Phyto-polyphenols as potential inhibitors of breast cancer metastasis

Phyto-polyphenols as potential inhibitors of breast cancer metastasis Breast cancer is the most common cancer among women as metastasis is currently the main cause of mortality. Breast cancer cells undergoing metastasis acquire resistance to death signals and increase of cellular motility and invasiveness. Plants are rich in polyphenolic compounds, many of them with known medicinal effects. Various phyto-polyphenols have also been demonstrated to suppress cancer growth. Their mechanism of action is usually pleiotropic as they target multiple signaling pathways regulating key cellular processes such as proliferation, apoptosis and differentiation. Importantly, some phyto- polyphenols show low level of toxicity to untransformed cells, but selective suppressing effects on cancer cells proliferation and differentiation. In this review, we summarize the current information about the mechanism of action of some phyto-polyphenols that have demonstrated anti-carcinogenic activities in vitro and in vivo. Gained knowledge of how these natural polyphenolic compounds work can give us a clue for the development of novel anti-metastatic agents. Keywords: Polyphenols, Breast cancer, Metastasis, Plant products, Resveratrol, EGCG, Kaempferol Background this regard, it is worth studying the mechanism of action Breast cancer is the most common cancer in women, ac- of the natural polyphenols which can give us clues for the counting for nearly 1 in 3 diagnosed cancers or 16% of development of new synthetic therapeutic molecules. all female cancers. The incidence of breast cancer in- In this review, we summarize the main in vitro and in creases with age and is expected to escalate due to the vivo effects of some promising phyto-polyphenols that increase in life expectancy and the adoption of the West- have shown suppressing actions in the initiation and ern lifestyle and rising rates of obesity. In spite of the ad- progression of metastasis in breast cancer. Some of these vances in treatment, metastasis remain the main cause polyphenolic compounds are already in phase I, II, or III of mortality in cancer patients contributing to 90% of clinical trials. deaths from solid tumors (Gupta & Massagué 2006). Natural products are used in traditional medicine over Breast cancer and metastasis the millennia for prevention and treatment of variety of Epidemiology of breast cancer and metastasis maladies, including cancer. Plants are rich in polyphenolic According to the American Cancer Society, the average compounds and many of these compounds have proven age at the time of breast cancer diagnosis is 61 years. Al- beneficial effects in preventing the initiation and develop- though, breast cancer predominates in women, about of ment of metastasis. Natural polyphenols have generally 1% of all cases occur in men. Among the different eth- pleiotropic effects in the cell, activating multiple signaling nicities, breast cancer incidence rates are higher in pathways thus affecting many aspects of cellular fate, in- non-Hispanic Caucasian women compared to African cluding cell apoptosis, proliferation, and differentiation. In American women, but mortality rates are higher among African Americans (32%) compared to non-Hispanic * Correspondence: davtanski@northwell.edu Gerald J. Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Caucasians (24%). The most recent data for American Health, New York, NY 10022, USA women diagnosed with breast cancer demonstrate sur- Division of Endocrinology and Metabolism, Department of Medicine, vival rates of 89, 82, and 77% at 5, 10, and 15 years after Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, 110 E 59th Street, Suite 8B, Room 837, New York, NY 10022, USA diagnosis (American Cancer Society, 2011). © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 2 of 17 Human breast cancer is a heterogenous disease, which they ultimately rely on the blood vessels to find their can be classified into different groups depending on the way to the distant site. presence or absence of estrogen receptor (ER), progester- To be able to metastasize the cancer cell must undergo one receptor (PR), and human epidermal growth factor re- physiological changes and overcome numerous obstacles. ceptor 2 (HER2) expression. The expression of these three Generally, the metastatic process could be divided into sev- receptors strongly defines breast cancer behavior and treat- eral defined stages: (1) loss of cellular adhesion, (2) increase ment options. For example, HER2-positive breast cancers of cellular motility and invasiveness, (3) entry and survival are moreaggressiveinnature, but respond better to the in the circulation, (4) spread into distant tissue, and (5) current therapy resulting in more favorable prognosis. colonization of the distant site (Chambers et al. 2002). At Much more challenging are the triple-negative breast can- the beginning of the metastatic process, the primary tumor cers (TNBC) (ER/PR/HER2-negative), constituting between needs to develop its own blood circulatory system which 10 and 20% of all breast cancers, which are characterized also provides a route for tumor migration. Progression to- by most aggressive behavior and lack effective therapies. ward metastasis requires acquiring a resistance to cell death The prognosis in breast cancer strongly depends on the signals accomplished by overexpression of anti-apoptotic presence or absence of metastasis in other organs. Today, effector genes such as B-cell lymphoma 2 (BCL2), BCL-XL, around 155,000 people in the United States live with and X-linked inhibitor of apoptosis protein (XIAP) (Mehlen metastatic breast cancer and approximately 6–10% of all &Puisieux 2006). Cancer cells undergoing metastasis are newly diagnosed breast cancer patients are present with characterized by increased expression of matrix metallopro- metastatic disease at the time of diagnosis (American teinases (MMPs), which proteolytically disrupt the protect- Cancer Society, 2011) (NCI SEER 2018). Cancer metasta- ive basal membrane (MacDougall & Matrisian 1995). ses occur in 20–30% of all breast cancer cases and the me- Secreted proteases generate a variety of bioactive dian survival of metastatic breast cancer patients is on cleavage peptides which further modulate cancer cell average 3 years (O’Shaughnessy 2005). migration, proliferation, survival, and tumor angiogen- esis (Gupta & Massagué 2006). Once the cancer cells Mechanism of breast cancer metastasis enter the bloodstream, they increase the secretion of Metastasis is a process involving interplay between proteins such as autocrine motility factor (AMF) and the cancer cells with their biological properties and motility-stimulating protein (MSP) which enable them the host distant site providing specific microenviron- to survive the harsh conditions in the bloodstream ment. Particular tumors have the affinity to spread in (Watanabe et al. 1991). Finally, the cancer cells ex- particular organs. In 1889 Stephen Paget formulated travasate from the circulation and enter the new site the so called “seed and soil” theory, which is based where they form pre-angiogenic micrometastases on autopsy records of 735 women with breast cancer (Chambers et al. 2002). (Paget 1989). According to this theory, the ‘seed’ is Underlying event in metastasis is the epithelial-to- the metastatic cell, and the ‘soil’ the metastatic site. mesenchymal transition (EMT), a process in which The basic idea behind the Paget’s theory is that in particular cells lose their epithelial characteristics and order to metastasize, cancer cell must find a suitable gain more mesenchymal-like features. During EMT location bearing certain characteristics. Later, in 1928, the cellular expression of cell adhesion molecules the American pathologist James Ewing challenged the (CAMs) decrease resulting in the formation of “seed and soil” theory, suggesting that the organ spe- spindle-shape morphology. EMT is a fundamental cific metastases could be explained by pure anatom- process occurring during the embryonal development ical and mechanical circulatory patterns between the (designated as Type I EMT), fibrosis or wound heal- primary tumor and the distant organs (Ewing 1928). ing (or Type II EMT), but EMT also plays a key role In fact, the compatibility between the cancer cells and in cancer metastasis (also known as Type III EMT) the host environment as well as the circulatory pat- (Kalluri & Weinberg 2009). Main event during EMT terns play roles in the metastatic process. The deter- is the cleavage of the tight junction cell surface pro- mination which organ would be a target for cancer tein E-cadherin and inhibition of its expression by invasion depends on the proximity of the tumor side SNAIL, SLUG, ZEB and TWIST transcription factors to the host organ and the connection between the accompanied by overexpression of N-cadherin, fibro- primary tumor and the metastatic site through the nectin, vimentin and other proteins (Peinado et al. vascular circulatory system. For example, breast can- 2007;Yang&Weinberg 2008). Cancer cells involved cer commonly metastasizes to bones or the ovaries. in EMT undergo dynamic cytoskeletal rearrange- In addition to using blood vessels, cancer cells (e.g. ments interacting intensively with the cell-matrix. breast carcinoma cells) can migrate by invading the This process is governed by growth factors, which lymph nodes and using the lymphatic system, but directly or indirectly modulate plasma membrane Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 3 of 17 proteases and focal adhesion disassembly (Gupta & cancer cells. The NF-κB signaling induces the expression Massagué 2006). of a number of target genes involved in angio- and lym- Migratory cancer cells show elevated expression phangiogenesis among them the vascular endothelial MMPs, which are Calcium-dependent Zinc-containing growth factor (VEGF). NF-κB directly induces the ex- endopeptidases capable of degrading extracellular matrix pression of urokinase-type plasminogen activator (uPA) (ECM) proteins (Verma & Hansch 2007). There is a (Sliva et al. 2002), MMP-9, and chemokine receptor strong correlation between the MMP expression and CXCR4 (Helbig et al. 2003), which in turn results in pro- cancer invasion and metastasis (Kanadaswami et al. motion of ECM degradation and metastasis. The regula- 2005). MMPs participate in all stages of carcinogenesis tion of tumor metastasis by NF-κB is exerted by and are particularly important for tumor invasion reciprocal regulation of prometastatic (heparanase, etc.) (McCawley & Matrisian 2000). Generally, overexpression and antimetastatic (MMP-1, MMP-2, plasminogen acti- of MMPs is linked to higher metastasis capacity in many vator inhibitor [PAI]-2, etc.) factors. Thus NF-κB is con- tumors (Kanayama 2001; Saito et al. 2007; Castellano et sidered as an attractive candidate for metastasis al. 2008; Lee et al. 2008). Expression of MMPs is induced treatment. Number of developed therapeutic agents aim by growth factors (like epithelial growth factors [EGFs]) to target NF-κB activity and function by different ap- and receptor tyrosine kinase (RTKs) (such as EGF proaches such as induction of IκBα expression or pre- receptor [EGFR]) involving PI3K (phosphatidylinositol-3-ki- vention of its degradation, inhibition of NF-κB nuclear nase) and NF-κB (nuclear factor kappa-light-chain-enhancer translocation, suppression of NF-κB binding to DNA, in- of activated B cells) signaling cascades (Sen & Chatterjee hibition of IKK functions, etc. (Wu & Kral 2005) 2011). Experimental results have shown that inhibition of It is widely accepted that tumors are initiated by small MMPs results in abolishment of tumor cell invasiveness proportion of cancer stem cells (CSCs) that possess cap- (Matrisian 1990; Rhee & Coussens 2002; Van den Steen et acity for indefinite self-renewal. CSCs bear CD44 / −/low al. 2002; Kanadaswami et al. 2005). For this reason, MMPs CD24 lineage characteristics and differentiate into are considered as important molecular targets for the anti- all other cellular phenotypes in the solid tumor as well cancer therapy. Among the 23 currently known human as they can initiate the formation of secondary tumors. MMPs, the gelatinases (also known as type IV collagenases) Recent experimental results suggest that microRNAs MMP-2 (s. gelatinase A) and MMP-9 (s. gelatinase B) play (miRs) play a critical role in the formation of CSCs and key roles in the metastatic process. MMP-2 and -9 are sup- the acquisition of EMT (Li et al. 2010). pressed by tissue inhibitors of metalloproteinases (TIMPs) (Visse & Nagase 2003). There are four different TIMPs, Role of tumor microenvironment in breast cancer TIMP1, 2, 3, and 4, which bind non-covalently to MMP metastasis thus inhibiting their expression (Brew & Nagase 2010). Tumor is a complex structure comprised not only by NF-κB is a main player in the metastatic process be- the neoplastic cells, but also by other cellular types of a cause it is crucial regulator of cell proliferation and sur- different origin, all of them residing in a specific ECM vival. NF-κB levels may predict the potential of the microenvironment and communicating via soluble sub- tumor cells to metastasize (Jin et al. 2014). In resting stances (Yu & Di 2017). Tumor-infiltrating lymphocytes cells NF-κB exists in inactive form, located in the cyto- (TILs) are component of the tumor microenvironment plasm, bound to a family of inhibitory proteins referred that play a major role in cancer development. Most of + + as IκB (inhibitors of κB). Members of IκB family include the TILs are CD8 T cells, CD4 helper T cells (Th), and IκB-α,IκB-β,IκB-γ,IκB-ε,IκB-ζ, p105, p100, and bcl3, CD4 regulatory T cells (Tregs), as evidence suggest that as IκB-α (also known as nuclear factor of kappa light TILs are predictor of tumor outcome (Haanen et al. polypeptide gene enhancer in B-cells inhibitor-alpha 2006). Huang et al. (2015) demonstrated that although + + [NFKBIA]) is the most abundant among them. The con- both, CD8 and CD4 cells have a role in cancer, during trol of NF-κB activity is carried out by IκB kinase (IKK) breast cancer development the number of Th cells in- kinases which include mitogen-activated protein kinase crease concomitantly with a change of their dominant kinase (MAPKK) family comprising of NF-κB-inducing subsets from Th1 to Treg. On the other hand, CD8 kinase (NIK) and MAPK/ERK kinase kinase (MEKK) 1, cells are inverse indicator of ER and PR status in the 2, and 3. When activated, NF-κB translocates to the nu- breast tumor and may predict the clinical outcome cleus where it serves as transcription factor regulating (Mahmoud et al. 2011). Another component of the genes controlling cell cycle, apoptosis, transformation, tumor microenvironment are the tumor-associated mac- and other processes. Constitutively active NF-κB is char- rophages (TAMs) which are monocytes recruited by cy- acteristic for many cancers. It protects the activation of tokines (such as the chemokine (C-C motif) ligand 2 apoptotic signal by inhibiting p53 activity thus promot- [CCL2]) from the peritumoral tissues or bone marrow. ing the survival and neoplastic transformation of the TAMs can be divided into M1 and M2 machrophages, but Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 4 of 17 studies also suggest that they may actually possess charac- invasion, and metastasis (Hida et al. 2013). Besides of the teristics of both (Yu & Di 2017). Driven by interleukin cellular components, ECM by itself plays a multifaceted role (IL)-4 and IL-10, tumor necrosis factor-alpha (TNFα), in tumor development through biochemical and biomech- macrophage colony-stimulating factor (M-CSF), or hyp- anical mechanisms (Yu & Di 2017). oxia, breast tumor microenvironment facilitate M1 differ- entiation into M2 (Laoui et al. 2011). Hypoxia of the white Phyto-polyphenols with promising inhibitory adipose tissue may be induced by obesity and can further effects on breast cancer metastasis lead to endocrine alterations promoting the secretion of Polyphenols (s. polyhydroxyphenols) are class of chemical proinflammatory and angiogenic cytokines, and downreg- compounds, broadly distributed in nature and character- ulating CCAAT-enhancer binding protein-alpha (C/EBPα) ized by the presence of phenol structures in their mole- thus inhibiting apoptosis and stimulating cell proliferation cules. A vast group of polyphenols universally present in (Ye et al. 2007;Khan et al. 2013). Since the cytokines re- the plant kingdom is the bioflavonoids. Comprising more leased by the M1 macrophages in the early stages of can- than 4000 distinct members, bioflavonoids are 15-Carbon cer development have anti-proliferative effects on tumor skeleton derivatives of beno-γ-pyrone (s. phenylchromone). cells, the increased proportion of M2 macrophages in the Flavonoids are divided into different classes that include later stage of tumor development facilitate cancer growth flavonols, glavans and proanthocyanidins, anthocyanidins, (Quail & Joyce 2013). Cancer-associated fibroblasts flavanones, flavones, isoflavones, and noeflavonoids. (CAFs) are other component of the tumor microenviron- Phyto-polyphenols are integral part of the human diet. ment. It is suggested that these cells have heterogeneous They have been also used worldwide in traditional medicine origin and derive from neighboring tissue fibroblasts, bone for thousands of years for their anti-bacterial, anti-viral, marrow mesenchymal cells, epithelial cells undergoing anti-inflammatory, anti-allergic, and anti-thrombotic prop- EMT or other cellular types (Shiga et al. 2015). CAFs dir- erties. The effects of phyto-polyphenols are usually pleio- ectly modulate tumor progression and metastasis by se- tropic, and many of these compounds have proven creting growth factors and cytokines that promote ECM anti-carcinogenic actions manifested by suppression of can- remodeling, cellular proliferation, EMT, and angiogenesis cer cell transformation, differentiation, proliferation and in- (Cirri & Chiarugi 2011). Adipocytes are main component vasiveness, angiogenesis and induction of apoptosis. The of the mammary gland. In human, fat volume comprises anti-carcinogenic properties of the phyto-polyphenols can an average of 25% (7–56%) (Vandeweyer & Hertens 2002) be attributed to their direct effects on the activities of key of the non-lactating and an average of 35% (9–54%) (Ram- protein kinases controlling tumor cell proliferation and say et al. 2005) of the lactating breast tissue. Mammary apoptosis or to the suppression of MMP function. For ex- adipose cells share characteristics with the subcutaneous ample quercetin, fisetin or luteolin and other phyto-poly- WAT adipocytes, but are distinctive from these cells phenols inhibit the activity of protein kinase C (PKC). PKC by their response to menstrual cycle and permanent plays an important role in a variety of processes in cancer, interactions with the surrounding epithelial cells from tumor initiation and progression to inflammation and (Choi et al. 2017). Adipose cells are also a major T lymphocyte function. Genistein (Akiyama et al. 1987;Pe- component of the tumor microenvitonment and are espe- terson & Barnes 1991; Pagliacci et al. 1994), luteolin (Huang cially prominent in the breast tumors. Cancer-associated ad- et al. 1999; Lee et al. 2002), quercetin (Agullo et al. 1997), ipocytes (CAAs) are smaller than the non-tumor-associated and butein (Yang et al. 1998) affect tumor development by adipocytes and are highly secretory cells reprogrammed by suppressing the activity of epidermal growth factor receptor the tumor cells into dedifferentiated preadipocyte stage. The (EGFR) tyrosine kinase resulting in downstream effects on role that CAAs play in tumor development is supported by number of substrates such as serine/threonine kinases, epidemiological observations of higher breast cancer inci- mitogen-activated protein kinases (MAPKs), and rapidly ac- dence in obese postmenopausal women (Calle & Kaaks celerated fibrosarcoma kinases (RAFs) (Carpenter & Cohen 2004) and associations of obesity with poorer clinical out- 1990). Another protein tyrosine kinase that is targeted by come (Reeves et al. 2007;Chanetal. 2014). CAAs affect phyto-polyphenols (luteolin, quercetin, etc.) is the focal ad- cancer cells proliferation, survival and invasion potential by hesion kinase (FAK) (Kanadaswami et al. 2005). FAK is a secreting various adipokines, lipids and reactive oxygen spe- key molecule in signaling pathways essential for the cell cies (ROS) thus provoking ECM remodeling and metabolic cycle, survival, and motility. transformations (Choi et al. 2017;Niemanetal. 2013; Whole extracts or specific polyphenols derived from Berstein et al. 2007). Another component of the tumor green tea or grape vines have been shown to possess microenvironment are the endothelial cells (tumor endothe- anti-carcinogenic and anti-metastatic properties in mul- lial cells [TEC]). These cells differ from the normal epithelial tiple in vitro and in vivo studies. Extracts from peach (Pru- cells in their responsiveness to EGF, VEGF and other growth nus persica)(Noratto et al. 2014), olive (Olea europaea) factors, and are associated with tumor cells adhesion, (Hassan et al. 2012), promegranate (Punica granatum) Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 5 of 17 (Kim et al. 2002), evening primrose (Oenothera paradoxa) breast tumors sincetheyalsoact as selectiveestrogenre- (Lewandowska et al. 2013a; Lewandowska et al. 2013b), ceptor modulators (SERMs) (Harris et al. 2005). Grape the spotted (s. prostrate) spurge (Euphorbia suprina, (s. E. polyphenols exert their effects by modulating the activities maculata))(Ko etal. 2015), Japanese quince (Chaenomeles of Akt, extracellular-signal-regulated kinases (ERKs), and japonica)(Lewandowskaetal. 2013c), Himalayan rhubarb MAPKs (Lu et al. 2009;Kauret al. 2011; Sun et al. 2012). (Rheum emodi)(Kumaretal. 2015; Naveen Kumar et al. These polyphenols inhibit the expression and activity of 2013)or Phyllanthus sp. (P. niruri, P. urinaria, P. watsonii, EGFR1 and EGFR2 (s. HER2) (Azios & Dharmawardhane P. amarus)(Leeetal. 2011), and others inhibit tumor 2005;Fridrichet al. 2008), and elevated EGFR tumor ex- growth and suppress breast cancer metastasis. pression is generally associated with higher cancer pro- gression and metastasis (Buret et al. 1999). HER2 plays a Grape polyphenols major role in the metastatic process and its overexpression Grape vine plant consists of three main species: the is often observed in metastatic cancers. Inhibition of European grapes (Vitis vinifera), the North American HER2 by grape polyphenols leads to inhibition of grapes (V. lanrusca and V. rotundifolia), and French hy- phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian brids. Grape vines belong to the Vitaceae family and target of rapamycin (mTOR) as well as activation of 5’ were domesticated as early as in the Neolithic period. AMP-activated protein kinase (AMPK) – all of these en- Grapes contain variety of polyphenolic compounds zymes are involved in the process of metastasis. Addition- largely anthocyanins, flavonols (catechin, epicatechin, ally, grape polyphenols upregulate forkhead box O1 quercetin, procyanidin polymers), stilbenes (resveratrol), (FOXO1) and IκBα thus inhibiting NF-κB activity and phenolic acids. Grape polyphenols are distributed (Castillo-Pichardo et al. 2009). mostly in the seed, skin, leaf and the stem of the plant, and in considerably less amount in its juicy middle sec- Resveratrol tion. Resveratrol, quercetin and catechin polyphenols Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid represent about 70% of the polyphenols present in the and phytoalexin produced by grapes, peanuts, berries, and grape plant and have the most potent anti-carcinogenic the Japanese “Kojokon” (Polygonum cuspidatum)inre- activities (Damianaki et al. 2000). Importantly, grape sponse to injury or pathogen invasion (Burns et al. 2002). polyphenols are easily absorbed and metabolized in the Chemically, resveratrol is a precursor of a family of poly- body in their intact form (Soleas et al. 2002). Experimental mers named viniferins. It quickly enters the bloodstream data demonstrate that grape polyphenols have cardio- and from the gastro-intestinal tract, reaching significant plasma neuro-protective, anti-microbial (Lagneau et al. 1998; concentrations (Bhat et al. 2001). Resveratrol has been Xia et al. 2010; Castillo-Pichardo et al. 2013), used for centuries in the traditional Asian medicine since it anti-oxidant (Torres et al. 2002; Negro et al. 2003; has broad range of effects, including anti-oxidant proper- Makris et al. 2007) and variety of anti-carcinogenic ties, modulation of lipid and lipoprotein