to both lymph nodes [56] FemaleIn vitro: BALB/c 8 μM mice transcription level of Modulating the 44.7 mg/kg/day i.p. and lungs. BJMC3879 InIn vivo:vitro: 22.98 μM mutanttranscription p53. level of A resveratrol tetramer FemaleBJMC3879 BALB/c mg/kg/dayIn vivo: 22.9 Suppressingmutant p53. [56] Down-regulating phosphorylation of the ± µ Enterolactone,A resveratrol tetramer an active polyphenol metabolitemiceFemale of Lignan BALB/c MDA-MB-23144.7mg/kg/day mg/kg/day cells metastasisSuppressing to both In vitro:[56] IC50 = 261.9 10.5 M FAK/paxillin pathway, inhibiting migration and [57] invasion of cells. mice i.p.44.7 mg/kg/day lymphmetastasis to both i.p. nodeslymph and lungs. Inhibiting cancer growth and spontaneous Curcumin loaded polymeric micelles Subcutaneous 4T1 breast cancer model In vivo: 30 mg/kg/day [58] nodes and lungs. pulmonary metastasis. In vitro: 5 µM Human metastatic breast cancer cell In vivo: 5 mg/kg/day GFP-MDA-MB-231 Reducing Akt activity, inducing the activation of Grape natural polyphenols: respectively i.g. [59] (ERα(−), ERβ(+)) AMPK and inhibiting mTOR signaling pathway. resveratrol,quercetin,catechin, Immunocompromised mice or 5 mg/kg/2days and (or combination with geﬁtinib) 200 mg/kg/2days i.g. In vitro: 0.5 or 5 µM Up-regulating FOXO1 and NFKBIA (IκBα), ER(−) GFP-MDA-MB-435 In vivo: 5 mg/kg/day activating apoptosis and inhibiting NF-κB activity, [60] Female athymic nu/nu mice together i.g reducing metastasis.

7 7 Molecules 2016, 21, 1634 10 of 27

Table 1. Cont.

Natural Polyphenols Cancer Type or Animal Type Effective Concentrations or Doses Result Ref. Mixed natural polyphenols resveratrol, baicalein, Suppressing invasion by down-regulation of 4T1 multicellular cancer spheroids In vitro: 100 µM [34] epicatechin, epigallocatechin polyphenon 60 MMP-9 expression and their anti-oxidative capacity. Reducing EZH2 and class I HDAC protein levels, MCF-7 inducing TIMP-3 mRNA and protein levels, In vitro: 10 µg/mL [26] MDA-MB-231 suppressing invasiveness and activity of MMP-2 and MMP-9. Increasing the expression of Bax-to-Bcl-2 ratio, Mouse mammary carcinoma 4T1 cells In vitro: 0.06–0.125 mg/mL activating caspase-8 and caspase-3, decreasing lung [61] Natural polyphenols extract from Green tea Female BALB/c mice In vivo: 0.6 g/kg/day i.g. and liver metastasis, protecting the bone from breast cancer-induced bone destruction. Decreasing the protein expression of Bcl-2 In vivo: 0.2% and 0.5% Mouse mammary carcinoma 4T1 cells concomitantly increase in Bax, cytochrome c release, w/v in drinking water and was started [62] Female BALB/c mice Apaf-1, and cleavage of caspase 3 and PARP 7 days before cancer cells inoculation proteins,inhibiting lungs metastasis. Inhibition of MMP-9 expression and AKT signaling MDA-MB-231 human breast Natural polyphenols extract from Green tea In vitro: 40, 60 µg/mL pathway by inhibiting both at the RNA [33] cancer cell line and protein level. In vivo: 750 mg/kg/day diet Increasing Ki-67 protein expression amd stimulating Natural polyphenols extract from Soy isoﬂavones Female BALB/c mice (4T1) [63] genistein equivalent metastatic cancer formation in lungs. In vitro: 25, 50, 75, 100 µM Decreasing the MMP-9 activity and stimulating the Natural polyphenols extract from Japanese quince fruit MDA-MB-231 [29] catechin equivalents TIMP-1 expression. Blocking vascular-like structure formation, Natural polyphenols extract from Nelumbo nucifera suppressing CTGF expression reducing the MMP2 MDA-MB-231 In vitro: 0.5~2.0 mg/mL [64] Gaertn leaves and VEGF expression, and attenuating PI3K-AKT-ERK activation. Natural polyphenols extract from MCF-7 In vitro: 10, 25 and 50 µg/mL Inhibition of MMP-2 and MMP-9 activities. [65] Leucobryum bowringii Mitt. In vivo: 0.8–1.6 mg chlorogenic acid Down-regulating the gene expression of MMPs, and Natural polyphenols extract from Peach phenolics MDA-MB-435 [66] equivalent /day i.g. up-regulating hβ2G gene expression in the lungs. Decreasing of proteolytic activity of MMP-2, Natural polyphenols extract from Artichoke MDA-MB-231 In vitro: 200 µM involved in degrading components of the [67] extracellular matrix. 4T1 cells Balb/c mice implanting 4T1 In vitro: 0.5 and 1.0 mg/ml in Natural polyphenols extract from Grape skin Blocking the PI3k/Akt and MAPK pathways. [68] subcutaneously drinking water Decreasing the activity of MMP-9 through reducing In vitro: IC = 58 µM Evening primrose MDA-MB-231 50 Natural polyphenols extract from (gallic acid equivalents) the expression levels of the following proteins: [69] VEGF, c-Fos, c-Jun. Molecules 2016, 21, 1634 11 of 27

Table 1. Cont.

Natural Polyphenols Cancer Type or Animal Type Effective Concentrations or Doses Result Ref.

In vitro: MDA-MB-231 Decreasing the level of nitric oxide and MDA-MB-231 (IC = 2.40 ± 0.26) 50 inﬂammation-related cytokines and genes, Murraya koenigii Left mammary fat pad 4T1 (IC = 1.50 ± 0.90) Natural polyphenols extract from 50 κ [70] subcutaneously 4T1 In vivo: 50 mg/kg including iNOS, iCAM, NF- B and c-MYC and 200 mg/kg reducing lung metastasis. Increasing the ratio of Bax:Bcl-2 proteins, Natural polyphenols extract from 4T1 cells were implanted cytochrome c release, induction of Apaf-1 and In vivo: 0.2% and 0.5%, w/w in a diet [71] Grape seed proanthocyanidins subcutaneously in Balb/c mice activation of caspase 3, inhibiting the metastasis of cancer cells to the lungs. In vitro: 100 µM Natural polyphenols extract from biotransformation of murine 4T1 human MCF7 and Decreasing lung metastasis by controlling MDA-MB-231 (gallic acid equivalent) [72] Serratia vaccinii blueberry juice by BALB/c mouse model In vivo: 2.9 mL/day PI3K/AKT, MAPK/ERK. Inhibiting the cancer cell adhesion to ECs through suppression of vascular cell adhesion molecule-1 Natural polyphenols extract from Korean A. annua L. MDA-MB-231 In vitro: 1, 10, 30 ug/mL [73] and invasion through suppression of EMT, MMP-2 and MMP-9. Molecules 2016, 21, 1634 12 of 27

2.1.2. MMPs Involving Common Signaling Pathways Previous studies have shown that AKT is one of the major pathways activated by MMP-9 expression [74]. The inhibitory effect of EGCG and GTP on the invasion of MDA-MB-231 cells was associated with decreased AKT phosphorylation, and down-regulation of MMP-9 expression [33]. In addition, EGCG and EGC also inhibited heregulin-β1 (HRG)-induced migration and invasion of MCF-7 cells, owing to EGCG down-regulation of ErbB2/ErbB3/PI3K/Akt signaling, EGC exerted these effects through pathways involved in the inhibition of ErbB2/ErbB3 but not Akt [30]. These data suggest that EGCG and EGC reduce MMP-9 expression through different signalling pathways. Kaempferol can inhibit cancer cell invasion by interrupting the PKCδ/MAPK/AP-1 cascade and subsequently down-regulating MMP-9 expression in MDA-MB-231 human breast carcinoma cells [35]. Baicalein is a natural polyphenols sourced from the root of Scutellaria baicalensis, widely used in Chinese herbal medicine. Recent studies have demonstrated that S. baicalensis alone, or in combination with other herbs, can inhibit cancer cell growth and induce apoptosis in breast carcinoma cell lines [75]. In MDA-MB-231 cells, treatment with baicalcin down-regulates the expression of MMP-2/9 through the MAPK signalling pathway [38]. Oroxylin A, one of the main bioactive natural polyphenols of S. radix., suppresses the invasive abilities of MDA-MB-435 cells by down-regulating the expression of MMP-2 and MMP-9, interfering with phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) [37]. Resveratrol, a polyphenol naturally produced by many fruits, reduced growth factor heregulin-β1 (HRG-β1)-mediated MMP-9 expression, phosphorylation of ERK1/2 and invasion in MCF-7 breast cancer cells. These results suggest that the inhibitory effect of resveratrol on MMP-9 expression and invasion is in part associated with down-regulated mitogen-activated protein kinases, MAPK/ERK signaling [41]. Tang and colleagues conﬁrmed that resveratrol signiﬁcantly inhibited the migration and invasion of MDA-MB-435 ER-negative human breast cancer cells, insulin-like growth factor (IGF-1)-mediated MMP-2 expression, and PI-3K/Akt signaling pathway activation [40,42]. Connective tissue growth factor (CTGF), also known as CCN2, is a member of the CCN family [76]. Down-regulation of CTGF in lung adenocarcinomas [77] and colon cancers [78] is related to invasion and metastasis both in vitro and in vivo. Nelumbonucifera gaertn, known as lotus, is used as a medicinal herb in Eastern Asia [79]. Recently, researchers have explored the molecular mechanisms of N. nucifera leaf extract on metastasis in breast cancer from the perspective of CTGF. The results demonstrated that down-regulation of CTGF expression in MDA-MB-231 cells markedly attenuated PI3K-AKT-ERK activation, consequently reducing the expression of MMP-2 [64].