metabolism, (anti-proliferative, pro-apoptotic, anti-invasive, anti-angio- anti-platelet aggregation, vaso-relaxation, wound-healing, genic, antioxidant, and cancer-preventive) properties estrogenic activities and multiple anti-carcinogenic effects. (Soleas et al. 2002; Asensi et al. 2002; Nifli et al. 2005; The anti-carcinogenic properties of resveratrol have Morré & Morré 2006;Hakimuddinet al. 2008; Gulati et been demonstrated in many types of cancer including al. 2006; Kim et al. 2004; Dechsupa et al. 2007;Aggarwal those of the breast (Fig. 1) (Delmas et al. 2006;Bus- &Shishodia 2006;Kaur et al. 2009). quets et al. 2007; Castillo-Pichardo et al. 2009). They The suppressing effects of the grape polyphenols on include tumor cell proliferation arrest, induction of breast cancer initiation and cell growth are demonstrated apoptosis, suppression of tumor cell mobility and mi- in multiple in vitro and in vivo systems (Singletary et al. gration, prevention of tumor-derived nitric oxide syn- 2003; Hakimuddin et al. 2004)(Singh etal. 2004) (Schlach- thase expression, inhibition of tumor progression, etc. terman et al. 2008). Using nude mice xenografted with (Jang et al. 1997; Nakagawa et al. 2001;Garvin etal. GFP-tagged highly metastatic ER-negative MDA-MB-468 2006) Resveratrol is a SERM that acts in different tis- breast cancer cells, Castillo-Pichardo et al. (2009)found sues as a pro- or anti-estrogen (Bowers et al. 2000). that low concentrations of grape polyphenols can inhibit Current literature exploring the in vivo doses of res- breast cancer metastasis initiation, specifically to liver and veratrol needed to achieve beneficial anti-carcinogenic bone. Experiments using BALB/c 4 T1 mammary xeno- effect is still not consolidated. In fact, low doses of reser- graft mouse model showed that treatment with dietary vatrol achievable from dietary sources (such as red wine) grape skin extracts in drinking water resulted in decrease seem to be sufficient in suppressing tumor growth of lung metastasis incidence and stimulate cell survival (Tessitore et al. 2000). Resveratrol might be an effective (Sun et al. 2012). Resveratrol, quercetin and catechin are chemopreventive agent and the mechanism behind this particularly important in estrogen receptor (ER)-positive effect includes direct inhibition of cyclooxygenase Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 6 of 17 Fig. 1 Effects of reservatrol on breast cancer metastasis (COX) activity and indirect suppression of ornithine (IFNγ) and reduces those of IL-6, IL-10, and VEGF, as dacarboxylase (ODC) (Jang et al. 1997; Subbaramaiah et showninrenal tumormodel (Chen etal. 2015). al. 1999; Baur & Sinclair 2006). The effect of resveratrol Reservatrol also reduces oxidative stress by acting as on COX and ODC activities could also explain its a direct scavenger of ROX, by inhibiting NADPH anti-neovascularization and anti-angiogenic properties. oxidase expression or xanthine oxidase activity In vitro and in vivo studies have showed that resvera- (Pelicano et al. 2004; Lin et al. 2000), or by increasing trol inhibits NF-κB and decreases its DNA binding sirtuin 1 (SIRT1) activity (Xu et al. 2012). resulting in modulation of transcription of genes in- In summary, although the anti-carcinogenic and volved in tumor growth and metastasis (Tsai et al. 1999; cancer-preventive properties of resveratrol are proven in Banerjee et al. 2002; Benitez et al. 2009). Results from a multiple studies, the real efficacy of this compound in study using Sprague-Dawley rats where resveratrol was vivo is still unclear. The clinical evidence for resveratrol given in the diet two weeks before vein injection with as an effective supplement for cancer prevention and the tumor-initiating agent 7,12-dimethylbenz(a)anthra- treatment is scarce as at this time there is very little clin- cene (DMBA) demonstrated that resveratrol acts as a ical data for the efficacy of resveratrol in cancer strong antioxidant and significantly induces apoptosis treatment. with concomitant upregulation of TGFβ1 expression and in- hibition of NF-κB in these carcinogen-challenged animals Green tea polyphenols (Chatterjee et al. 2011). Experiments using female FVB/N Green tea is a product of leafs and the leaf buds of HER2/neu transgenic mice spontaneously developing mam- Camellia sinensis plant that belongs to Theacea fam- mary tumors revealed significant reduction of lung metasta- ily. Green tea contains more than 200 bioactive com- ses incidence after oral resveratrol supplementation pounds, among them polyphenols (catechins and (Provinciali et al. 2005). Contrary to the previous results, flavonols), alkaloids (caffeine), amino acid analogs resveratrol was found to promote tumor growth and metas- (theanine), vitamins, minerals, etc. Polyphenols are tases incidence in immunocompromised mice grafted with the largest and most active group of chemical compounds low-metastatic ERα-negative/ERβ-positive MDA-MB-231 or in the green tea comprising about 40% of the leave dry highly-metastatic ERα/ERβ-negative MDA-MB-468 breast weight. Polyphenols found in green tea include: cancer cells (Castillo-Pichardo et al. 2013). The reason for epigallocatechin-3-gallate (EGCG) (48.6%), epicathechin the discrepancy between the experimental in vivo data may gallate (ECG) (12.3%), epigallocatechin (EGC) (4.1%), epi- be explained with the different protocols followed for drug catechin (EC) (4.1%), gallocatechin gallate (GCG) (1.8%), administration, the variable concentration of reservatrol gallocatechin (GC) (1.8%), catechin (1.2%), and gallic acid used or combination of multiple other factors. (0.2%) (Slivova et al. 2005). Besides acting on tumor cells, reservatrol have modulat- Green tea polyphenols demonstrate beneficial effects ing effects on tumor microenvironment. It induces CD8 in different pathological conditions including obesity, T cells antitumor immunity, decreases the percentage of diabetes and cancer. Polyphenols contained in the green Tregs in the tumor, increases the levels of interferon-gamma tea were also found to inhibit tumor growth and Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 7 of 17 invasion of cancers such as leukemia, those of prostate, lung, liver, and breast (Dreosti et al. 1997; Isemura et al. 1993) (Sartippour et al. 2001). In vitro studies using hu- man MDA-MB-231 and MCF-7 breast cancer cells showed downregulation of MMP-2 and -9, EGFR and upregulation of TIMP-1 and -2, involvement of FAK/ ERK/NF-κB signaling pathways with concomitant inhib- ition of cellular invasion (Farabegoli et al. 2011; Sen et al. 2010). Aqueous extract of green tea induced apop- tosis and inhibited cell proliferation, migration and invasion in metastasis-specific mouse mammary car- cinoma 4 T1 cells in vitro. Green tea extract was ef- fective in vivo in decreasing tumor weight and significantly reduced lung and liver metastases inci- dence in female BALB/c mice bearing 4 T1 tumors (Luo et al. 2014). In vivo, green tea polyphenols inhibited the development and progression of lung, prostate, esophagus, stomach, intestine, skin, and other cancers (Katiyar & Mukhtar 1996;Yang et al. 2002). The induction of apoptosis by green tea polyphenols was found to be driven by mitochondria-targeted, caspase 3-executed mechanism (Hsu et al., 2003). The anti-invasive properties of the green tea polyphenols in breast cancer might be a result of preventing the formation of molecular complexes controlling cell adhesion and migration, specifically inhib- ition of activator protein-1 (AP-1) and NF-κB and conse- quent suppression of uPA secretion (Slivova et al. 2005). Epidemiological studies, though inconclusive, suggest possible cancer preventive action of the green tea poly- Fig. 2 Effects of epigallocatachin gallate (EGCG) on breast phenols. Nevertheless the beneficial effect of tea con- cancer metastasis sumption for cancer prevention or progression is doubtful. In order to reach sufficient serum concentra- tions, high doses of polyphenols consumption are mice resulted in reduction of tumor growth and lung metas- needed. Still, regular consumption of green tea has been tasis incidence. The 67-kDa laminin receptor (67LR) has associated with better prognosis in breast cancer pa- been identified as an essential cell surface target for EGCG tients (Nakachi et al. 1998) and possibly a decreased risk action (Tachibana et al. 2004;Umeda et al. 2008). The of recurrence (Inoue et al. 2001). mechanism of the tumor-suppressive and anti-metastatic ac- tions of EGCG is a result of involvement of Akt/eNOS/NO/ Epigallocatechin gallate (EGCG) cGMP/PKCδ signaling cascade (Kumazoe et al. 2013). Simi- EGCG is the ester of epigallocatechin and gallic acid and larly to other polyphenolic compounds, the effect of EGCG it is the most abundant polyphenol in the green tea. In in cancer cells is pleiotropic. It inhibits the activities of PTKs addition to green tea, EGCG is present in trace amounts (EGFR, FGFR, PDGFR, HER2/neu tyrosine kinases) and in apples, plums, onions, hazelnuts, pecans, etc. Aktkinase(Liang etal. 1997; Pianetti et al. 2002)via Experimental data demonstrate that EGCG inhibits STAT3, PI3K, mTOR, and NF-κB signaling pathways tumor cell proliferation, adhesion and invasion and in- (Masuda et al. 2002; Van Aller et al. 2011). Results duces apoptosis in variety of cancers including those of from in vitro study by using MDA-MB-231 cells dem- the breast (Fig. 2) (Ahmad et al. 1997; Yang et al. 2009; onstrated that EGCG modulates cell matrix adhesion Shammas et al. 2006). Treatment of 4 T1 cells with molecules and growth factor receptors through FAK/ERK EGCG decreases Bcl-2 expression and mitochondrial signaling pathway mechanism (Sen & Chatterjee 2011). disruption thus releasing cytochrome C as well as up- IGCG also inhibits the expression and activities of regulating Apaf-1, leading to the cleavage of caspase MMP-2 and -9 (Sen et al. 2009;Yang et al. 2005; 3 and poly [ADP-ribose] polymerase (PARP) proteins Sen et al. 2010) (Farabegoli et al. 2011), and this (Baliga et al. 2005). In the same study, oral administra- seems to be the main driver for its anti-metastatic tion of green tea polyphenols to 4 T1-xenografted BALB/c actions (Yang & Wang 1993). The inhibition of Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 8 of 17 MMPs can be explained by the fact that EGCG sup- and in vivo studies demonstrated that kaempferol has presses FAK, PI3K, and ERK which further leads to pleiotropic effects in cancer targeting cancer cell pro- downregulation of EGF (Sen & Chatterjee 2011). In liferation, apoptosis and mobility, tumor growth, addition, the suppression of MMPs involves epigen- angiogenesis and metastasis (Fig. 3)(Kim&Choi etic induction of TIMP-3 levels through inhibition of 2013; Calderón-Montaño et al. 2011;Boam 2015;Sri- the enhancer of zeste homolog 2 (EZH2) and class I nivas 2015). Kaempferol is an endocrine-disruptor histone deacetylases (HDACs) (Deb et al. 2014). that influences the activity of ER, having both, estro- Short-term supplementation with the active compounds genic and anti-estrogenic properties (Calderón-Mon- in green tea in men with prostate cancer showed that taño et al. 2011). This makes kaempferol potentially EGCG significantly reduces serum levels of VEGF useful in ER-positive breast cancers, where it sup- (McLarty et al. 2009). Based on experimental data, it ap- presses tumor growth by ER-dependent mechanism pears that plasma concentrations of EGCG comparable to (Oh et al. 2006). those observed in regular green tea consumers are suffi- Kaempferol interacts with major signaling pathways cient to inhibit MMPs and thus to affect negatively the in- such as ERK1/2 (Aiyer et al. 2012), MAPK (Li et al. vasion potential and metastasis in breast cancer patients 2015), and p53 (Calderón-Montaño et al. 2011), and is a (Garbisa et al. 2001). potential anti-metastasis agent. It inhibits the invasion, In addition of suppressing tumor growth, ECGC was adhesion, and migration of U-2 osteosarcoma cells found to modulate tumor microenvironment by redu- (Chen et al. 2013). Anti-metastatic effects of kaempferol cing TAM infiltration (Jang et al. 2013). In the same were observed in SCC4 oral cancer cells where it downreg- study, ex vivo incubation of TAM with exosomes from ulated MMP-2 and TIMP-2 mRNA and protein expression ECGC-treated mouse mammary tumor 4 T1 cells by suppressing c-Junactivity(Lin et al. 2013). Recent study skewed macrophages from tumor-promoting M2-like found that kaempferol inhibits MDA-MB-231 breast can- to tumor-inhibitor M1-like phenotype (Jang et al. cer cell adhesion, migration and invasion, and reduces lung 2013). Further, EGCG targets tumor microenviron- metastasis incidence in mice (Li et al. 2015). ment by preventing and reversing the advancement of The mechanisms behind the anti-metastatic effects of fibroblast-mediated effects by inhibiting signaling cas- kaempferol include supression of MMPs (MMP-2 and cades downstream of TGFβ (Gray et al. 2014). MMP-9) and uPA expression and activity via ERK, p38, JNK, and MAPK signaling (Chen et al. 2013). Kaemp- Other phyto-polyphenols ferol inhibits the translocation of the MAPK upstream Along with the above discussed phyto-polyphenols, a num- regulator PKCδ from the cytoplasm to the plasma mem- ber of other compounds have been investigated for their brane where it is physiologically active, thus suppressing anti-carcinogenic properties, including anti-metastatic ac- MAPK signaling pathway (Li et al. 2015). Another mech- tions. Plants rich in these polyphenolic compounds have anism by which kaempferol suppress metastasis is by been used for centuries in culinary and traditional medicine. inhibiting VEGF production as demonstrated in ovarian cancer OVCAR-3 cells in vitro (Luo et al. 2008). In the Kaempferol same cell line, kaempferol was also shown to downregu- Kaempferol (3,5,7-Trihydroxy-2-(4-hydroxyphenil)-4H-chro- late cMyc and promote apoptosis (Luo et al. 2010). Add- men-4-one) is a naturally occurring flavonol in broad range itionally, kaempferol inhibits lymphangiogenesis, which of plants from Pteridophyta, Pinophyta and Angiospermae is an integral step in the metastatic process. It reduces divisions. Among the commonly consumed foods contain- the density of tumor-associated lymphatic vessels as well ing kaempferol are grapes, green tea, apples, tomatoes, pota- as the incidence of lymph node metastases in breast can- toes, onions, broccoli, squash, Brussels sprouts, cucumbers, cer xenograft models in a VEGFR2/3 kinase manner lettuce, green beans, peaches, blackberries, raspberries, (Astin et al. 2014). spinach, etc. Kaempferol is actively absorbed in the small intestine and can be found in the plasma in nanomo- Curcumin lar concentrations (Calderón-Montaño et al. 2011). This Curcumin (s. diferuloylmethane, E100 (Natural Yellow 3)) polyphenol is easily metabolized in the liver and is delivered ((1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-hepta- to various other organs in the form of glucuronides and diene-3,5-dione) is a natural diarylheptanoid polyphenol sulfoconjugates (Calderón-Montaño et al. 2011). derived from turmeric plant (Curcuma longa) belonging To date, kaempferol has been shown to exert a variety to the ginger family (Zingiberaceae). Turmeric is common of effects including antioxidant, anti-inflammatory, ingredient of the traditional Indian cuisine (main ingredi- anti-microbial, anxiolytic, anti-allergic as well as ent of curry) as well as it is used worldwide as a food addi- anti-carcinogenic and cancer preventive activities tive for coloring (bright-yellow agent E100). Additionally, (Calderón-Montaño et al. 2011). Multiple in vitro turmeric is known for its medicinal properties. Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 9 of 17 Fig. 3 Effects of kaempferol on breast cancer metastasis Powdered turmeric underground stems (rhizomes) more sensitive to curcumin than the non-carcinogenic have been used for more than 6000 years for treating epithelial MCF-10A cells (Ramachandran & You 1999). broad range of conditions related to inflammation, al- The anti-carcinogenic properties of curcumin are lergies, parasitic infections, respiratory diseases, dia- pleiotropic and are based on its effects on both, the betes, neurodegenerative diseases and many others. tumor cells and the tumor microenvironment. For Turmeric-derived curcumin has also well established example, curcumin can modulate inflammatory anti-carcinogenic activities on cell transformation, pathways and tumor progression and metastasis, af- proliferation, apoptosis, survival, invasion, metastasis, fecting tumor cell survival, proliferation, and invasiveness adhesion as well as angiogenesis. The anti-carcinogenic (Gupta et al. 2010). Curcumin as well as other plant-derived effects of curcumin have been demonstrated in different natural polyphenols such as EGCG or resveratrol, induce studies on hematogenous, multiple myeloma, glioblastoma, epigenetic changes (inhibition of DNA methyltransfer- skin, head and neck, lung, colon, prostate, breast, and other ases (DNMTs), regulation of histone acetyltransferases types of cancer (Bachmeier et al. 2007; Kuo et al. 1996;Sung (HATs) and HDACs, or microRNA modulation) et al. 2009;Dhandapani etal. 2007; Limtrakul et al. 1997; (Gonwa et al. 1989)thatlead to suppressionof EMT Wilken et al. 2011; Moghaddam et al. 2009;Chenetal. and metastasis (Bandyopadhyay 2014; Bachmeier et al. 1999; Kawamori et al. 1999; Johnson & Mukhtar 2007; 2007; Kunnumakkara et al. 2008). Chendil et al. 2004; Mehta et al. 1997; Huang et al. 1998; The anti-metastatic action of curcumin involves Killian et al. 2012). inhibition of MMP-2, − 9, and MT1-MMP (Ohashi et Curcumin is poorly metabolized and extensively ex- al. 2003; Kim et al. 2012)(Fig. 4). Curcumin acts as spe- creted. It can be found in low concentrations in plasma cific supressor of p300/CREB-binding protein and affects and variety of tissues (Anand et al. 2007). Despite its lower major signalling pathways, protein tyrosine kinases and bioavailability, curcumin in low concentrations has been cytokines such as MAPK (Kim et al. 2012), JAK2/STAT3, shown to possess toxicity selectively to cancer, but not to Src/Akt (Saini et al. 2011), c-Jun/AP-1 (Collett & untransformed cells (Syng-Ai et al. 2004). For example, Campbell 2004), PKC (Garg et al. 2008), sonic hedgehog experimental data showed that human multidrug-resistant (Elamin et al. 2010), CXCL1 and 2 (Killian et al. 2012), etc. breast cancer MCF-7/TH cells are approximately 3.5-fold It also inhibits HDACs 1, 3, and 8 and HATs enzyme Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 10 of 17 Fig. 4 Effects of curcumin on breast cancer metastasis activities and modulates chromatin modification By inhibiting NF-κB signaling, curcumin suppresses me- (Balasubramanyam et al. 2004;Reuteret al. 2011). In tastasis in the very early stages of EMT. In lipopolysacchar- addition, curcumin suppresses NF-κB signaling by ide (LPS)-induced EMT in MCF-7 and MDA-MB-231 negative modulation of IKK, either directly or through cells, curcumin downregulated the expression of vimentin action of its upstream activators (Bharti et al. 2003; and upregulated those of E-cadherin as well as inhibited Jobin et al. 1999), preventing in such a way phos- LPS-induced morphological transformation of the cells phorylation of IκB (Plummer et al. 1999). Curcumin through inactivation of NF-κB-SNAIL signaling pathway abolishes the DNA binding of NF-κBand inhibits re- (Huang et al. 2013). porter gene expression in H1299 non-small cell lung Curcumin acts also as a phytoestrogen (Bachmeier carcinoma cell line, thus downregulating MMP-9 et al. 2010). The anti-proliferative effects of curcumin activation (Shishodia et al. 2003). In mice, where were found to be estrogen-dependent in ER-positive MDA-MB-231 breast cancer cells were injected intra- MCF-7 counteracting the estrogen responsive element cardiac, oral curcumin administration significantly re- (ERE)-CAT activities of estradiol (Shao et al. 2002). duced the number of lung metastases (Bachmeier et HER2/neu-positive or tamoxifen-resistant breast tu- al. 2007). This effect was most likely a result of in- mors are associated with specific microRNA signa- hibition of NF-κB activity and transcriptional down- ture, including overexpression of miR-181 (Miller et regulation of AP-1 and downregulation of cyclin D1, al. 2008;Loweryetal. 2009). In breast cancer, curcu- COX-2, and MMP-9, which further leads to inhibition min was shown to inhibit metastasis by inducing the of the breast cancer cell metastasis (Aggarwal et al. expression of miR-181b and downregulatinng those of 2005; Kim et al. 2012). CXCL-1 and -2 (Kronski et al. 2014). Chronic inflammation is considered to be a major factor A variety effects on tumor microenvironment were de- in tumor progression. For example, chronic prostatitis, scribed after curcumin treatment. In colon cancer, curcu- chronic obstructive pulmonary disease, inflammatory min interacts with the stromal fibroblasts in the colon bowel disease or chronic pancreatitis – all represent risk tumor microenvironment thus suppressing their crosstalk factors for developing prostate, lung, colon or pancreatic with CSCs (Buhrmann et al. 2014). Treatment with cancer. Curcumin inhibits chronic inflammation by dis- curcumin-polyethylene glycol conjugate (an amphiphilic rupting the feedback loop between NF-κB and the curcumin-based micelle) suppressed the percentage of pro-inflammatory cytokines, CXCL-1 and -2 (reviewed by myeloid-derived suppressor cells (MDSCs), which was Bandyopadhyay (Bandyopadhyay 2014)). suggested to be the reason behind the observed Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 11 of 17 inhibition of Treg and the activation of the effector T-cells anti-angiogenic effects, and inhibition of cancer metasta- (Lu et al. 2016). Combination of curcumin and ECGC in- sis incidence by effects on tumor proliferation, migration hibits colorectal carcinoma microenvironment-induced and invasion. These properties have been demonstrated angiogenesis by activating JAK/STAT3/IL-8 signaling in various cancer types such as sarcoma (Nagase et al. pathway (Jin et al. 2017). Curcumin downregulates 2001; Su et al. 2013), multiple melanoma (Ishitsuka et al. the expression of VEGF as shown in prostate cancer 2005), leukemia (Hirano et al. 1994; Hibasami et al. cells (Gupta et al. 2013) and blocked IL-1 and VEGF 1998; Battle et al. 2005), lung (Yang et al. 2002; Singh & expression in chondrosarcoma cells (Kalinski et al. 2014). Katiyar 2013), skin (Konoshima et al. 1991), pancreas Currently, curcumin is an object of more than 120 (Bai et al. 2003), ovary (Li et al. 2008), prostate clinical trials evaluating its effects against different (Shigemura et al. 2007), colorectal (Wang et al. 2004), maladies including cancer. breast (Nagalingam et al. 2012; Avtanski et al. 2014), and other cancers (Nagase et al. 2001; Garcia et al. 2008; Honokiol Deng et al. 2008; Chen et al. 2011; Chang et al. 2013). Honokiol is a biphenolic lignan with bioactive para-allyl One important characteristic of honokiol is that it easily and ortho-allyl phenolic groups, a product of Magnolia crosses the blood-brain barrier and achieves significant sp. (M. biondii, M. obovate, and M. officinalis) that dem- serum concentrations because of its hydrophobic and onstrates promising actions on tumor metastases. Bark lipophilic properties (Wang et al. 2011; Lin et al. 2012; or seed cones of magnolia plants has been used for Woodbury et al. 2013). centuries in the traditional Asian medicine for its Honokiol has pleiotropic effects in the cells (Fig. 5), anti-inflammatory, antithrombotic, anxiolytic, anti- including modulation of NF-κB(Tseetal. 2005;Lee depressant, antispasmodic, antioxidant, and antibacterial et al. 2005; Ahn et al. 2006;Sheuetal. 