2.1.3. MMPs Involving NF-κB The NF-κB family of transcription factors are key regulators of immune responses, inflammation, and cancer [80]. Sufficient research has demonstrated that NF-κB signaling pathways are closely related to cancer metastasis, suggesting that inhibition of NF-κB activity would disrupt the metastatic potential of mammary epithelial cells in a model system [81]. NF-κB regulates genes linked to cell motility, invasion and metastasis, including the genes encoding MMPs [82]. Curcumin, commonly used polyphenol species, is sourced from the turmeric plant (Curcuma longa). Pre-treatment with curcumin specifically blocked TPA-stimulated NF-κB and AP-1 activation, subsequently inhibiting TPA-induced MMP-9 expression in MCF-7 cells [47]. Previous reports have indicated that NF-κB activation can up-regulate MMP-9 [83]. Demethoxycurcumin (DMC) is a natural polyphenolic compound found in curcuma species [84]. Treatment with DMC inhibits expression of MMPs by mediating the DNA binding activity of NF-κB[52]. Dendrosomal curcumin can inhibit MMP-9 expression in breast tumor, the brain, the lung, the liver and the spleen through the suppression of NF-κB in an animal model of metastatic breast cancer [48,50]. Another active ingredient of green tea, EC, can down-regulate MMP-9 expression explaining the inhibitory effect of EC on invasion of cancer cells into embryonic stem cell-derived, vascularized tissues [34]. Murraya koenigii, a whitish moss, grows in dense cushion with long spongy leaves, in dampy soil or as epophytes. The methanolic extract remarkably inhibited the adhesion, migration and invasion of MCF-7 cells, partially through the inhibition of MMP-2 and MMP-9 activities [65]. Molecules 2016, 21, 1634 13 of 27

2.2. Anti-Angiogenesis Tumor angiogenesis is necessary for the metastatic process because cancer cells leaving primary sites utilize the route provided by newly formed blood vessels [85]. VEGF is a potent angiogenic factor and can be secreted by various types of cancer cells of breast, lung, gastrointestinal tract and others [86]. Previous research has stressed the major role played by VEGF in the proliferation and metastasis of endothelial cells and in neovascularization. Previous studies have shown that natural polyphenols can inhibit cancer metastasis by interfering with the VEGF signalling pathway. Evening primrose flavanol preparation (EPFP) decreased MDA-MB-231 invasiveness by causing a reduction in VEGF expression at 100 µM gallic acid equivalents. Furthermore, the studies observed a pronounced inhibition of Ki-67 gene expression, the product of which is a universal marker of angiogenesis in breast cancer patients [87]. It was concluded that EPFP treatment reduced the expression levels of Bcl-2, VEGF and 2 transcription factors (c-Jun, c-Fos) via modulation of mRNA expression, which ultimately lead to inhibition of invasiveness by suppressing angiogenesis [69]. Phosphoinositide 3-kinase (PI3K)/Akt signaling is activated and phosphorylated during angiogenesis, which induces the expression of cancer growth related proteins and additional angiogenic factors [88]. Grape skin extract inhibits phosphorylation of Akt, PDK1, p38 and ERk1/2, which partly inhibited cancer angiogenesis and suppressed 4T1 cell proliferation and migration in vitro [68]. Selaginella tamariscina (Beauv.) Spring, which was first recorded in ‘Shen Nong Ben Cao Jing’ (a classical traditional Chinese medicine book) approximately 1700 years ago, and amentoflavone was found to be the main component of the total flavonoids [54]. Chen and his colleagues investigated whether amentoflavone induced anti-angiogenic and anti-metastatic effects through suppression of NF-κB activation, which is a family of transcription factors implicated in various aspects of the tumor biology such as cell proliferation, angiogenesis, metastasis and drug resistance in breast cancer [89]. Obtained results indicated that amentoflavone reduce NF-κB activation, expression and secretion of angiogenesis- and metastasis-related proteins, and cell invasion, so the conclusion is inhibition of NF-κB activation decreases expression and secretion of angiogenesis- and metastasis-related proteins [90]. The formation of blood vessels plays a vital role in the growth of vascular dependent tumor, especially for breast cancer, and angiogenesis plays an important role in its invasion and metastasis. Glabridin, is a polyphenolic flavonoid and is a main constituent in the hydrophobic fraction of licorice extract [91]. Mu and his team studied the underlying molecular mechanisms, and results showed that glabridin attenuated the angiogenic ability via inhibition of microRNA-520a (miR-520a)-mediated NF-κB/IL-6/STAT-3 signalling, the VEGF secretion, and the angiogenesis in MDA-MB-231 breast cancer cell line [55]. Tasquinimod is a small-molecule immunotherapy with demonstrated effects on the tumor microenvironment involving immunomodulation, anti-angiogenesis and inhibition of metastasis [92]. A target molecule of tasquinimod is the inflammatory protein S100A9 which has been shown to affect the accumulation and function of suppressive myeloid cell subsets in tumors. The MC38-C215 colon carcinoma tumors were studied and datas showed that tasquinimod affected tumor infiltrating myeloid cells, leading to a change in phenotype from pro-angiogenic which consistent with the effects of tumor vascularization and metastasis [92]. These results giving further insights to the anti-tumor mechanism of natural polyphenols from a perspective of anti-angiogenesis in breast cancer metastases.

2.3. NF-κB NF-κB is a transcription factor involved in multicellular biological responses [93]. NF-κB signaling has been reported to be intimately involved in bone and liver metastasis [94]. NF-κB exists as an inactive complex with the inhibitory protein I-κB in the cytoplasm in normal resting cells [95], Upon activation, it enters the nucleus where it regulates the expression of diverse genes encoding cytokines, cell adhesion molecules, growth factors, and apoptotic-related proteins [96]. Combined dietary grape natural polyphenols up-regulated FOXO1 and NFKBIA (I-κBα), thus activating apoptosis and potentially inhibiting NF-κB activity [60]. Curcumin suppressed I-κB phosphorylation in MDA-MB-231 breast cancer cells and diminished NF-κB translocation to the nucleus as monitored by the p65 unit Molecules 2016, 21, 1634 14 of 27 of NF-κB. The results also showed that a signiﬁcant decrease of AP-1 binding upon treatment with curcumin, suggesting an association between NF-κB and the c-Jun/AP-1 pathway [50]. Continuing studies illustrated that curcumin reduced the metastasis of MDA-MB-231 cells by inhibiting NF-κB signaling pathway activation through indication of miR181b expression, miR181b down-regulates the pro-inﬂammatory cytokine CXCL1, causing subsequent loss of metastatic potential and disrupting the feedback loop between CXCL1/2 and NF-κB[49]. Butein, another natural polyphenol derived from the stembark of cashews and the heartwood of Dalbergia odorifera, down-regulates the expression of CXCR4 (a Gi protein-coupled receptor for the ligand CXCL12) in HER2-overexpressing breast cancer cells via transcriptional regulation as indicated by inhibition of NF-κB activation and down-regulation of mRNA expression [45].

2.4. EMT EMT is a key step, that, through loss of intercellular contacts of epithelium-derived cancer cells, up-regulates components of the contractile cytoskeleton, generating a mesenchymal phenotype with highly invasive characteristics that emigrate the primary cancer [97]. Steroid hormones such as estrogen play crucial roles in breast cancer progression. Most responses are mediated through estrogen receptor alpha (ERα) and ERβ [98]. The presence of ERα is considered to be a good prognostic factor and correlates with a higher degree of cancer differentiation [98]. MMP-9 has been previously reported to promote the metastasis of cancer cells. Recent research has shown that high levels of MMP-9 were negatively correlated with ER [99]. EGCG treatment activated Forkhead box O transcription factor, FOXO3a, a major transcriptional regulator of ERα, inhibits the invasive phenotype through activation of ERα signaling in breast cancer cells. The fact that EGCG represses EMT [31], a critical feature of embryogenesis, has been recognized for several decades. Cancer cells lose expression of proteins that promote cell-cell contact such as γ-catenin and E-cadherin and acquire mesenchymal markers such as the zinc-finger transcription factor Snail, fibronectin, N-cadherin, and vimentin during EMT [100]. Curcumin is an antioxidant that exerts antiproliferative and apoptotic effects and has anti-invasive and anti-metastatic properties. The effect of curcumin (30 µM for 48 h) was evaluated on the expression of EMT-related genes. The results showed that curcumin decreased E-cadherin, N-cadherin, β-catenin, Slug, AXL, Twist1, vimentin and fibronectin protein expression, and all of these changes induced a decrease in migratory and invasive capabilities in a breast cancer cell line [51,101]. Health benefits of xanthohumol, a natural extract sourced from hops and beer [102], suppressed markers of EMT and of cell mobility such as paxillin, MCL2 and S100A4, and also attenuated cancer cell-mediated defects at the lymphendothelial barrier, inhibiting EMT-like effects [46]. The Korean annual weed, Artemisia annua L., has been used as a folk medicine for treatment of various diseases. Ko and his team investigated anti-metastatic effects of natural polyphenols from Korean A. annua L. (pKAL) on the highly metastatic MDA-MB-231 breast cancer cell line, focusing on cancer cell adhesion to the endothelial cell and epithelial-mesenchymal transition (EMT). These results suggest that pKAL exhibits anti-invasive effects through suppression of MMP-2 and MMP-9, two key molecules in proteolytic digestion of ECM. This is consistent with previous reports using quercetin or kaempferol [73,103].

2.5. mTOR mTOR, a central regulator of cell growth, proliferation, differentiation and metastasis, has been intensely studied for over a decade. Recent data has shown that the phosphoinositide 3-kinase (PI3-K)/Akt/mTOR pathway, and mTOR in particular, plays a critical role in the regulation of cancer metastasis [104]. Quercetin, one of the natural polyphenols, in combination with resveratrol and catechin (RQC), has been reported to inhibit the PI3K/Akt/mTOR signaling pathway and breast cancer progression in vitro and in vivo. The results showed that RQC reduces mTOR pathway activation and induces apoptosis via inhibition of Akt and activation of AMPK in breast cancer [59]. Of the RQC natural polyphenols, quercetin is the most effective inhibitor of the PI3K enzyme, with an IC50 ≈ 3.8 µM[105], compared with resveratrol that has an IC50 ≈ 25 µM[106]. Quercetin at 15 µM in vitro and 15 mg/kg in vivo, inhibits Akt/mTOR signalling, induces cell cycle arrest, and inhibits breast cancer growth and metastasis [36]. Molecules 2016, 21, 1634 15 of 27

2.6. Others Lee-Chang and his team found that cancer metastasis requires an additional player, a unique subset of TGFβ-producing regulatory B cells designated cancer-evoked regulatory B cells (tBregs) [46]. RSV inhibits the generation and function of tBregs by inactivating Stat3 phosphorylation and acetylation [43]. Enterolactone, an active polyphenol metabolite of lignan, inhibited migration and invasion of breast cancer cells via the inhibition of phosphorylation in the FAK/paxillin signaling pathway, which is associated with cell adhesion to the extracellular matrix or to surroundings [57]. Previous research has shown that biotransformation of blueberry juice by Serratia vaccinii increases its polyphenolic content and reduces lung metastasis of mammary carcinoma through inﬂuencing cellular signaling cascades of breast cancer stem cells, controlling PI3K/AKT, MAPK/ERK, and STAT3 pathways in mammary cancer stem cell inﬂammatory signaling [72].

3. The Molecular Mechanism of Natural Polyphenols on Breast Cancer Metastasis In Vivo Human cancer xenografts constitute the major percentage of cancer biology models used for cancer drug discovery. These models overcome the disadvantages of in vitro models by containing a microenvironment in which the cancer cells can grow. Examination of molecular mechanisms in animal models treated with natural polyphenols has offered some promising results in terms of treating metastases (Table1).

3.1. Natural Polyphenols Monomers The administration of resveratrol (20 or 50 mg/mouse) to female BALB/c mice with 4T1-cancer reduced breast cancer growth efficiently inhibited lung metastasis. The mechanism of this process occurred through resveratrol-mediated inactivation of Stat3, which prevented the generation and function of tBregs, including expression of TGF-β [43]. Similarly, in female BALB/c mice that received inoculums of 4T1 cells, the macroscopic appearance of the lungs from untreated and treated mice clearly showed that treatment with resveratrol reduced the number of 4T1 colonies in the lungs. In addition, plasma MMP-9 activity was decreased in response to treatment with resveratrol in mice [40]. However, in another model of mouse breast cancer, hairless SCID and athymic nude female mice bearing MDA-MB-231 and metastatic variant of MDA-MB-435 breast cancers were orally gavaged with 0.5, 5, or 50 mg/kg body weight resveratrol for 35 days. The necropsy reports showed that resveratrol at low concentrations can promote mammary cancer growth and metastasis to lungs, livers, kidneys, and bones, primarily due to a significant induction of Rac activity and a trend in increased expression of the Rac downstream effector PAK1, as well as other cancer promoting molecules. In contrast to other studies, these findings strongly illuminate the importance of delineating resveratrol’s concentration-dependent effects [44]. Therefore, the data reported on administration of resveratrol in animal models of breast cancer metastasis are contradictory. Exposure to 20 mg/kg picetannol significantly reduced the number and volume of pulmonary cancer nodules and expression of MMP-9 in both lung and cancer in nude mice [28]. For this study, BJMC3879 cells were inoculated subcutaneously in female BALB/c mice, which were then given vaticanol C (Vat-C, a novel resveratrol tetramer) at either 100-ppm or 200-ppm in their diet for 8 weeks. The results demonstrated that the multiplicities of lymphatic and pulmonary metastasis were significantly lower in the 200-ppm Vat-C group, as were overall metastasis to any organ [56]. Curcumin has been widely used in Southeast Asian countries as spice or traditional medicine [107]. It has been previously reported that curcumin prevents the formation of hematogenous breast cancer metastases in immunodeficient mice in a highly significant manner. MDA-MB-231 cells were injected into the heart of mice that were then fed diets supplemented with 1% curcumin. The results showed that curcumin administration significantly prevented lung metastases. To explore the mechanism underlying the influence of curcumin on the expression of a series of miRNAs in metastatic breast cancer cells, MDA-MB-231miR181bt+ or MDA-MB-231MOCK cells were implanted in the left cardiac ventricle of CD-1 Foxn1nu female mice. The data demonstrated that over-expression of miR181b inhibits metastasis formation, particularly in the lung [49]. However, owing to poor solubility [108] Molecules 2016, 21, 1634 16 of 27 and extensive fast rate of metabolism [109], the therapeutic efficacy of curcumin was limited. Therefore, curcumin loaded biodegradable self-assembled polymeric micelles (Cur-M) were prepared and investigated for their treatment effect on the subcutaneous 4T1 breast cancer model with Cur-M treatment (30 mg/kg) for ten days. These findings indicated Cur-M not only blocked implanted cancer growth but also impaired cancer metastasis [58]. Exposure to 80 mg/kg dendrosomal curcumin significantly decreased metastasis formation in the lung, the sternum and the liver of BALB/c mice injected subcutaneously with 4T1 cells. The results also reported suppression of NF-κB expression via down-regulation of VEGF, COX-2, and MMP-9 expression in the breast cancer as well as in brain, lung, liver and spleen tissues [48]. Likewise, mice subcutaneously injected with MCF-7 cells and exposed to oleuropein at 125 mg/kg demonstrated for the first time that oleuropein prevented both peripulmonary and parenchymal lung metastases [53]. Otherwise, female SCID mice with MDA-MB-231 cells were exposed to 15 or 45 mg/kg quercetin. The results show that quercetin treatment decreased metastasis [36].

3.2. Combined Natural Polyphenols and Other Antimetastatic Drugs The effects of combining natural polyphenols with conventional drugs in animal models are necessary to evaluate their pharmacodynamic actions, and lay the foundation for preclinical study. Tea catechins in combination with anticancer drugs are being evaluated as a new cancer treatment strategy [110]. Combined administration of EGCG and curcumin (25 mg/kg & 200 mg/kg, respectively) in athymic female mice implanted with ERα-breast cancer cells showed reduced tumor volume with decreased VEGFR-1 expression [111]. Administration of EGCG and taxol in BALB/c mice injected with 4T1 mouse breast cancer cells dramatically decreased cancer growth and numbers of the lung metastases, however, there were no significant effects when mice were exposed to EGCG or taxol alone [112]. Another line of evidence for synergism between paclitaxel and natural polyphenols was presented by Kang and colleagues, who discovered that the combination of paclitaxel and curcumin decreased cancer cell proliferation, increased apoptosis, and decreased expression of MMP-9 in a breast cancer murine model using MDA-MB-231 cells. This study demonstrated the combined effects of the paclitaxel and natural polyphenols, illustrating that this two compounds combine to inhibiting cancer metastasis [113]. MDA-MB-231 cells were injected into hairless severe combined immunodeficiency (SCID) female mice to produce orthotopic primary cancers, and mice were orally gavaged with a combination of 5 mg/kg RQC and 200 mg/kg gefitinib, or treatments were given separately. The results demonstrated combined RQC and gefitinib was more efficient than either treatment alone at inhibiting mammary cancer growth and metastasis via inhibition of Akt signaling and mTOR. Activation of AMPK occurred even in the presence of gefitinib [59]. Similarly, the administration of RQC (5 mg/kg) to female nude mice with MDA-MB-435 cells reduced metastasis especially to liver and bone [60]. The results demonstrated that natural polyphenols generally increase conventional drug efficacy, making them attractive candidates for adjuvant therapy against metastatic cancer.

3.3. Natural Polyphenols Extracts Camellia sinensis (0.6 g/kg) was effective in reducing tumor weight by 34.8% in female BALB/c mice compared to the control group that received water treatment (100%). In addition, C. sinensis treatment significantly decreased lung and liver metastasis by 54.5% and 72.6%, respectively [61]. MDA-MB-435/HAL cells were injected into female athymic nude mice, and various experimental designs were used to assess the anti-metastatic effect of the soy isoflavone genistein through postsurgical dietary intervention. The results demonstrated that the growth ability of previously seeded and potentially metastatic cells could be affected by dietary intervention following surgical resection and then the application of a diet enriched in genistein. This anti-metastatic action illustrates the potential of genistein as a postsurgical adjuvant therapy for ER–negative breast cancer, which has been supported by additional studies [39]. However, dietary enrichment in soy isoflavones has also been associated with increases in Ki-67 protein expression and metastatic lung cancer formation [63]. These Molecules 2016, 21, 1634 17 of 27 studies illuminate the need for further delineating polyphenolic effects, especially in breast cancer, before these compounds can be tested in the clinic. Mice feda diet supplemented with Murraya koenigii (50Molecules and 200 2016 mg/kg), 21, 1634 for 30 days were subsequently inoculated with different numbers of 4T1 cells17 of in 26 low and high-risk cancer groups. Murraya koenigii treatment continued until day 21 post-inoculation, and thehigh-risk reported cancer data showed groups. thatMurrayaM. koenigii koenigii reducedtreatment lung continued metastasis, until day and 21 diminished post-inoculation, the level and of the nitric oxidereported and inflammation-related data showed that M. cytokineskoenigii reduced and genes, lung includingmetastasis, NF- andκ B,diminished iCAM, c-MYC the level and of iNOS nitric [ 70]. Theoxide anti-metastatic and inflammation-related effects of peach cytokines polyphenolics and genes, were including investigated NF-κB, iCAM, using c-MYC a xenograft and iNOS model [70]. with MDA-MB-435The anti-metastatic breast cancer effects cellsof peachin vivo polyphenolics. Mice received were peach investigated phenolics using (0.2- a xenograft to 1.6-mg modelchlorogenic with acid equivalentMDA-MB-435(CAE)/day) breast by cancer oral gavage.cells in vivo. The resultsMice received showed peach that lung phenolics metastases (0.2- to were 1.6-mg inhibited chlorogenic through inhibitionacid equivalent of MMPs (CAE)/day) gene expression by oral gavage. [66]. In The addition, results the show specificed that phenolic lung metastases compounds were derived inhibited from peachesthrough and inhibition plums haveof MMPs been gene demonstrated expression [66]. to suppressIn addition, tumor the specific growth phenolic and metastasis compounds in derived xenograft modelsfrom [peaches114]. Using and plums a xenograft have been model demonstrated in which to suppress MDA-MB-435 tumor growth was cultured and metastasis with peachin xenograft phenolics (1.6-mgmodels CAE/day), [114]. Using which a xenograft equates model to the in which equivalent MDA-MB-435 human was intake cultured of two with to threepeach phenolics peaches (1.6-mg every day, peachCAE/day), phenolics which were equates able to to inhibit the equivalent gene expression human in oftake MMP-2, of two MMP-13 to three andpeaches MMP-3 every [66 day,]. Artichokes peach decreasedphenolics the were proteolytic able to inhibit activity gene ofexpression MMP-2, of which MMP-2, is MMP-13 involved and in MMP-3 degrading [66]. Artichokes the components decreased of the ECMthe [ 67proteolytic]. activity of MMP-2, which is involved in degrading the components of the ECM [67].