2008;Arora effects and its protective action against hepatotoxicity, et al. 2011), MAPK (Kim et al. 2012; Zhang et al. neurotoxicity and angiopathy (Fried & Arbiser 2009; Lee 2014), STAT3 (Rajendran et al. 2012;Avtanskiet al. et al. 2011). The anti-carcinogenic activities of honokiol 2014), Akt [238,], VEGF (Wen et al. 2015), ERK (Zhu et range from tumor suppression, pro-apoptotic and al. 2014; Yeh et al. 2016), s-Scr (Park et al. 2009), and Fig. 5 Effects of honokiol on breast cancer metastasis Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 12 of 17 other major signaling pathways (Fried & Arbiser 2009). metastasis initiation and progression by targeting both, For example, in SVR angiosarcoma cells, honokiol induces cancer cells and cancer microenvironment. Novel strat- apoptosis by suppressing the phosphorylation of ERK, egies for targeting metastasis aim to modulate the levels Akt, and c-Src (Bai et al. 2003). In addition to its of specific microRNAs that play a role in the transform- anti-proliferative properties, honokiol inhibits the migra- ation of the malignant cells. This approach could be tion and tube formation of human umbilical vein endothe- used against CSCs or cells undergoing EMT that are lial cells (HUVECs) and suppresses angiogenesis in typically drug resistant (Li et al. 2010). Importantly, zebrafish angiogenesis model (Zhu et al. 2011). Honokiol some phyto-polyphenolic compounds have been shown downregulates IKK activation and thus inhibits NF-κBsig- to exert beneficial effects through direct modulation of naling pathway and MMP-9, TNFα,IL-8, ICAM-1,and specific microRNAs at low concentrations. MCP-1 expression (Tse et al. 2005; Lee et al. 2005;Ahn et Natural polyphenolic compounds are usually charac- al. 2006;Sheu et al. 2008). It also inhibits the migration terized by low level of toxicity, but main disadvantage is and invasion of MCF-7 and MDA-MB-231 cells by upreg- their poor bioavailability and weak resorption reaching. ulating the activity of liver kinase B1 (LKB1) leading to ac- In this regard, new strategies for target-specific delivery tivation of AMP-activated protein kinase (AMPK) have been experimentally developed and proven to be ef- (Nagalingam et al. 2012). In vivo, honokiol inhibited fective. Recent advances in nano-medicine open the tumor growth of MDA-MB-231 cells-xenografted nude doors for the development of vehicles for drug delivery mice by blocking breast cancer cellular proliferation with long-circulation that can be used to target trans- (Nagalingam et al. 2012). Our in vitro and in vivo studies formed cells. Polyphenolic compounds administered by revealed that honokiol inhibits EMT of breast cancer cells traditional methods are not always effective because of by suppressing STAT3 signaling resulting in repression of they are poorly absorbed and extensively excreted. But ZEB1 expression and its recruitment on the E-cadherin pro- the chemopreventive efficacy of these polyphenols can moter (Avtanski et al. 2014). Honokiol modulated micro- be significantly improved by encapsulating them into RNA profile in the breast cancer cell, specifically amplifying nonoparticles. Thus, integration of various disciplines miR-34a expression in a STAT3-dependent manner, inhibit- such as biochemistry, molecular biology, chemistry, and ing Wnt1-metastatic-associated protein 1 (MTA1)-β-catenin nanotechnology could contribute to the development of signaling axis (Avtanski et al. 2015a). The mechanism be- novel therapies against breast cancer methastasis. hind the effects of honokiol on EMT and breast cancer mi- This paper is dedicated to the memory of Rumiana gration involves induction of SirT1, SirT3 and miR-34a Cherneva, who lost the battle with breast cancer. expression and cytoplasmic localization of LKB1 (Avtanski Abbreviations et al. 2015b). 67LR: 67-kDa Laminin Receptor; AMF: Autocrine Motility Factor; AMPK: 5’ Aside from directly targeting tumor cells, honokiol AMP-Activated Protein Kinase; AP-1: Activator Protein-1; BCL: B-Cell was also demonstrated to have effects on tumor micro- Lymphoma; C/EBPα: CCAAT-Enhancer Binding Protein-Alpha; CAA: Cancer- Associated Adipocyte; CAF: Cancer-Associated Fibroblast; CAM: Cell Adhesion environment. Honokiol decreased desmoplasia in pan- Molecule; CCL2: Chemokine (C-C motif) Ligand 2; COX: Cyclooxygenase; creatic tumor xenografts, as characterized by reduced CSC: Cancer Stem Cells; CXCR4: C-S-C chemokine Receptor type 4; secretion of extracellular matrix protein (collagen I) and DNMT: DNA Methyltransferase; EC: Epicatechin; ECG: Epicathechin Gallate; ECM: Extracellular Matrix; EGC: Epigallocatechin; EGCG: Epigallocatechin-3- suppressed myofibroblast marker α-smooth muscle actin Gallate; EGF: Epidermal Growth Factor; EGFR: Epidermal Growth Factor (α-SMA) immunostaining (Averett et al. 2016). Findings Receptor; EMT: Epithelial-to-Mesenchymal Transition; ER: Estrogen Receptor; from the same study revealed an inhibitory effect of ERE: Estrogen Responsive Element; ERK: Extracellular-Signal-Regulated Kinase; EZH: Enhancer of Zeste Homolog; FAK: Focal Adhesion Kinase; FGFR: Fibroblast honokiol on C-S-C chemokine receptor type 4 (CXCR4) Growth Factor Receptor; FOXO1: Forkhead Box O1 Protein; GC: Gallocatechin; signaling, which is known to play an important role in GCG: Gallocatechin Gallate; HAT: Histone Acetyltransferase; HDAC: Histone the crosstalk between the tumor and the stromal cells. Deacetylase; HER2: Human Epidermal Growth Factor Receptor 2; HUVEC: Human Umbilical Vein Endothelial Cells; IFNγ: Interferon-Gamma; IkB: Inhibitors of kappa B; IKK: Inhibitors of kappa B Kinase Kinases; IL: Interleukin; LKB1: Liver Kinase B1; Conclusions LPS: Lipopolysaccharide; α-SMA: Alpha-Smooth Muscle Actin; MAPK: Mitogen- Nature is abundant in chemicals with potential thera- Activated Protein Kinases; MAPKK: Mitogen-Activated Protein Kinase Kinase; M-CSF: Macrophage Colony-Stimulating Factor; MDSC: Myeloid-Derived peutic effects that are worth studying. A variety of poly- Suppressor Cells; MEKK: MAPK/ERK Kinase Kinase; miR: MicroRNA; MMP: Matrix phenols from plant origin demonstrate pleiotropic Metalloproteinase; MSP: Motility-Stimulating Protein; mTOR: Mammalian Target therapeutic properties against a broad range of patho- of Rapamycin; NF-κB: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells; NIK: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B logical conditions, including different types of cancer. Cells-Inducing Kinase; NFKBIA: Nuclear Factor of Kappa Light Polypeptide Such polyphenolic compounds can be viewed as promis- Gene Enhancer in B-Cells Inhibitor-Alpha; ODC: Ornithine Dacarboxylase; ing candidates for supplements to the traditional cancer PAI: Plasminogen Activator Inhibitor; PARP: Poly [ADP-Ribose] Polymerase; PDGFR: Platelet-Derived Growth Factor Receptor; PI3K: Phosphatidylinositol-3- prevention and treatment modalities as well as a basis Kinase; PKC: Protein Kinase C; PR: Progesterone Receptor; RAF: Rapidly for designing novel synthetic drugs. Naturally derived Accelerated Fibrosarcoma Kinase; ROS: Reactive Oxygen Species; RTK: Receptor plant polyphenols have been demonstrated to inhibit Tyrosin Kinase; SERM: Selective Estrogen Receptor Modulators; TEC: Tumor Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 13 of 17 Endothelial Cells; TIL: Tumor-Infiltrating Lymphocyte; TIMP: Tissue Inhibitors of Azios NG, Dharmawardhane SF. Resveratrol and estradiol exert disparate effects Metalloproteinases; TNFα: Tumor Necrosis Factor-Alpha; uPA: Urokinase-Type on cell migration, cell surface actin structures, and focal adhesion assembly Plasminogen Activator; VEGF: Vascular Endothelial Growth Factor; XIAP: X-linked in MDA-MB-231 human breast cancer cells. Neoplasia. 2005;7:128–40. Inhibitor of Apoptosis Protein Bachmeier BE, et al. The chemopreventive polyphenol curcumin prevents hematogenous breast cancer metastases in immunodeficient mice. Cell Physiol Biochem. 2007;19:137–52. Availability of data and materials Bachmeier BE, et al. Reference profile correlation reveals estrogen-like Data sharing not applicable to this article as no datasets were generated or trancriptional activity of curcumin. Cell Physiol Biochem. 2010;26:471–82. analyzed during the current study. BaiX,et al. Honokiol,a smallmolecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem. 2003;278:35501–7. Authors’ contributions Balasubramanyam K, et al. Curcumin, a novel p300/CREB-binding protein-specific DA drafted the manuscript. LP revised the manuscript critically. Both authors inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone read and approved the final manuscript. proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 2004;279:51163–71. Ethics approval and consent to participate Baliga MS, Meleth S, Katiyar SK. Growth inhibitory and Antimetastatic effect of Not applicable. green tea polyphenols on metastasis-specific mouse mammary carcinoma 4T1 cells in vitro and in vivo systems. Clin Cancer Res. 2005;11:1918–27. Bandyopadhyay D. Farmer to pharmacist: curcumin as an anti-invasive and Competing interests antimetastatic agent for the treatment of cancer. Front Chem. 2014;2:113. The authors declare that they have no competing interests. Banerjee S, Bueso-Ramos C, Aggarwal BB. 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Phyto-polyphenols as potential inhibitors of breast cancer metastasis

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Biomedicine; Molecular Medicine
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Abstract

Breast cancer is the most common cancer among women as metastasis is currently the main cause of mortality. Breast cancer cells undergoing metastasis acquire resistance to death signals and increase of cellular motility and invasiveness. Plants are rich in polyphenolic compounds, many of them with known medicinal effects. Various phyto-polyphenols have also been demonstrated to suppress cancer growth. Their mechanism of action is usually pleiotropic as they target multiple signaling pathways regulating key cellular processes such as proliferation, apoptosis and differentiation. Importantly, some phyto- polyphenols show low level of toxicity to untransformed cells, but selective suppressing effects on cancer cells proliferation and differentiation. In this review, we summarize the current information about the mechanism of action of some phyto-polyphenols that have demonstrated anti-carcinogenic activities in vitro and in vivo. Gained knowledge of how these natural polyphenolic compounds work can give us a clue for the development of novel anti-metastatic agents. Keywords: Polyphenols, Breast cancer, Metastasis, Plant products, Resveratrol, EGCG, Kaempferol Background this regard, it is worth studying the mechanism of action Breast cancer is the most common cancer in women, ac- of the natural polyphenols which can give us clues for the counting for nearly 1 in 3 diagnosed cancers or 16% of development of new synthetic therapeutic molecules. all female cancers. The incidence of breast cancer in- In this review, we summarize the main in vitro and in creases with age and is expected to escalate due to the vivo effects of some promising phyto-polyphenols that increase in life expectancy and the adoption of the West- have shown suppressing actions in the initiation and ern lifestyle and rising rates of obesity. In spite of the ad- progression of metastasis in breast cancer. Some of these vances in treatment, metastasis remain the main cause polyphenolic compounds are already in phase I, II, or III of mortality in cancer patients contributing to 90% of clinical trials. deaths from solid tumors (Gupta & Massagué 2006). Natural products are used in traditional medicine over Breast cancer and metastasis the millennia for prevention and treatment of variety of Epidemiology of breast cancer and metastasis maladies, including cancer. Plants are rich in polyphenolic According to the American Cancer Society, the average compounds and many of these compounds have proven age at the time of breast cancer diagnosis is 61 years. Al- beneficial effects in preventing the initiation and develop- though, breast cancer predominates in women, about of ment of metastasis. Natural polyphenols have generally 1% of all cases occur in men. Among the different eth- pleiotropic effects in the cell, activating multiple signaling nicities, breast cancer incidence rates are higher in pathways thus affecting many aspects of cellular fate, in- non-Hispanic Caucasian women compared to African cluding cell apoptosis, proliferation, and differentiation. In American women, but mortality rates are higher among African Americans (32%) compared to non-Hispanic * Correspondence: davtanski@northwell.edu Gerald J. Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Caucasians (24%). The most recent data for American Health, New York, NY 10022, USA women diagnosed with breast cancer demonstrate sur- Division of Endocrinology and Metabolism, Department of Medicine, vival rates of 89, 82, and 77% at 5, 10, and 15 years after Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, 110 E 59th Street, Suite 8B, Room 837, New York, NY 10022, USA diagnosis (American Cancer Society, 2011). © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 2 of 17 Human breast cancer is a heterogenous disease, which they ultimately rely on the blood vessels to find their can be classified into different groups depending on the way to the distant site. presence or absence of estrogen receptor (ER), progester- To be able to metastasize the cancer cell must undergo one receptor (PR), and human epidermal growth factor re- physiological changes and overcome numerous obstacles. ceptor 2 (HER2) expression. The expression of these three Generally, the metastatic process could be divided into sev- receptors strongly defines breast cancer behavior and treat- eral defined stages: (1) loss of cellular adhesion, (2) increase ment options. For example, HER2-positive breast cancers of cellular motility and invasiveness, (3) entry and survival are moreaggressiveinnature, but respond better to the in the circulation, (4) spread into distant tissue, and (5) current therapy resulting in more favorable prognosis. colonization of the distant site (Chambers et al. 2002). At Much more challenging are the triple-negative breast can- the beginning of the metastatic process, the primary tumor cers (TNBC) (ER/PR/HER2-negative), constituting between needs to develop its own blood circulatory system which 10 and 20% of all breast cancers, which are characterized also provides a route for tumor migration. Progression to- by most aggressive behavior and lack effective therapies. ward metastasis requires acquiring a resistance to cell death The prognosis in breast cancer strongly depends on the signals accomplished by overexpression of anti-apoptotic presence or absence of metastasis in other organs. Today, effector genes such as B-cell lymphoma 2 (BCL2), BCL-XL, around 155,000 people in the United States live with and X-linked inhibitor of apoptosis protein (XIAP) (Mehlen metastatic breast cancer and approximately 6–10% of all &Puisieux 2006). Cancer cells undergoing metastasis are newly diagnosed breast cancer patients are present with characterized by increased expression of matrix metallopro- metastatic disease at the time of diagnosis (American teinases (MMPs), which proteolytically disrupt the protect- Cancer Society, 2011) (NCI SEER 2018). Cancer metasta- ive basal membrane (MacDougall & Matrisian 1995). ses occur in 20–30% of all breast cancer cases and the me- Secreted proteases generate a variety of bioactive dian survival of metastatic breast cancer patients is on cleavage peptides which further modulate cancer cell average 3 years (O’Shaughnessy 2005). migration, proliferation, survival, and tumor angiogen- esis (Gupta & Massagué 2006). Once the cancer cells Mechanism of breast cancer metastasis enter the bloodstream, they increase the secretion of Metastasis is a process involving interplay between proteins such as autocrine motility factor (AMF) and the cancer cells with their biological properties and motility-stimulating protein (MSP) which enable them the host distant site providing specific microenviron- to survive the harsh conditions in the bloodstream ment. Particular tumors have the affinity to spread in (Watanabe et al. 1991). Finally, the cancer cells ex- particular organs. In 1889 Stephen Paget formulated travasate from the circulation and enter the new site the so called “seed and soil” theory, which is based where they form pre-angiogenic micrometastases on autopsy records of 735 women with breast cancer (Chambers et al. 2002). (Paget 1989). According to this theory, the ‘seed’ is Underlying event in metastasis is the epithelial-to- the metastatic cell, and the ‘soil’ the metastatic site. mesenchymal transition (EMT), a process in which The basic idea behind the Paget’s theory is that in particular cells lose their epithelial characteristics and order to metastasize, cancer cell must find a suitable gain more mesenchymal-like features. During EMT location bearing certain characteristics. Later, in 1928, the cellular expression of cell adhesion molecules the American pathologist James Ewing challenged the (CAMs) decrease resulting in the formation of “seed and soil” theory, suggesting that the organ spe- spindle-shape morphology. EMT is a fundamental cific metastases could be explained by pure anatom- process occurring during the embryonal development ical and mechanical circulatory patterns between the (designated as Type I EMT), fibrosis or wound heal- primary tumor and the distant organs (Ewing 1928). ing (or Type II EMT), but EMT also plays a key role In fact, the compatibility between the cancer cells and in cancer metastasis (also known as Type III EMT) the host environment as well as the circulatory pat- (Kalluri & Weinberg 2009). Main event during EMT terns play roles in the metastatic process. The deter- is the cleavage of the tight junction cell surface pro- mination which organ would be a target for cancer tein E-cadherin and inhibition of its expression by invasion depends on the proximity of the tumor side SNAIL, SLUG, ZEB and TWIST transcription factors to the host organ and the connection between the accompanied by overexpression of N-cadherin, fibro- primary tumor and the metastatic site through the nectin, vimentin and other proteins (Peinado et al. vascular circulatory system. For example, breast can- 2007;Yang&Weinberg 2008). Cancer cells involved cer commonly metastasizes to bones or the ovaries. in EMT undergo dynamic cytoskeletal rearrange- In addition to using blood vessels, cancer cells (e.g. ments interacting intensively with the cell-matrix. breast carcinoma cells) can migrate by invading the This process is governed by growth factors, which lymph nodes and using the lymphatic system, but directly or indirectly modulate plasma membrane Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 3 of 17 proteases and focal adhesion disassembly (Gupta & cancer cells. The NF-κB signaling induces the expression Massagué 2006). of a number of target genes involved in angio- and lym- Migratory cancer cells show elevated expression phangiogenesis among them the vascular endothelial MMPs, which are Calcium-dependent Zinc-containing growth factor (VEGF). NF-κB directly induces the ex- endopeptidases capable of degrading extracellular matrix pression of urokinase-type plasminogen activator (uPA) (ECM) proteins (Verma & Hansch 2007). There is a (Sliva et al. 2002), MMP-9, and chemokine receptor strong correlation between the MMP expression and CXCR4 (Helbig et al. 2003), which in turn results in pro- cancer invasion and metastasis (Kanadaswami et al. motion of ECM degradation and metastasis. The regula- 2005). MMPs participate in all stages of carcinogenesis tion of tumor metastasis by NF-κB is exerted by and are particularly important for tumor invasion reciprocal regulation of prometastatic (heparanase, etc.) (McCawley & Matrisian 2000). Generally, overexpression and antimetastatic (MMP-1, MMP-2, plasminogen acti- of MMPs is linked to higher metastasis capacity in many vator inhibitor [PAI]-2, etc.) factors. Thus NF-κB is con- tumors (Kanayama 2001; Saito et al. 2007; Castellano et sidered as an attractive candidate for metastasis al. 2008; Lee et al. 2008). Expression of MMPs is induced treatment. Number of developed therapeutic agents aim by growth factors (like epithelial growth factors [EGFs]) to target NF-κB activity and function by different ap- and receptor tyrosine kinase (RTKs) (such as EGF proaches such as induction of IκBα expression or pre- receptor [EGFR]) involving PI3K (phosphatidylinositol-3-ki- vention of its degradation, inhibition of NF-κB nuclear nase) and NF-κB (nuclear factor kappa-light-chain-enhancer translocation, suppression of NF-κB binding to DNA, in- of activated B cells) signaling cascades (Sen & Chatterjee hibition of IKK functions, etc. (Wu & Kral 2005) 2011). Experimental results have shown that inhibition of It is widely accepted that tumors are initiated by small MMPs results in abolishment of tumor cell invasiveness proportion of cancer stem cells (CSCs) that possess cap- (Matrisian 1990; Rhee & Coussens 2002; Van den Steen et acity for indefinite self-renewal. CSCs bear CD44 / −/low al. 2002; Kanadaswami et al. 2005). For this reason, MMPs CD24 lineage characteristics and differentiate into are considered as important molecular targets for the anti- all other cellular phenotypes in the solid tumor as well cancer therapy. Among the 23 currently known human as they can initiate the formation of secondary tumors. MMPs, the gelatinases (also known as type IV collagenases) Recent experimental results suggest that microRNAs MMP-2 (s. gelatinase A) and MMP-9 (s. gelatinase B) play (miRs) play a critical role in the formation of CSCs and key roles in the metastatic process. MMP-2 and -9 are sup- the acquisition of EMT (Li et al. 2010). pressed by tissue inhibitors of metalloproteinases (TIMPs) (Visse & Nagase 2003). There are four different TIMPs, Role of tumor microenvironment in breast cancer TIMP1, 2, 3, and 4, which bind non-covalently to MMP metastasis thus inhibiting their expression (Brew & Nagase 2010). Tumor is a complex structure comprised not only by NF-κB is a main player in the metastatic process be- the neoplastic cells, but also by other cellular types of a cause it is crucial regulator of cell proliferation and sur- different origin, all of them residing in a specific ECM vival. NF-κB levels may predict the potential of the microenvironment and communicating via soluble sub- tumor cells to metastasize (Jin et al. 2014). In resting stances (Yu & Di 2017). Tumor-infiltrating lymphocytes cells NF-κB exists in inactive form, located in the cyto- (TILs) are component of the tumor microenvironment plasm, bound to a family of inhibitory proteins referred that play a major role in cancer development. Most of + + as IκB (inhibitors of κB). Members of IκB family include the TILs are CD8 T cells, CD4 helper T cells (Th), and IκB-α,IκB-β,IκB-γ,IκB-ε,IκB-ζ, p105, p100, and bcl3, CD4 regulatory T cells (Tregs), as evidence suggest that as IκB-α (also known as nuclear factor of kappa light TILs are predictor of tumor outcome (Haanen et al. polypeptide gene enhancer in B-cells inhibitor-alpha 2006). Huang et al. (2015) demonstrated that although + + [NFKBIA]) is the most abundant among them. The con- both, CD8 and CD4 cells have a role in cancer, during trol of NF-κB activity is carried out by IκB kinase (IKK) breast cancer development the number of Th cells in- kinases which include mitogen-activated protein kinase crease concomitantly with a change of their dominant kinase (MAPKK) family comprising of NF-κB-inducing subsets from Th1 to Treg. On the other hand, CD8 kinase (NIK) and MAPK/ERK kinase kinase (MEKK) 1, cells are inverse indicator of ER and PR status in the 2, and 3. When activated, NF-κB translocates to the nu- breast tumor and may predict the clinical outcome cleus where it serves as transcription factor regulating (Mahmoud et al. 2011). Another component of the genes controlling cell cycle, apoptosis, transformation, tumor microenvironment are the tumor-associated mac- and other processes. Constitutively active NF-κB is char- rophages (TAMs) which are monocytes recruited by cy- acteristic for many cancers. It protects the activation of tokines (such as the chemokine (C-C motif) ligand 2 apoptotic signal by inhibiting p53 activity thus promot- [CCL2]) from the peritumoral tissues or bone marrow. ing the survival and neoplastic transformation of the TAMs can be divided into M1 and M2 machrophages, but Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 4 of 17 studies also suggest that they may actually possess charac- invasion, and metastasis (Hida et al. 2013). Besides of the teristics of both (Yu & Di 2017). Driven by interleukin cellular components, ECM by itself plays a multifaceted role (IL)-4 and IL-10, tumor necrosis factor-alpha (TNFα), in tumor development through biochemical and biomech- macrophage colony-stimulating factor (M-CSF), or hyp- anical mechanisms (Yu & Di 2017). oxia, breast tumor microenvironment facilitate M1 differ- entiation into M2 (Laoui et al. 2011). Hypoxia of the white Phyto-polyphenols with promising inhibitory adipose tissue may be induced by obesity and can further effects on breast cancer metastasis lead to endocrine alterations promoting the secretion of Polyphenols (s. polyhydroxyphenols) are class of chemical proinflammatory and angiogenic cytokines, and downreg- compounds, broadly distributed in nature and character- ulating CCAAT-enhancer binding protein-alpha (C/EBPα) ized by the presence of phenol structures in their mole- thus inhibiting apoptosis and stimulating cell