FigureFigure 4. 4. Model for for the the molecular molecular metchanisms metchanisms of natural of polyphenols natural polyphenols effects on metastasis. effects on(A) General metastasis. (A)schematic General representation schematic representation of signalling pathway of signalling that regulate pathway MMP-2 that and regulate MMP-9 MMP-2 expression, and VEGF MMP-9 expression,gene and VEGFNF-κB; gene(B) The and proteins NF-κB; that (B promote) The proteins cell-cell that cont promoteact and mesenchymal cell-cell contact markers and during mesenchymal EMT. markers during EMT. In summary, an increasing amount of research has been dedicated to identifying potential mechanisms underlying the suppression of breast cancer metastasis by natural polyphenols. Proposed molecular mechanisms include down-regulation of MMPs expression, modulation of EMT regulators, Molecules 2016, 21, 1634 18 of 27

In summary, an increasing amount of research has been dedicated to identifying potential mechanisms underlying the suppression of breast cancer metastasis by natural polyphenols. Proposed molecular mechanisms include down-regulation of MMPs expression, modulation of EMT regulators, interfering with VEGF signaling, inhibition of NF-κB and mTOR expression, and other possible mechanisms (as shown in Figure4). In addition, many researchers have described the biological phenomenon of metastasis and its mechanism of action. The complexity of natural polyphenol extract is well known, so further exploring the effects of natural polyphenol metabolism in the context of cancer is the foundation of continued molecular mechanism studies.

4. Metabolomics Metabolomics is a powerful technology in pharmaceutical and clinical research that describes the similarities and differences between biological samples by profiling and comparing the metabolite panel in an organism, resulting in the development of personalized methods for patient monitoring, treatment response evaluation, and disease diagnosis [115]. Natural polyphenols are transformed into a variety of diverse metabolites in the body [116], some of which are still unidentified [117]. Metabolomics provides an effective method to simultaneously detect hundreds of natural polyphenols or their metabolites in a global way. Metabolomics results have been utilized for analyzing the molecular mechanism of diseases, such as malignant tumors [118], and to classify food and plant species [119] in recent decades. High-throughput analytical methods such as NMR spectroscopy, liquid chromatography-quadrupole time-of-flight (LC-QTOF) [120] or MS allow simultaneous analysis of hundreds of metabolites forming the metabolome from urine or plasma [121]. Table2 showes the modifications of endogenous metabolites derived from natural polyphenols intake.

Table 2. Catechin intake resulting in endogenous metabolite modiﬁcations.

Analytical- Modified Endogenous Biological Intervention Subjects (Samples) Ref. Technique Metabolites Hypotheses Animal study: normolipidemic Possible inhibition of microbiota growth by (5% w/w) or ↑ Pipecolinic acid catechin. Chronic hyperlipidemic ↑ Nicotinic acid Male Wistar rats (urine) LC-QTOF liver dysfunction or [120] (15 and 25%) diets with ↑ Dihydroxyquinoline peroxisomal disorders or without catechin ↑ Deoxycytidine supplementation and increase in DNA (0.2% w/w). breakdown. ↓ Taurine Modification in Animal study: 220–270 g male ↓ Creatinine carbohydrate a single dose Sprague-Dawley (SD) 1H-NMR ↓ Dimethylamine metabolism; Changes [122] of 22 mg of epicatechin rats (urine) ↓ 2-Oxoglutarate in liver and kidney ↓ Citrate. functions. Human study: Consumption of green ↑ Stimulation of 17 nonsmoking male Succinate tea (6 g/day), black tea 1H-NMR ↑ Oxaloacetate oxidative energy [123] (urine and plasma) (6 g/day) or caffeine ↑ 2-oxoglutarate metabolism (control) for 2 days ↑ Caffeine ↑ Taurine Human study: ↑ 3,4-Dihydroxyphenyle a single dose (acute) of thylene glycol GTE or placebo (PLA) (age 22 ± 5 year, ↓ Hippurate Influencing the and following 1 day, weight 78 ± 10.6 kg) changes in lipid HPLC-MRM-MS ↑Salicylate [124] 7 days, GTE (2 × 559 mg 39 healthy physically ↑ Fatty acids metabolism and catechins/day, 120 mg vascular function. active male (plasma) ↑ Serotonin caffeine/day), or PLA ↑ Triglycerides supplementation ↓ Cholesterylesters and ↑ Sphingosines ↑ ornithine Human study : Range 22–32 years ↑ valine ↑ tyrosine a dose equivalent to UPLC-QTOFMS healthy men and and ↑ 2-methylguanosine 5 cups of commercially Pu-erh tea metabolites [125] women (urine) GC-TOFMS ↑ 2-aminobutyric acid prepared tea. ↓ urea Promoting vascular Human study: ↑ Nitric oxide endothelial function, MIX and the GJX ↑ Phenylacetylglutamine indicator of gut supplements was (Age: 18–70 years) 1 ↑ 4-hydroxymandelic acid microbiota-mediated H-NMR [126] 800 mg gallic acid 33 men and 25 women GC-MS ↑ Vanillylmandelic acid degradation, equivalents (GAEs) per ↑ Homovanillic acid benefiting the day for 4 weeks. Urine:↑ Hippuric acid neurological or cardiovascular health. Molecules 2016, 21, 1634 19 of 27

4.1. Natural Polyphenols Previous studies have used various metabolomic approaches to explore the changes in metabolic profiles induced by hyperlipidemic diets. A relatively high urine excretion of deoxycytidine nucleosides has been closely linked to a higher risk for immune deficiency syndrome and cancer [127]. An improvement of deoxycytidine excretion in urine achieved with high-fat diets might result from an increase in DNA breakdown or a higher production of deoxycytidine by enteric bacteria [128]. Peroxisomal or chronic liver dysfunction disorders [129] result in high urinary content of pipecolinic acid [130]. Similarly, the origin of the variations in the urinary excretion of dihydroxyquinoline and nicotinic acid observed following high-fat diets. After catechin supplementation, the excretion of the compounds mentioned above returned to the level observed in rats fed with the low-fat diet [120]. Inspection of the principal component (PC) loadings followed by subsequent examinition of the corresponding urinary 1H-NMR spectra enabled identification of the endogenous metabolites induced from exposure to EC, and the levels were perturbed. The spectral descriptors most affected by EC dosing were found to correspond to a reduction in the urinary concentrations of 2-oxoglutarate, citrate, dimethylamine, creatinine, and taurine [122]. This metabolite could be impacting the effects of dietary natural polyphenols on liver and kidney function and could reflect a shift in energy metabolism from carbohydrate metabolism to lipid or amino acid metabolism [131].

4.2. Polyphenolic Extracts Natural polyphenols constitute 10%–12% of the dry weight of green and black tea leaves and black and green tea consumption have different effects on human metabolism. The consumption of green tea indicated that green tea polyphenols may be affecting oxidative energy metabolism or biosynthetic pathways. Black tea increased levels of ketone body β-hydroxybutyrate in urinary excretion, suggesting impacts on fatty acid oxidation and liver ketogenesis [123]. It has been shown that green tea can protect against the advancement of a series of chronic diseases [132]. In particular, studies have focused a great deal on the prevention of cancer [133] and cancer metastasis [134]. The pharmacokinetics and bioavailability of green tea extract (GTE) catechins following a single bolus dose intake may induce significant acute impacts on multiple endogenous metabolites. This differs from the metabolite changes observed after one-week of continued supplementation. Long-term GTE supplementation is necessary to achieve regulation of various enzymes and proteins at certain sites in the body, leading to systemic shifts in levels of the endogenous metabolites, while acute metabolic effects may suffer from different mechanisms, while acute metabolic events may be occurring by distinct mechanisms. The acute effects on the phosphatidylcholines and cholesterylesters may point to changes in lipid metabolism. Other changes, for instance in sertonine, sphingosines and salicylic acid may be correlated with vascular function [124]. Pu-erh tea, a fermented tea including large quantities of polyphenolic constituents [135], has been shown to exert preventive and anti-metastatic effects on oral cancer and on buccal mucosa cancer [136]. Valuable and complementary information on Pu-erh tea degradation was provided by the combined UPLC-QTOFMS and GC-TOFMS based metabolomics technology. One of the tea metabolites, caffeines, was positively correlated with its biodegradated metabolites paraxanthine, paraxanthine, Theophylline was positively corrected with valine, tyrosine, ornithine, and 2-methylguanosine, whereas theophylline was positively corrected with 2-methylguanosine but negatively corrected with aminomalonic acid and urea [125]. Understanding the metabolic characteristics of Pu-erh tea may accelerate the development of its pharmacological properties in preclinical studies. Using a metabolomics technology to explore the metabolic effect of polyphenol-rich red wine and grape juice (MIX) consumption in humans, gas chromatographymass spectrometry (GC-MS) was used for focused profiling of urinary phenolic acids, while 1H-NMR spectroscopy was used for global metabolite analysis. After a 4-week intake of the MIX, hippuric acid, an index of gut microbiota-mediated degradation of dietary natural polyphenols, increased significantly in urine samples. Noticeablely, 3-methoxy-4-hydroxymandelic acid, phenylacetylglutamine and 4-hydroxymandelic acid production results from the modulation of endogenous biological pathways, Molecules 2016, 21, 1634 20 of 27 not metabolites of dietary natural polyphenols [126]. Overall, MIX polyphenols seem to have a slight effect on endogenous metabolism, most obviously in several amino acid derivatives containing bacterial metabolites of tryptophan and tyrosine. These results demonstrate that short-term intake of MIX or their metabolites leads to altered microbial amino acid metabolism and microbial protein fermentation [137].

5. Conclusions and Future Perspectives Natural polyphenols plays a signiﬁcant role in the prevention of breast cancer. Many studies have shown the capabilities of natural polyphenols to suppress breast cancer cell migration and invasion and to inhibit metastasis formation both in vitro and in vivo. More and more research is devoted to studying the potential mechanisms of breast cancer metastasis from the cascades of breast cancer metastasis. These molecular and cellular mechanisms include down-regulation of MMPs expression, interference with the VEGF signaling, modulation of EMT regulators, inhibition of NF-κB and mTOR expression, and other creditabe mechanisms. Breast cancer distant metastases rank ﬁrst among causes of cancer-related deaths, and the incidence of brain metastases continues to increase with current estimates in the U.S. [138]. Unfortunately, clinical trials aimed at treating brain metastases using traditional breast cancer drugs have produced little success [139,140], likely due in part to the blood-brain barrier (BBB) and the blood-cancer barrier (BTB), which establish a protective environment for metastatic growth, preventing the absorption of chemotherapy drugs. Thus, more work should be done to explore the effect of natural polyphenols on breast cancer brain metastasis, looking at the advantages of molecular diversity, which can increase CNS penetration. Of course, natural polyphenols are unlikely to be anticancer agents when used individually; however, their use as an adjuvant to chemtherapy drugs may help impede the progression of breast cancer metastasis.