proliferation cules. A vast group of polyphenols universally present in (Ye et al. 2007;Khan et al. 2013). Since the cytokines re- the plant kingdom is the bioflavonoids. Comprising more leased by the M1 macrophages in the early stages of can- than 4000 distinct members, bioflavonoids are 15-Carbon cer development have anti-proliferative effects on tumor skeleton derivatives of beno-γ-pyrone (s. phenylchromone). cells, the increased proportion of M2 macrophages in the Flavonoids are divided into different classes that include later stage of tumor development facilitate cancer growth flavonols, glavans and proanthocyanidins, anthocyanidins, (Quail & Joyce 2013). Cancer-associated fibroblasts flavanones, flavones, isoflavones, and noeflavonoids. (CAFs) are other component of the tumor microenviron- Phyto-polyphenols are integral part of the human diet. ment. It is suggested that these cells have heterogeneous They have been also used worldwide in traditional medicine origin and derive from neighboring tissue fibroblasts, bone for thousands of years for their anti-bacterial, anti-viral, marrow mesenchymal cells, epithelial cells undergoing anti-inflammatory, anti-allergic, and anti-thrombotic prop- EMT or other cellular types (Shiga et al. 2015). CAFs dir- erties. The effects of phyto-polyphenols are usually pleio- ectly modulate tumor progression and metastasis by se- tropic, and many of these compounds have proven creting growth factors and cytokines that promote ECM anti-carcinogenic actions manifested by suppression of can- remodeling, cellular proliferation, EMT, and angiogenesis cer cell transformation, differentiation, proliferation and in- (Cirri & Chiarugi 2011). Adipocytes are main component vasiveness, angiogenesis and induction of apoptosis. The of the mammary gland. In human, fat volume comprises anti-carcinogenic properties of the phyto-polyphenols can an average of 25% (7–56%) (Vandeweyer & Hertens 2002) be attributed to their direct effects on the activities of key of the non-lactating and an average of 35% (9–54%) (Ram- protein kinases controlling tumor cell proliferation and say et al. 2005) of the lactating breast tissue. Mammary apoptosis or to the suppression of MMP function. For ex- adipose cells share characteristics with the subcutaneous ample quercetin, fisetin or luteolin and other phyto-poly- WAT adipocytes, but are distinctive from these cells phenols inhibit the activity of protein kinase C (PKC). PKC by their response to menstrual cycle and permanent plays an important role in a variety of processes in cancer, interactions with the surrounding epithelial cells from tumor initiation and progression to inflammation and (Choi et al. 2017). Adipose cells are also a major T lymphocyte function. Genistein (Akiyama et al. 1987;Pe- component of the tumor microenvitonment and are espe- terson & Barnes 1991; Pagliacci et al. 1994), luteolin (Huang cially prominent in the breast tumors. Cancer-associated ad- et al. 1999; Lee et al. 2002), quercetin (Agullo et al. 1997), ipocytes (CAAs) are smaller than the non-tumor-associated and butein (Yang et al. 1998) affect tumor development by adipocytes and are highly secretory cells reprogrammed by suppressing the activity of epidermal growth factor receptor the tumor cells into dedifferentiated preadipocyte stage. The (EGFR) tyrosine kinase resulting in downstream effects on role that CAAs play in tumor development is supported by number of substrates such as serine/threonine kinases, epidemiological observations of higher breast cancer inci- mitogen-activated protein kinases (MAPKs), and rapidly ac- dence in obese postmenopausal women (Calle & Kaaks celerated fibrosarcoma kinases (RAFs) (Carpenter & Cohen 2004) and associations of obesity with poorer clinical out- 1990). Another protein tyrosine kinase that is targeted by come (Reeves et al. 2007;Chanetal. 2014). CAAs affect phyto-polyphenols (luteolin, quercetin, etc.) is the focal ad- cancer cells proliferation, survival and invasion potential by hesion kinase (FAK) (Kanadaswami et al. 2005). FAK is a secreting various adipokines, lipids and reactive oxygen spe- key molecule in signaling pathways essential for the cell cies (ROS) thus provoking ECM remodeling and metabolic cycle, survival, and motility. transformations (Choi et al. 2017;Niemanetal. 2013; Whole extracts or specific polyphenols derived from Berstein et al. 2007). Another component of the tumor green tea or grape vines have been shown to possess microenvironment are the endothelial cells (tumor endothe- anti-carcinogenic and anti-metastatic properties in mul- lial cells [TEC]). These cells differ from the normal epithelial tiple in vitro and in vivo studies. Extracts from peach (Pru- cells in their responsiveness to EGF, VEGF and other growth nus persica)(Noratto et al. 2014), olive (Olea europaea) factors, and are associated with tumor cells adhesion, (Hassan et al. 2012), promegranate (Punica granatum) Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 5 of 17 (Kim et al. 2002), evening primrose (Oenothera paradoxa) breast tumors sincetheyalsoact as selectiveestrogenre- (Lewandowska et al. 2013a; Lewandowska et al. 2013b), ceptor modulators (SERMs) (Harris et al. 2005). Grape the spotted (s. prostrate) spurge (Euphorbia suprina, (s. E. polyphenols exert their effects by modulating the activities maculata))(Ko etal. 2015), Japanese quince (Chaenomeles of Akt, extracellular-signal-regulated kinases (ERKs), and japonica)(Lewandowskaetal. 2013c), Himalayan rhubarb MAPKs (Lu et al. 2009;Kauret al. 2011; Sun et al. 2012). (Rheum emodi)(Kumaretal. 2015; Naveen Kumar et al. These polyphenols inhibit the expression and activity of 2013)or Phyllanthus sp. (P. niruri, P. urinaria, P. watsonii, EGFR1 and EGFR2 (s. HER2) (Azios & Dharmawardhane P. amarus)(Leeetal. 2011), and others inhibit tumor 2005;Fridrichet al. 2008), and elevated EGFR tumor ex- growth and suppress breast cancer metastasis. pression is generally associated with higher cancer pro- gression and metastasis (Buret et al. 1999). HER2 plays a Grape polyphenols major role in the metastatic process and its overexpression Grape vine plant consists of three main species: the is often observed in metastatic cancers. Inhibition of European grapes (Vitis vinifera), the North American HER2 by grape polyphenols leads to inhibition of grapes (V. lanrusca and V. rotundifolia), and French hy- phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian brids. Grape vines belong to the Vitaceae family and target of rapamycin (mTOR) as well as activation of 5’ were domesticated as early as in the Neolithic period. AMP-activated protein kinase (AMPK) – all of these en- Grapes contain variety of polyphenolic compounds zymes are involved in the process of metastasis. Addition- largely anthocyanins, flavonols (catechin, epicatechin, ally, grape polyphenols upregulate forkhead box O1 quercetin, procyanidin polymers), stilbenes (resveratrol), (FOXO1) and IκBα thus inhibiting NF-κB activity and phenolic acids. Grape polyphenols are distributed (Castillo-Pichardo et al. 2009). mostly in the seed, skin, leaf and the stem of the plant, and in considerably less amount in its juicy middle sec- Resveratrol tion. Resveratrol, quercetin and catechin polyphenols Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid represent about 70% of the polyphenols present in the and phytoalexin produced by grapes, peanuts, berries, and grape plant and have the most potent anti-carcinogenic the Japanese “Kojokon” (Polygonum cuspidatum)inre- activities (Damianaki et al. 2000). Importantly, grape sponse to injury or pathogen invasion (Burns et al. 2002). polyphenols are easily absorbed and metabolized in the Chemically, resveratrol is a precursor of a family of poly- body in their intact form (Soleas et al. 2002). Experimental mers named viniferins. It quickly enters the bloodstream data demonstrate that grape polyphenols have cardio- and from the gastro-intestinal tract, reaching significant plasma neuro-protective, anti-microbial (Lagneau et al. 1998; concentrations (Bhat et al. 2001). Resveratrol has been Xia et al. 2010; Castillo-Pichardo et al. 2013), used for centuries in the traditional Asian medicine since it anti-oxidant (Torres et al. 2002; Negro et al. 2003; has broad range of effects, including anti-oxidant proper- Makris et al. 2007) and variety of anti-carcinogenic ties, modulation of lipid and lipoprotein metabolism, (anti-proliferative, pro-apoptotic, anti-invasive, anti-angio- anti-platelet aggregation, vaso-relaxation, wound-healing, genic, antioxidant, and cancer-preventive) properties estrogenic activities and multiple anti-carcinogenic effects. (Soleas et al. 2002; Asensi et al. 2002; Nifli et al. 2005; The anti-carcinogenic properties of resveratrol have Morré & Morré 2006;Hakimuddinet al. 2008; Gulati et been demonstrated in many types of cancer including al. 2006; Kim et al. 2004; Dechsupa et al. 2007;Aggarwal those of the breast (Fig. 1) (Delmas et al. 2006;Bus- &Shishodia 2006;Kaur et al. 2009). quets et al. 2007; Castillo-Pichardo et al. 2009). They The suppressing effects of the grape polyphenols on include tumor cell proliferation arrest, induction of breast cancer initiation and cell growth are demonstrated apoptosis, suppression of tumor cell mobility and mi- in multiple in vitro and in vivo systems (Singletary et al. gration, prevention of tumor-derived nitric oxide syn- 2003; Hakimuddin et al. 2004)(Singh etal. 2004) (Schlach- thase expression, inhibition of tumor progression, etc. terman et al. 2008). Using nude mice xenografted with (Jang et al. 1997; Nakagawa et al. 2001;Garvin etal. GFP-tagged highly metastatic ER-negative MDA-MB-468 2006) Resveratrol is a SERM that acts in different tis- breast cancer cells, Castillo-Pichardo et al. (2009)found sues as a pro- or anti-estrogen (Bowers et al. 2000). that low concentrations of grape polyphenols can inhibit Current literature exploring the in vivo doses of res- breast cancer metastasis initiation, specifically to liver and veratrol needed to achieve beneficial anti-carcinogenic bone. Experiments using BALB/c 4 T1 mammary xeno- effect is still not consolidated. In fact, low doses of reser- graft mouse model showed that treatment with dietary vatrol achievable from dietary sources (such as red wine) grape skin extracts in drinking water resulted in decrease seem to be sufficient in suppressing tumor growth of lung metastasis incidence and stimulate cell survival (Tessitore et al. 2000). Resveratrol might be an effective (Sun et al. 2012). Resveratrol, quercetin and catechin are chemopreventive agent and the mechanism behind this particularly important in estrogen receptor (ER)-positive effect includes direct inhibition of cyclooxygenase Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 6 of 17 Fig. 1 Effects of reservatrol on breast cancer metastasis (COX) activity and indirect suppression of ornithine (IFNγ) and reduces those of IL-6, IL-10, and VEGF, as dacarboxylase (ODC) (Jang et al. 1997; Subbaramaiah et showninrenal tumormodel (Chen etal. 2015). al. 1999; Baur & Sinclair 2006). The effect of resveratrol Reservatrol also reduces oxidative stress by acting as on COX and ODC activities could also explain its a direct scavenger of ROX, by inhibiting NADPH anti-neovascularization and anti-angiogenic properties. oxidase expression or xanthine oxidase activity In vitro and in vivo studies have showed that resvera- (Pelicano et al. 2004; Lin et al. 2000), or by increasing trol inhibits NF-κB and decreases its DNA binding sirtuin 1 (SIRT1) activity (Xu et al. 2012). resulting in modulation of transcription of genes in- In summary, although the anti-carcinogenic and volved in tumor growth and metastasis (Tsai et al. 1999; cancer-preventive properties of resveratrol are proven in Banerjee et al. 2002; Benitez et al. 2009). Results from a multiple studies, the real efficacy of this compound in study using Sprague-Dawley rats where resveratrol was vivo is still unclear. The clinical evidence for resveratrol given in the diet two weeks before vein injection with as an effective supplement for cancer prevention and the tumor-initiating agent 7,12-dimethylbenz(a)anthra- treatment is scarce as at this time there is very little clin- cene (DMBA) demonstrated that resveratrol acts as a ical data for the efficacy of resveratrol in cancer strong antioxidant and significantly induces apoptosis treatment. with