Acknowledgments: This work was supported by the China National Science Foundation (81173139), the Major Research Plan of NSFC (21233003) and Asia-Pacific Cancer Research Foundation. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Sang, S.; Lambert, J.D.; Ho, C.T.; Yang, C.S. The chemistry and biotransformation of tea constituents. Pharmacol. Res. 2011, 64, 87–99. [CrossRef][PubMed] 2. Manach, C.; Scalbert, A.; Morand, C.; Rémésy, C.; Jiménez, L. Polyphenols: Food sources and bioavailability. Am. J. Clin. Nutr. 2004, 79, 727–747. [PubMed] 3. Lall, R.K.; Syed, D.N.; Adhami, V.M.; Khan, M.I.; Mukhtar, H. Dietary polyphenols in prevention and treatment of prostate cancer. Int. J. Mol. Sci. 2015, 16, 3350–3376. [CrossRef][PubMed] 4. Harbowy, M.E.; Balentine, D.A.; Dr., Davies, A.P.; Dr., Cai, Y. Critical reviews in plant sciences. Tea Chem. 1997, 16, 415–480. 5. Chacko, S.M.; Thambi, P.T.; Kuttan, R.; Nishigaki, I. Beneﬁcial effects of green tea: A literature review. Chin. Med. 2010, 5, 13. [CrossRef][PubMed] 6. Carocho, M.; Ferreira, I.C. A review on antioxidants, prooxidants and related controversy: Natural and synthetic compounds, screening and analysis methodologies and future perspectives. Food Chem. Toxicol. 2013, 51, 15–25. [CrossRef][PubMed] 7. Link, A.; Balaguer, F.; Goel, A. Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics. Biochem. Pharmacol. 2010, 80, 1771–1792. [CrossRef][PubMed] 8. Zhou, Q.; Bennett, L.L.; Zhou, S. Multifaceted ability of naturally occurring polyphenols against metastatic cancer. Clin. Exp. Pharmacol. Physiol. 2016, 43, 394–409. [CrossRef][PubMed] 9. Tevaarwerk, A.J.; Gray, R.J.; Schneider, B.P.; Smith, M.L.; Wagner, L.I.; Fetting, J.H.; Davidson, N.; Goldstein, L.J.; Miller, K.D.; Sparano, J.A. Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy. Cancer 2013, 119, 1140–1148. [CrossRef][PubMed] 10. American Cancer Society. Cancer Facts and Figures 2015; American Cancer Society: Atlanta, GA, USA, 2015. Molecules 2016, 21, 1634 21 of 27

11. Massagué, J.; Obenauf, A.C. Metastatic colonization by circulating tumour cells. Nature 2016, 529, 298–306. [CrossRef][PubMed] 12. Kodack, D.; Askoxylakis, V.; Ferraro, G.; Dai, F.; Jain, R. Emerging strategies for treating brain metastases from breast cancer. Cancer Cell 2015, 27, 163–175. [CrossRef][PubMed] 13. Hess, K.R.; Varadhachary, G.R.; Taylor, S.H.; Wei, W.; Raber, M.N.; Lenzi, R.; Abbruzzese, J.L. Metastatic patterns in adenocarcinoma? Cancer 2006, 106, 1624–1633. [CrossRef][PubMed] 14. Bos, P.D.; Zhang, H.F.; Nadal, C.; Shu, W.; Gomis, R.R.; Nguyen, D.X.; Minn, A.J.; Vijver, M.J.V.D.; Gerald, W.L.; Foekens, J.A. Genes that mediate breast cancer metastasis to the brain. Nature 2009, 459, 1005–1009. [CrossRef][PubMed] 15. Wishart, D.S. Emerging applications of metabolomics in drug discovery and precision medicine. Nat. Rev. Drug Discov. 2016, 15, 484. [CrossRef][PubMed] 16. Delmas, D.; Xiao, J.B. Natural polyphenols properties: Chemopreventive and chemosensitizing activities. Anticancer Agents Med. Chem. 2012, 12, 835. [CrossRef][PubMed] 17. Steeg, P.S.; Theodorescu, D. Metastasis: A therapeutic target for cancer. Nat. Clin. Pract. Oncol. 2008, 5, 206–219. [CrossRef][PubMed] 18. Jiang, Y.L.; Liu, Z.P. Natural products as anti-invasive and anti-metastatic agents. Curr. Med. Chem. 2011, 18, 808–829. [CrossRef][PubMed] 19. Loffek, S.; Schilling, O.; Franzke, C.W. Biological role of matrix metalloproteinases: A critical balance. Eur. Respir. J. 2011, 38, 191–208. [CrossRef][PubMed] 20. Zitka, O.; Kukacka, J.; Krizkova, S.; Huska, D.; Adam, V.; Masarik, M.; Prusa, R.; Kizek, R. Matrix metalloproteinases. Curr. Med. Chem. 2010, 17, 3751–3768. [CrossRef][PubMed] 21. Gialeli, C.; Theocharis, A.D.; Karamanos, N.K. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011, 278, 16–27. [CrossRef][PubMed] 22. Ling, H.; Yang, H.; Tan, S.H.; Chui, W.K.; Chew, E.H. 6-Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase-9 expression via blockade of nuclear factor-kappa b activation. Br. J. Pharmacol. 2010, 161, 1763–1777. [CrossRef][PubMed] 23. Ibaragi, S.; Shimo, T.; Iwamoto, M.; Hassan, N.M.M.; Kodama, S.; Isowa, S.; Sasaki, A. Parathyroid hormone-related peptide regulates matrix metalloproteinase-13 gene expression in bone metastatic breast cancer cells. Anticancer Res. 2012, 30, 5029–5036. 24. Bahar, M.; Khaghani, S.; Pasalar, P.; Paknejad, M.; Khorramizadeh, M.R.; Mirmiranpour, H.; Nejad, S.G. Exogenous coenzyme q10 modulates MMP-2 activity in MCF-7 cell line as a breast cancer cellular model. Nutr. J. 2010, 9, 2131–2132. [CrossRef][PubMed] 25. Mylona, E.; Magkou, C.; Giannopoulou, I.; Agrogiannis, G.; Markaki, S.; Keramopoulos, A.; Nakopoulou, L. Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: Relation to tumor phenotype and clinical outcome. Breast Cancer Res. 2006, 8, 1–8. [CrossRef][PubMed] 26. Deb, G.; Thakur, V.S.; Limaye, A.M.; Gupta, S. Epigenetic induction of tissue inhibitor of matrix metalloproteinase-3 by green tea polyphenols in breast cancer cells. Mol. Carcinog. 2015, 54, 485–499. [CrossRef][PubMed] 27. Hassan, Z.K.; Elamin, M.H.; Daghestani, M.H.; Omer, S.A.; Al-Olayan, E.M.; Elobeid, M.A.; Virk, P.; Mohammed, O.B. Oleuropein induces anti-metastatic effects in breast cancer. Asian Pac. J. Cancer Prev. 2012, 13, 4555–4559. [CrossRef][PubMed] 28. Song, H.; Jung, J.I.; Cho, H.J.; Her, S.; Kwon, S.H.; Yu, R.; Kang, Y.H.; Lee, K.W.; Park, J.H. Inhibition of tumor progression by oral piceatannol in mouse 4T1 mammary cancer is associated with decreased angiogenesis and macrophage inﬁltration. J. Nutr. Biochem. 2015, 26, 1368–1378. [CrossRef][PubMed] 29. Lewandowska, U.; Szewczyk, K.; Owczarek, K.; Hrabec, Z.; Podsedek, A.; Koziolkiewicz, M.; Hrabec, E. Flavanols from japanese quince (Chaenomeles japonica) fruit inhibit human prostate and breast cancer cell line invasiveness and cause favorable changes in Bax/Bcl-2 mRNA ratio. Nutr. Cancer 2013, 65, 273–285. [CrossRef][PubMed] 30. Kushima, Y.; Iida, K.; Nagaoka, Y.; Kawaratani, Y.; Shirahama, T.; Sakaguchi, M.; Baba, K.; Hara, Y.; Uesato, S. Inhibitory effect of (−)-epigallocatechin and (−)-epigallocatechin gallate against heregulin beta 1-induced migration/invasion of the MCF-7 breast carcinoma cell line. Biol. Pharm. Bull. 2009, 32, 899–904. [CrossRef] [PubMed] Molecules 2016, 21, 1634 22 of 27

31. Belguise, K.; Guo, S.; Sonenshein, G.E. Activation of FOXO3a by the green tea polyphenol epigallocatechin-3-gallate induces estrogen receptor alpha expression reversing invasive phenotype of breast cancer cells. Cancer Res. 2007, 67, 5763–5770. [CrossRef][PubMed] 32. Mineva, N.D.; Paulson, K.E.; Naber, S.P.; Yee, A.S.; Sonenshein, G.E. Epigallocatechin-3-gallate inhibits stem-like inﬂammatory breast cancer cells. PLoS ONE 2013, 8, e73464. [CrossRef][PubMed] 33. Thangapazham, R.L.; Passi, N.; Maheshwari, R.K. Green tea polyphenol and epigallocatechin gallate induce apoptosis and inhibit invasion in human breast cancer cells. Cancer Biol. Ther. 2014, 6, 1938–1943. [CrossRef] 34. Gunther, S.; Ruhe, C.; Derikito, M.G.; Bose, G.; Sauer, H.; Wartenberg, M. Polyphenols prevent cell shedding from mouse mammary cancer spheroids and inhibit cancer cell invasion in confrontation cultures derived from embryonic stem cells. Cancer Lett. 2007, 250, 25–35. [CrossRef][PubMed] 35. Li, C.; Zhao, Y.; Yang, D.; Yu, Y.; Guo, H.; Zhao, Z.; Zhang, B.; Yin, X. Inhibitory effects of kaempferol on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. Biochem. Cell. Biol. 2015, 93, 16–27. [CrossRef][PubMed] 36. Rivera Rivera, A.; Castillo-Pichardo, L.; Gerena, Y.; Dharmawardhane, S. Anti-breast cancer potential of quercetin via the Akt/AMPK/mammalian target of rapamycin (mTOR) signaling cascade. PLoS ONE 2016, 11, e0157251. [CrossRef][PubMed] 37. Sun, Y.; Lu, N.; Ling, Y.; Gao, Y.; Chen, Y.; Wang, L.; Hu, R.; Qi, Q.; Liu, W.; Yang, Y.; et al. Oroxylin a suppresses invasion through down-regulating the expression of matrix metalloproteinase-2/9 in MDA-MB-435 human breast cancer cells. Eur. J. Pharmacol. 2009, 603, 22–28. [CrossRef][PubMed] 38. Wang, L.; Ling, Y.; Chen, Y.; Li, C.L.; Feng, F.; You, Q.D.; Lu, N.; Guo, Q.L. Flavonoid baicalein suppresses adhesion, migration and invasion of MDA-MB-231 human breast cancer cells. Cancer Lett. 2010, 297, 42–48. [CrossRef][PubMed] 39. Vantyghem, S.A.; Wilson, S.M.; Postenka, C.O.; Al-Katib, W.; Tuck, A.B.; Chambers, A.F. Dietary genistein reduces metastasis in a postsurgical orthotopic breast cancer model. Cancer Res. 2005, 65, 3396–3403. [PubMed] 40. Lee, H.S.; Ha, A.W.; Kim, W.K. Effect of resveratrol on the metastasis of 4T1 mouse breast cancer cells in vitro and in vivo. Nutr. Res. Pract. 2012, 6, 294–300. [CrossRef][PubMed] 41. Tang, F.Y.; Chiang, E.P.; Sun, Y.C. Resveratrol inhibits heregulin-β1-mediated matrix metalloproteinase-9 expression and cell invasion in human breast cancer cells. J. Nutr. Biochem. 2008, 19, 287–294. [CrossRef] [PubMed] 42. Tang, F.Y.; Su, Y.C.; Chen, N.C.; Hsieh, H.S.; Chen, K.S. Resveratrol inhibits migration and invasion of human breast-cancer cells. Mol. Nutr. Food Res. 2008, 52, 683–691. [CrossRef][PubMed] 43. Lee-Chang, C.; Bodogai, M.; Martin-Montalvo, A.; Wejksza, K.; Sanghvi, M.; Moaddel, R.; de Cabo, R.; Biragyn, A. Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory b cells. J. Immunol. 2013, 191, 4141–4151. [CrossRef][PubMed] 44. Castillo-Pichardo, L.; Cubano, L.A.; Dharmawardhane, S. Dietary grape polyphenol resveratrol increases mammary tumor growth and metastasis in immunocompromised mice. BMC Complement. Altern. Med. 2013, 13, 1–10. [CrossRef][PubMed] 45. Chua, A.W.; Hay, H.S.; Rajendran, P.; Shanmugam, M.K.; Li, F.; Bist, P.; Koay, E.S.; Lim, L.H.; Kumar, A.P.; Sethi, G. Butein downregulates chemokine receptor CXCR4 expression and function through suppression of NF-κb activation in breast and pancreatic tumor cells. Biochem. Pharmacol. 2010, 80, 1553–1562. [CrossRef] [PubMed] 46. Viola, K.; Kopf, S.; Rarova, L.; Jarukamjorn, K.; Kretschy, N.; Teichmann, M.; Vonach, C.; Atanasov, A.G.; Giessrigl, B.; Huttary, N.; et al. Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis. Arch. Toxicol. 2013, 87, 1301–1312. [CrossRef][PubMed] 47. Kim, J.M.; Noh, E.M.; Kwon, K.B.; Kim, J.S.; You, Y.O.; Hwang, J.K.; Hwang, B.M.; Kim, B.S.; Lee, S.H.; Lee, S.J.; et al. Curcumin suppresses the TPA-induced invasion through inhibition of PKCα-dependent MMP-expression in MCF-7 human breast cancer cells. Phytomedicine 2012, 19, 1085–1092. [CrossRef] [PubMed] 48. Farhangi, B.; Alizadeh, A.M.; Khodayari, H.; Khodayari, S.; Dehghan, M.J.; Khori, V.; Heidarzadeh, A.; Khaniki, M.; Sadeghiezadeh, M.; Najaﬁ, F. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor. Eur. J. Pharmacol. 2015, 758, 188–196. [CrossRef][PubMed] Molecules 2016, 21, 1634 23 of 27

49. Kronski, E.; Fiori, M.E.; Barbieri, O.; Astigiano, S.; Mirisola, V.; Killian, P.H.; Bruno, A.; Pagani, A.; Rovera, F.; Pfeffer, U.; et al. miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down-regulation of the inflammatory cytokines CXCL1 and -2. Mol. Oncol. 2014, 8, 581–595. [CrossRef][PubMed] 50. Bachmeier, B.; Nerlich, A.G.; Iancu, C.M.; Cilli, M.; Schleicher, E.; Vené, R.; Dell'Eva, R.; Jochum, M.; Albini, A.; Pfeffer, U. The chemopreventive polyphenol curcumin prevents hematogenous breast cancer metastases in immunodeficient mice. Cell. Physiol. Biochem. 2007, 19, 137–152. [CrossRef][PubMed] 51. Gallardo, M.; Calaf, G.M. Curcumin inhibits invasive capabilities through epithelial mesenchymal transition in breast cancer cell lines. Int. J. Oncol. 2016, 49, 1019–1027. [CrossRef][PubMed] 52. Yodkeeree, S.; Ampasavate, C.; Sung, B.; Aggarwal, B.B.; Limtrakul, P. Demethoxycurcumin suppresses migration and invasion of MDA-MB-231 human breast cancer cell line. Eur. J. Pharmacol. 2009, 627, 8–15. [CrossRef][PubMed] 53. Sepporta, M.V.; Fuccelli, R.; Rosignoli, P.; Ricci, G.; Servili, M.; Morozzi, G.; Fabiani, R. Oleuropein inhibits tumour growth and metastases dissemination in ovariectomised nude mice with MCF-7 human breast tumour xenografts. J. Funct. Foods 2014, 8, 269–273. [CrossRef] 54. Zheng, X.; Ke, Y.; Feng, A.; Yuan, P.; Zhou, J.; Yu, Y.; Wang, X.; Feng, W. The mechanism by which amentoflavone improves insulin resistance in HepG2 cells. Molecules 2016, 21.[CrossRef][PubMed] 55. Mu, J.; Ning, S.; Wang, X.; Si, L.; Jiang, F.; Li, Y.; Li, Z. The repressive effect of miR-520a on NF-κB/IL-6/STAT-3 signal involved in the glabridin-induced anti-angiogenesis in human breast cancer cells. RSC Adv. 2015, 5, 34257–34264. [CrossRef] 56. Shibata, M.A.; Akao, Y.; Shibata, E.; Nozawa, Y.; Ito, T.; Mishima, S.; Morimoto, J.; Otsuki, Y. Vaticanol C, a novel resveratrol tetramer, reduces lymph node and lung metastases of mouse mammary carcinoma carrying p53 mutation. Cancer Chemother. Pharmacol. 2007, 60, 681–691. [CrossRef][PubMed] 57. Xiong, X.Y.; Hu, X.J.; Li, Y.; Liu, C.M. Inhibitory effects of enterolactone on growth and metastasis in human breast cancer. Nutr. Cancer 2015, 67, 1324–1332. [CrossRef][PubMed] 58. Liu, L.; Sun, L.; Wu, Q.; Guo, W.; Li, L.; Chen, Y.; Li, Y.; Gong, C.; Qian, Z.; Wei, Y. Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis. Int. J. Pharm. 2013, 443, 175–182. [CrossRef][PubMed] 59. Castillo-Pichardo, L.; Dharmawardhane, S.F. Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer. Nutr. Cancer 2012, 64, 1058–1069. [CrossRef] [PubMed] 60. Castillo-Pichardo, L.; Martinez-Montemayor, M.M.; Martinez, J.E.; Wall, K.M.; Cubano, L.A.; Dharmawardhane, S. Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols. Clin. Exp. Metastasis 2009, 26, 505–516. [CrossRef][PubMed] 61. Luo, K.W.; Ko, C.H.; Yue, G.G.; Lee, J.K.; Li, K.K.; Lee, M.; Li, G.; Fung, K.P.; Leung, P.C.; Lau, C.B. Green tea (Camellia sinensis) extract inhibits both the metastasis and osteolytic components of mammary cancer 4T1 lesions in mice. J. Nutr. Biochem. 2014, 25, 395–403. [CrossRef][PubMed] 62. Baliga, M.S.; Meleth, S.; Kadiyar, S.K. Growth inhibitory and antimetastatic effect of green tea polyphenols on metastasis-specific mouse mammary carcinoma 4T1 cells in vitro and in vivo systems. Clin. Cancer Res. 2005, 11, 1918–1927. [CrossRef][PubMed] 63. Yang, X.; Belosay, A.; Hartman, J.A.; Song, H.; Zhang, Y.; Wang, W.; Doerge, D.R.; Helferich, W.G. Dietary soy isoflavones increase metastasis to lungs in an experimental model of breast cancer with bone micro-tumors. Clin. Exp. Metastasis 2015, 32, 323–333. [CrossRef][PubMed] 64. Chang, C.H.; Ou, T.T.; Yang, M.Y.; Huang, C.C.; Wang, C.J. Nelumbo nucifera gaertn leaves extract inhibits the angiogenesis and metastasis of breast cancer cells by downregulation connective tissue growth factor (CTGF) mediated PI3K/AKT/ERK signaling. J. Ethnopharmacol. 2016, 188, 111–122. [CrossRef][PubMed] 65. Manoj, G.S.; Kumar, T.R.S.; Varghese, S.; Murugan, K. Effect of methanolic and water extract of Leucobryum bowringii Mitt. On growth, migration and invasion of MCF 7 human breast cancer cells in vitro. Ind. J. Exp. Biol. 2012, 50, 602–611. 66. Noratto, G.; Porter, W.; Byrne, D.; Cisneros-Zevallos, L. Polyphenolics from peach (Prunus persica var. Rich lady) inhibit tumor growth and metastasis of MDA-MB-435 breast cancer cells in vivo. J. Nutr. Biochem. 2014, 25, 796–800. [CrossRef][PubMed] Molecules 2016, 21, 1634 24 of 27

67. Mileo, A.M.; di Venere, D.; Linsalata, V.; Fraioli, R.; Miccadei, S. Artichoke polyphenols induce apoptosis and decrease the invasive potential of the human breast cancer cell line MDA-MB231. J. Cell Physiol. 2012, 227, 3301–3309. [CrossRef][PubMed] 68. Sun, T.; Chen, Q.Y.; Wu, L.J.; Yao, X.M.; Sun, X.J. Antitumor and antimetastatic activities of grape skin polyphenols in a murine model of breast cancer. Food Chem. Toxicol. 2012, 50, 3462–3467. [CrossRef] [PubMed] 69. Lewandowska, U.; Szewczyk, K.; Owczarek, K.; Hrabec, Z.; Podsedek, A.; Sosnowska, D.; Hrabec, E. Procyanidins from evening primrose (Oenothera paradoxa) defatted seeds inhibit invasiveness of breast cancer cells and modulate the expression of selected genes involved in angiogenesis, metastasis, and apoptosis. Nutr. Cancer 2013, 65, 1219–1231. [CrossRef][PubMed] 70. Yeap, S.K.; Abu, N.; Mohamad, N.E.; Beh, B.K.; Ho, W.Y.; Ebrahimi, S.; Yusof, H.M.; Ky, H.; Tan, S.W.; Alitheen, N.B. Chemopreventive and immunomodulatory effects of Murraya koenigii aqueous extract on 4T1 breast cancer cell-challenged mice. BMC Complement. Altern. Med. 2015, 15, 306. [CrossRef][PubMed] 71. Mantena, S.K.; Baliga, M.S.; Katiyar, S.K. Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells. Carcinogenesis 2006, 27, 1682–1691. [CrossRef] [PubMed] 72. Vuong, T.; Mallet, J.F.; Ouzounova, M.; Rahbar, S.; Hernandez-Vargas, H.; Herceg, Z.; Matar, C. Role of a polyphenol-enriched preparation on chemoprevention of mammary carcinoma through cancer stem cells and inflammatory pathways modulation. J. Transl. Med. 2016, 14, 13. [CrossRef][PubMed] 73. Ko, Y.S.; Lee, W.S.; Panchanathan, R.; Joo, Y.N.; Choi, Y.H.; Kim, G.S.; Jung, J.M.; Ryu, C.H.; Shin, S.C.; Kim, H.J. Polyphenols from artemisia annua l inhibit adhesion and emt of highly metastatic breast cancer cells MDA-MB-231. Phytother. Res. 2016, 30, 1180–1188. [CrossRef][PubMed] 74. Dihlmann, S.; Kloor, M.; Fallsehr, C.; Doeberitz, M.V.K. Regulation of AKT1 expression by β-catenin/Tcf/Lef signaling in colorectal cancer cells. Carcinogenesis 2005, 26, 1503–1512. [CrossRef][PubMed] 75. So, F.V.; Guthrie, N.; Chambers, A.F.; Carroll, K.K. Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen. Cancer Lett. 1997, 112, 127–133. [CrossRef] 76. Bork, P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett. 1993, 327, 125–130. [CrossRef] 77. Chang, C.C.; Shih, J.Y.; Jeng, Y.M.; Su, J.L.; Lin, B.Z.; Chen, S.T.; Chau, Y.P.; Yang, P.C.; Kuo, M.L. Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis. J. Natl. Cancer Inst. 2004, 96, 364–375. [CrossRef][PubMed] 78. Lin, B.R. Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer. Gastroenterology 2005, 128, 9–23. [CrossRef][PubMed] 79. Lin, M.C.; Kao, S.H.; Chung, P.J.; Chan, K.C.; Yang, M.Y.; Wang, C.J. Improvement for high fat diet-induced hepatic injuries and oxidative stress by flavonoid-enriched extract from nelumbo nucifera leaf. J. Agric. Food Chem. 2009, 57, 5825–5932. [CrossRef][PubMed] 80. O’Dea, E.; Hoffmann, A. NF-κb signaling. Wiley Interdiscip. Rev. Syst. Bio. Med. 2009, 1, 107–115. [CrossRef] [PubMed] 81. Huber, M.A.; Azoitei, N.; Baumann, B.; Grünert, S.; Sommer, A.; Pehamberger, H.; Kraut, N.; Beug, H.; Wirth, T.; Huber, M.A.; et al. NF-κb is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Investig. 2004, 114, 569–584. [CrossRef][PubMed] 82. Zunling, L.; Yanxia, G.; Hanming, J.; Tingguo, Z.; Changzhu, J.; Young, C.Y.; Huiqing, Y. Differential regulation of MMPS by E2F1, Sp1 and NF-κb controls the small cell lung cancer invasive phenotype. BMC Cancer 2014, 14, 276. 83. Aggarwal, B.B. Nuclear factor-κB: The enemy within. Cancer Cell 2004, 6, 203–208. [CrossRef][PubMed] 84. Zhang, J.S.; Guan, J.; Yang, F.Q.; Liu, H.G.; Cheng, X.J.; Li, S.P. Qualitative and quantitative analysis of four species of curcuma rhizomes using twice development thin layer chromatography. J. Pharm. Biomed. Anal. 2008, 48, 1024–1028. [CrossRef][PubMed] 85. Fidler, I.J. Angiogenesis and cancer metastasis. Cancer J. 2000, 6 (Suppl. S2), 388–390. 86. Song, M.Q.; Ramaswamy, S.; Ramachandran, S.; Flowers, L.C.; Horowitz, I.R.; Rock, J.A.; Parthasarathy, S. Angiogenic role for glycodelin in tumorigenesis. Proc. Natl. Acad. Sci. USA 2001, 98, 9265–9270. [CrossRef] [PubMed] Molecules 2016, 21, 1634 25 of 27

87. Viale, G.; Regan, M.M.; Mastropasqua, M.G.; Maffini, F.; Maiorano, E.; Colleoni, M.; Price, K.N.; Golouh, R.; Perin, T.; Brown, R.W.; et al. Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J. Natl. Cancer Inst. 2008, 100, 207–212. [CrossRef] [PubMed] 88. Park, E.H.; Park, J.Y.; Yoo, H.S.; Yoo, J.E.; Lee, H.L. Assessment of the anti-metastatic properties of sanguiin H-6 in huvecs and MDA-MB-231 human breast cancer cells. Bioorg. Med. Chem. Lett. 2016, 26, 3291–3294. [CrossRef][PubMed] 89. Li, F.; Zhang, J.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Kumar, A.P.; Ahn, K.S.; Sethi, G. NF-κb in cancer therapy. Arch. Toxicol. 2015, 89, 711–731. [CrossRef][PubMed] 90. Chen, J.H.; Chen, W.L.; Liu, Y.C. Amentoflavone induces anti-angiogenic and anti-metastatic effects through suppression of NF-κb activation in MCF-7 cells. Anticancer Res. 2015, 35, 6685–6693. [PubMed] 91. Pandey, P.; Singh, S.; Tewari, N.; Srinivas, K.V.N.S.; Shukla, A.; Gupta, N.; Vasudev, P.G.; Khan, F.; Pal, A.; Bhakuni, R.S. Hairy root mediated functional derivatization of artemisinin and their bioactivity analysis. J. Mol. Catal. B Enzym. 2015, 113, 95–103. [CrossRef] 92. Shen, L.; Sundstedt, A.; Ciesielski, M.; Miles, K.M.; Celander, M.; Adelaiye, R.; Orillion, A.; Ciamporcero, E.; Ramakrishnan, S.; Ellis, L. Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Cancer Immunol. Res. 2015, 3, 136–148. [CrossRef][PubMed] 93. Sen, R.; Baltimore, D. Inducibility of κ immunoglobulin enhancer-binding protein NF-κb by a posttranslational mechanism. Cell 1987, 47, 921–928. [CrossRef] 94. Cicek, M.; Oursler, M.J. Breast cancer bone metastasis and current small therapeutics. Cancer Metastasis Rev. 2006, 25, 635–644. [CrossRef][PubMed] 95. Karin, M.; Cao, Y.; Greten, F.R.; Li, Z.W. NF-κb in cancer: From innocent bystander to major culprit. Nat. Rev. Cancer 2002, 2, 301–310. [CrossRef][PubMed] 96. Ghosh, S.; Karin, M. Missing pieces in the NF-κb puzzle. Cell 2002, 109, S81–96. [CrossRef] 97. Dhamija, S.; Diederichs, S. From junk to master regulators of invasion: lncRNA functions in migration, EMT and metastasis. Int. J. Cancer 2015, 139, 269–280. [CrossRef][PubMed] 98. Couse, J.; Korach, K. Estrogen receptor null mice: What have we learned and where will they lead us? Endocr. Rev. 1999, 20, 358–417. [CrossRef][PubMed] 99. Wu, X.; Sun, L.; Xiao, W.; Peng, S.; Li, Z.; Zhang, C.; Yan, W.; Peng, G.; Rong, M. Breast cancer invasion and metastasis by mPRα through the PI3K/Akt signaling pathway. Pathol. Oncol. Res. 2016, 22, 1–6. [CrossRef] [PubMed] 100. Tashiro, E.; Henmi, S.; Odake, H.; Ino, S.; Imoto, M. Involvement of the MEK/ERK pathway in egf-induced e-cadherin down-regulation. Biochem. Biophys. Res. Commun. 2016, 477, 801–806. [CrossRef][PubMed] 101. Gallardo, M.; Calaf, G.M. Curcumin and epithelial-mesenchymal transition in breast cancer cells transformed by low doses of radiation and estrogen. Int. J. Oncol. 2016, 48, 2534–2542. [CrossRef][PubMed] 102. Magalhães, P.J.; Carvalho, D.O.; Cruz, J.M.; Guido, L.F.; Barros, A.A. Fundamentals and health benefits of xanthohumol, a natural product derived from hops and beer. Nat. Prod. Commun. 2009, 4, 591–610. [PubMed] 103. Lindstedt, S.; Hansson, J.; Hlebowicz, J. The effect of negative wound pressure therapy on haemodynamics in a laparostomy wound model. Int. Wound J. 2013, 10, 285–290. [CrossRef][PubMed] 104. Zhou, H.; Huang, S. Mtor signaling in cancer cell motility and tumor metastasis. Crit. Rev. Eukaryot. Gene Expr. 2010, 20, 1–16. [CrossRef][PubMed] 105. Walker, E.H.; Pacold, M.E.; Perisic, O.; Stephens, L.; Hawkins, P.T.; Wymann, M.P.; Williams, R.L. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell 2000, 6, 909–919. [CrossRef] 106. Weixel, K.M.; Marciszyn, A.; Alzamora, R.; Li, H.; Fischer, O.; Edinger, R.S.; Hallows, K.R.; Johnson, J.P. Resveratrol inhibits the epithelial sodium channel via phopshoinositides and AMP-activated protein kinase in kidney collecting duct cells. PLoS ONE 1932, 8, e78019. [CrossRef][PubMed] 107. Jagetia, G.C.; Aggarwal, B.B. “Spicing up” Of the immune system by curcumin. J. Clin. Immunol. 2007, 27, 19–35. [CrossRef][PubMed] 108. Safavy, A.; Raisch, K.P.; Mantena, S.; Sanford, L.L.; Sham, S.W.; Krishna, N.R.; Bonner, J.A. Design and development of water-soluble curcumin conjugates as potential anticancer agents. J. Med. Chem. 2007, 50, 6284–6288. [CrossRef][PubMed] Molecules 2016, 21, 1634 26 of 27

109. Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: Problems and promises. Mol. Pharm. 2007, 4, 807–818. [CrossRef][PubMed] 110. Shang, W.; Lu, W.; Han, M.; Qiao, J. The interactions of anticancer agents with tea catechins: Current evidence from preclinical studies. Anticancer Agents Med. Chem. 2014, 14, 1343–1350. [CrossRef][PubMed] 111. Somers-Edgar, T.J.; Scandlyn, M.J.; Stuart, E.C.; Nedelec, M.J.L.; Valentine, S.P.; Rosengren, R.J. The combination of epigallocatechin gallate and curcumin suppresses erα-breast cancer cell growth in vitro and in vivo. Int. J. Cancer 2008, 122, 1966–1971. [CrossRef][PubMed] 112. Luo, T.; Wang, J.; Yin, Y.; Hua, H.; Jing, J.; Sun, X.; Li, M.; Zhang, Y.; Jiang, Y. (−)-epigallocatechin gallate sensitizes breast cancer cells to paclitaxel in a murine model of breast carcinoma. Breast Cancer Res. 2010, 12, 1–10. [CrossRef][PubMed] 113. Kang, H.J.; Lee, S.H.; Price, J.E.; Kim, L.S. Curcumin suppresses the paclitaxel-induced nuclear factor-κb in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model. Breast J. 2009, 15, 223–229. [CrossRef][PubMed] 114. Tomás-Barberán, F.A.; Gil, M.I.; Cremin, P.; Waterhouse, A.L.; Hess-Pierce, B.; Kader, A.A. HPLC-DAD-ESIMS analysis of phenolic compounds in nectarines, peaches, and plums. J. Agric. Food Chem. 2001, 49, 4748–4760. [CrossRef][PubMed] 115. Puchades-Carrasco, L.; Pineda-Lucena, A. Metabolomics in pharmaceutical research and development. Curr. Opin. Biotechnol. 2015, 35, 73–77. [CrossRef][PubMed] 116. Spencer, J.; Abd, E.M.M.; Minihane, A. Metabolism of dietary phytochemicals: A review of the metabolic forms identified in humans. Curr. Top. Nutraceutical. Res. 2006, 4, 187–203. 117. Felgines, C.; Texier, O.; Besson, C.; Lyan, B. Strawberry pelargonidin glycosides are excreted in urine as intact glycosides and glucuronidated pelargonidin derivatives in rats. Br. J. Nutr. 2007, 98, 1126–1131. [CrossRef] [PubMed] 118. Denkert, C.; Budczies, J.; Kind, T.; Weichert, W.; Tablack, P.; Sehouli, J.; Niesporek, S.; Konsgen, D.; Dietel, M.; Fiehn, O. Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors. Cancer Res. 2006, 66, 10795–10804. [CrossRef][PubMed] 119. Yi, L.; Dong, N.; Shao, L.; Yi, Z.; Yi, Z. Chemical features of pericarpium citri reticulatae and pericarpium citri reticulatae viride revealed by GC-MS metabolomics analysis. Food Chem. 2014, 186, 192–199. [CrossRef] [PubMed] 120. Fardet, A.; Llorach, R.; Martin, J.F.; Besson, C.; Lyan, B.; Pujosguillot, E.; Scalbert, A. A liquid chromatography-quadrupole time-of-flight (LC-QTOF)-based metabolomic approach reveals new metabolic effects of catechin in rats fed high-fat diets. J. Proteome Res. 2008, 7, 2388–2398. [CrossRef][PubMed] 121. Kusano, M.; Yang, Z.G.; Okazaki, Y.; Nakabayashi, R.; Fukushima, A.; Saito, K. Using metabolomic approaches to explore chemical diversity in rice. Mol. Plant 2015, 8, 58–67. [CrossRef][PubMed] 122. Solanky, K.S.; Bailey, N.J.; Holmes, E.; Lindon, J.C.; Davis, A.L.; Mulder, T.P.; Van Duynhoven, J.P.; Nicholson, J.K. NMR-based metabonomic studies on the biochemical effects of epicatechin in the rat. J. Agric. Food Chem. 2003, 51, 4139–4145. [CrossRef][PubMed] 123. Van Dorsten, F.A.; Daykin, C.A.; Mulder, T.P.; van Duynhoven, J.P. Metabonomics approach to determine metabolic differences between green tea and black tea consumption. J. Agri. Food Chem. 2006, 54, 6929–6938. [CrossRef][PubMed] 124. Hodgson, A.B.; Randell, R.K.; Mahabir-Jagessar-T, K.; Lotito, S.; Mulder, T.; Mela, D.J.; Jeukendrup, A.E.; Jacobs, D.M. Acute effects of green tea extract intake on exogenous and endogenous metabolites in human plasma. J. Agri. Food Chem. 2014, 62, 1198–1208. [CrossRef][PubMed] 125. Xie, G.; Zhao, A.; Zhao, L.; Chen, T.; Chen, H.; Qi, X.; Zheng, X.; Ni, Y.; Cheng, Y.; Lan, K. Metabolic fate of tea polyphenols in humans. J. Proteome. Res. 2012, 11, 3449–3457. [CrossRef][PubMed] 126. Van Dorsten, F.A.; Grün, C.H.; van Velzen, E.J.J.; Jacobs, D.M.; Draijer, R.; van Duynhoven, J.P.M. The metabolic fate of red wine and grape juice polyphenols in humans assessed by metabolomics. Mol. Nutr. Food Res. 2010, 54, 897–908. [CrossRef][PubMed] 127. Dudley, E.; Lemiere, F.; Dongen, W.V.; Langridge, J.I.; El-Sharkawi, S.; Games, D.E.; Esmans, E.L.; Newton, R.P. Analysis of urinary nucleosides. III. Identification of 50-Deoxycytidine in urine of a patient with head and neck cancer. Rapid Commun. Mass Spectrom. 2003, 17, 1132–1136. [CrossRef][PubMed] 128. Schram, K.H. Urinary nucleosides &dagger. Mass Spectrom. 1998, 17, 131–251. Molecules 2016, 21, 1634 27 of 27

129. Fenyves, D.; Pomier-Layrargues, G.; Willems, B.; Côté, J. Intrahepatic pressure measurement: Not an accurate reﬂection of portal vein pressure. Hepatology 1988, 8, 211–216. [CrossRef][PubMed] 130. Peduto, A.; Baumgartner, M.R.; Verhoeven, N.M.; Rabier, D.; Spada, M.; Nassogne, M.C.; Poll-The, B.T.T.; Bonetti, G.; Jakobs, C.; Saudubray, J.M. Hyperpipecolic acidaemia: A diagnostic tool for peroxisomal disorders. Mol. Genet. Metab. 2004, 82, 224–230. [CrossRef][PubMed] 131. Bollard, M.E.; Holmes, E.; Lindon, J.C.; Mitchell, S.C.; Branstetter, D.; Zhang, W.; Nicholson, J.K. Investigations into biochemical changes due to diurnal variation and estrus cycle in female rats using high-resolution 1 h NMR spectroscopy of urine and pattern recognition. Anal. Biochem. 2001, 295, 194–202. [CrossRef][PubMed] 132. Thielecke, F.; Boschmann, M. The potential role of green tea catechins in the prevention of the metabolic syndrome—A review. Chemlnform 2009, 70, 11–24. [CrossRef][PubMed] 133. Fujiki, H.; Sueoka, E.; Watanabe, T.; Suganuma, M. Synergistic enhancement of anticancer effects on numerous human cancer cell lines treated with the combination of egcg, other green tea catechins, and anticancer compounds. J. Cancer Res. Clin. Oncol. 2015, 141, 1511–1522. [CrossRef][PubMed] 134. Zapf, M.A.C.; Kothari, A.N.; Weber, C.E.; Arffa, M.L.; Wai, P.Y.; Driver, J.; Gupta, G.N.; Kuo, P.C.; Mi, Z.Y. Green tea component epigallocatechin-3-gallate decreases expression of osteopontin via a decrease in mrna half-life in cell lines of metastatic hepatocellular carcinoma. Surgery 2015, 158, 1039–1047. [CrossRef] [PubMed] 135. Wang, D.; Xiao, R.; Hu, X.; Xu, K.; Hou, Y.; Zhong, Y.; Meng, J.; Fan, B.; Liu, L. Comparative safety evaluation of Chinese Pu-erh green tea extract and Pu-erh black tea extract in wistar rats. J. Agric. Food Chem. 2010, 58, 1350–1358. [CrossRef][PubMed] 136. Zhao, X.; Qian, Y.; Zhou, Y.L.; Wang, R.; Wang, Q.; Li, G.J. Pu-erh tea has in vitro anticancer activity in TCA8113 cells and preventive effects on buccal mucosa cancer in U14 cells injected mice in vivo. Nutr. Cancer 2014, 66, 1059–1069. [CrossRef][PubMed] 137. Jacobs, D.M.; Fuhrmann, J.C.; van Dorsten, F.A.; Rein, D.; Peters, S.; van Velzen, E.J.; Hollebrands, B.; Draijer, R.; van, D.J.; Garczarek, U. Impact of short-term intake of red wine and grape polyphenol extract on the human metabolome. J. Agric. Food Chem. 2012, 60, 3078–3085. [CrossRef][PubMed] 138. Johnson, R.H. Incidence of breast cancer with distant involvement among women in the United States, 1976–2009. JAMA 2013, 309, 1229. [CrossRef][PubMed] 139. Lin, N.U.; Carey, L.A.; Liu, M.C.; Younger, J.; Come, S.E.; Ewend, M.; Harris, G.J.; Bullitt, E.; Ad, V.D.A.; Henson, J.W. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 2008, 26, 1993–1999. [CrossRef][PubMed] 140. Ekenel, M.; Hormigo, A.M.; Peak, S.; Deangelis, L.M.; Abrey, L.E. Capecitabine therapy of central nervous system metastases from breast cancer. J. Neurooncol. 2007, 85, 223–227. [CrossRef][PubMed]

© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).