concomitant upregulation of TGFβ1 expression and in- hibition of NF-κB in these carcinogen-challenged animals Green tea polyphenols (Chatterjee et al. 2011). Experiments using female FVB/N Green tea is a product of leafs and the leaf buds of HER2/neu transgenic mice spontaneously developing mam- Camellia sinensis plant that belongs to Theacea fam- mary tumors revealed significant reduction of lung metasta- ily. Green tea contains more than 200 bioactive com- ses incidence after oral resveratrol supplementation pounds, among them polyphenols (catechins and (Provinciali et al. 2005). Contrary to the previous results, flavonols), alkaloids (caffeine), amino acid analogs resveratrol was found to promote tumor growth and metas- (theanine), vitamins, minerals, etc. Polyphenols are tases incidence in immunocompromised mice grafted with the largest and most active group of chemical compounds low-metastatic ERα-negative/ERβ-positive MDA-MB-231 or in the green tea comprising about 40% of the leave dry highly-metastatic ERα/ERβ-negative MDA-MB-468 breast weight. Polyphenols found in green tea include: cancer cells (Castillo-Pichardo et al. 2013). The reason for epigallocatechin-3-gallate (EGCG) (48.6%), epicathechin the discrepancy between the experimental in vivo data may gallate (ECG) (12.3%), epigallocatechin (EGC) (4.1%), epi- be explained with the different protocols followed for drug catechin (EC) (4.1%), gallocatechin gallate (GCG) (1.8%), administration, the variable concentration of reservatrol gallocatechin (GC) (1.8%), catechin (1.2%), and gallic acid used or combination of multiple other factors. (0.2%) (Slivova et al. 2005). Besides acting on tumor cells, reservatrol have modulat- Green tea polyphenols demonstrate beneficial effects ing effects on tumor microenvironment. It induces CD8 in different pathological conditions including obesity, T cells antitumor immunity, decreases the percentage of diabetes and cancer. Polyphenols contained in the green Tregs in the tumor, increases the levels of interferon-gamma tea were also found to inhibit tumor growth and Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 7 of 17 invasion of cancers such as leukemia, those of prostate, lung, liver, and breast (Dreosti et al. 1997; Isemura et al. 1993) (Sartippour et al. 2001). In vitro studies using hu- man MDA-MB-231 and MCF-7 breast cancer cells showed downregulation of MMP-2 and -9, EGFR and upregulation of TIMP-1 and -2, involvement of FAK/ ERK/NF-κB signaling pathways with concomitant inhib- ition of cellular invasion (Farabegoli et al. 2011; Sen et al. 2010). Aqueous extract of green tea induced apop- tosis and inhibited cell proliferation, migration and invasion in metastasis-specific mouse mammary car- cinoma 4 T1 cells in vitro. Green tea extract was ef- fective in vivo in decreasing tumor weight and significantly reduced lung and liver metastases inci- dence in female BALB/c mice bearing 4 T1 tumors (Luo et al. 2014). In vivo, green tea polyphenols inhibited the development and progression of lung, prostate, esophagus, stomach, intestine, skin, and other cancers (Katiyar & Mukhtar 1996;Yang et al. 2002). The induction of apoptosis by green tea polyphenols was found to be driven by mitochondria-targeted, caspase 3-executed mechanism (Hsu et al., 2003). The anti-invasive properties of the green tea polyphenols in breast cancer might be a result of preventing the formation of molecular complexes controlling cell adhesion and migration, specifically inhib- ition of activator protein-1 (AP-1) and NF-κB and conse- quent suppression of uPA secretion (Slivova et al. 2005). Epidemiological studies, though inconclusive, suggest possible cancer preventive action of the green tea poly- Fig. 2 Effects of epigallocatachin gallate (EGCG) on breast phenols. Nevertheless the beneficial effect of tea con- cancer metastasis sumption for cancer prevention or progression is doubtful. In order to reach sufficient serum concentra- tions, high doses of polyphenols consumption are mice resulted in reduction of tumor growth and lung metas- needed. Still, regular consumption of green tea has been tasis incidence. The 67-kDa laminin receptor (67LR) has associated with better prognosis in breast cancer pa- been identified as an essential cell surface target for EGCG tients (Nakachi et al. 1998) and possibly a decreased risk action (Tachibana et al. 2004;Umeda et al. 2008). The of recurrence (Inoue et al. 2001). mechanism of the tumor-suppressive and anti-metastatic ac- tions of EGCG is a result of involvement of Akt/eNOS/NO/ Epigallocatechin gallate (EGCG) cGMP/PKCδ signaling cascade (Kumazoe et al. 2013). Simi- EGCG is the ester of epigallocatechin and gallic acid and larly to other polyphenolic compounds, the effect of EGCG it is the most abundant polyphenol in the green tea. In in cancer cells is pleiotropic. It inhibits the activities of PTKs addition to green tea, EGCG is present in trace amounts (EGFR, FGFR, PDGFR, HER2/neu tyrosine kinases) and in apples, plums, onions, hazelnuts, pecans, etc. Aktkinase(Liang etal. 1997; Pianetti et al. 2002)via Experimental data demonstrate that EGCG inhibits STAT3, PI3K, mTOR, and NF-κB signaling pathways tumor cell proliferation, adhesion and invasion and in- (Masuda et al. 2002; Van Aller et al. 2011). Results duces apoptosis in variety of cancers including those of from in vitro study by using MDA-MB-231 cells dem- the breast (Fig. 2) (Ahmad et al. 1997; Yang et al. 2009; onstrated that EGCG modulates cell matrix adhesion Shammas et al. 2006). Treatment of 4 T1 cells with molecules and growth factor receptors through FAK/ERK EGCG decreases Bcl-2 expression and mitochondrial signaling pathway mechanism (Sen & Chatterjee 2011). disruption thus releasing cytochrome C as well as up- IGCG also inhibits the expression and activities of regulating Apaf-1, leading to the cleavage of caspase MMP-2 and -9 (Sen et al. 2009;Yang et al. 2005; 3 and poly [ADP-ribose] polymerase (PARP) proteins Sen et al. 2010) (Farabegoli et al. 2011), and this (Baliga et al. 2005). In the same study, oral administra- seems to be the main driver for its anti-metastatic tion of green tea polyphenols to 4 T1-xenografted BALB/c actions (Yang & Wang 1993). The inhibition of Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 8 of 17 MMPs can be explained by the fact that EGCG sup- and in vivo studies demonstrated that kaempferol has presses FAK, PI3K, and ERK which further leads to pleiotropic effects in cancer targeting cancer cell pro- downregulation of EGF (Sen & Chatterjee 2011). In liferation, apoptosis and mobility, tumor growth, addition, the suppression of MMPs involves epigen- angiogenesis and metastasis (Fig. 3)(Kim&Choi etic induction of TIMP-3 levels through inhibition of 2013; Calderón-Montaño et al. 2011;Boam 2015;Sri- the enhancer of zeste homolog 2 (EZH2) and class I nivas 2015). Kaempferol is an endocrine-disruptor histone deacetylases (HDACs) (Deb et al. 2014). that influences the activity of ER, having both, estro- Short-term supplementation with the active compounds genic and anti-estrogenic properties (Calderón-Mon- in green tea in men with prostate cancer showed that taño et al. 2011). This makes kaempferol potentially EGCG significantly reduces serum levels of VEGF useful in ER-positive breast cancers, where it sup- (McLarty et al. 2009). Based on experimental data, it ap- presses tumor growth by ER-dependent mechanism pears that plasma concentrations of EGCG comparable to (Oh et al. 2006). those observed in regular green tea consumers are suffi- Kaempferol interacts with major signaling pathways cient to inhibit MMPs and thus to affect negatively the in- such as ERK1/2 (Aiyer et al. 2012), MAPK (Li et al. vasion potential and metastasis in breast cancer patients 2015), and p53 (Calderón-Montaño et al. 2011), and is a (Garbisa et al. 2001). potential anti-metastasis agent. It inhibits the invasion, In addition of suppressing tumor growth, ECGC was adhesion, and migration of U-2 osteosarcoma cells found to modulate tumor microenvironment by redu- (Chen et al. 2013). Anti-metastatic effects of kaempferol cing TAM infiltration (Jang et al. 2013). In the same were observed in SCC4 oral cancer cells where it downreg- study, ex vivo incubation of TAM with exosomes from ulated MMP-2 and TIMP-2 mRNA and protein expression ECGC-treated mouse mammary tumor 4 T1 cells by suppressing c-Junactivity(Lin et al. 2013). Recent study skewed macrophages from tumor-promoting M2-like found that kaempferol inhibits MDA-MB-231 breast can- to tumor-inhibitor M1-like phenotype (Jang et al. cer cell adhesion, migration and invasion, and reduces lung 2013). Further, EGCG targets tumor microenviron- metastasis incidence in mice (Li et al. 2015). ment by preventing and reversing the advancement of The mechanisms behind the anti-metastatic effects of fibroblast-mediated effects by inhibiting signaling cas- kaempferol include supression of MMPs (MMP-2 and cades downstream of TGFβ (Gray et al. 2014). MMP-9) and uPA expression and activity via ERK, p38, JNK, and MAPK signaling (Chen et al. 2013). Kaemp- Other phyto-polyphenols ferol inhibits the translocation of the MAPK upstream Along with the above discussed phyto-polyphenols, a num- regulator PKCδ from the cytoplasm to the plasma mem- ber of other compounds have been investigated for their brane where it is physiologically active, thus suppressing anti-carcinogenic properties, including anti-metastatic ac- MAPK signaling pathway (Li et al. 2015). Another mech- tions. Plants rich in these polyphenolic compounds have anism by which kaempferol suppress metastasis is by been used for centuries in culinary and traditional medicine. inhibiting VEGF production as demonstrated in ovarian cancer OVCAR-3 cells in vitro (Luo et al. 2008). In the Kaempferol same cell line, kaempferol was also shown to downregu- Kaempferol (3,5,7-Trihydroxy-2-(4-hydroxyphenil)-4H-chro- late cMyc and promote apoptosis (Luo et al. 2010). Add- men-4-one) is a naturally occurring flavonol in broad range itionally, kaempferol inhibits lymphangiogenesis, which of plants from Pteridophyta, Pinophyta and Angiospermae is an integral step in the metastatic process. It reduces divisions. Among the commonly consumed foods contain- the density of tumor-associated lymphatic vessels as well ing kaempferol are grapes, green tea, apples, tomatoes, pota- as the incidence of lymph node metastases in breast can- toes, onions, broccoli, squash, Brussels sprouts, cucumbers, cer xenograft models in a VEGFR2/3 kinase manner lettuce, green beans, peaches, blackberries, raspberries, (Astin et al. 2014). spinach, etc. Kaempferol is actively absorbed in the small intestine and can be found in the plasma in nanomo- Curcumin lar concentrations (Calderón-Montaño et al. 2011). This Curcumin (s. diferuloylmethane, E100 (Natural Yellow 3)) polyphenol is easily metabolized in the liver and is delivered ((1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-hepta- to various other organs in the form of glucuronides and diene-3,5-dione) is a natural diarylheptanoid polyphenol sulfoconjugates (Calderón-Montaño et al. 2011). derived from turmeric plant (Curcuma longa) belonging To date, kaempferol has been shown to exert a variety to the ginger family (Zingiberaceae). Turmeric is common of effects including antioxidant, anti-inflammatory, ingredient of the traditional Indian cuisine (main ingredi- anti-microbial, anxiolytic, anti-allergic as well as ent of curry) as well as it is used worldwide as a food addi- anti-carcinogenic and cancer preventive activities tive for coloring (bright-yellow agent E100). Additionally, (Calderón-Montaño et al. 2011). Multiple in vitro turmeric is known for its medicinal properties. Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 9 of 17 Fig. 3 Effects of kaempferol on breast cancer metastasis Powdered turmeric underground stems (rhizomes) more sensitive to curcumin than the non-carcinogenic have been used for more than 6000 years for treating epithelial MCF-10A cells (Ramachandran & You 1999). broad range of conditions related to inflammation, al- The anti-carcinogenic properties of curcumin are lergies, parasitic infections, respiratory diseases, dia- pleiotropic and are based on its effects on both, the betes, neurodegenerative diseases and many others. tumor cells and the tumor microenvironment. For Turmeric-derived curcumin has also well established example, curcumin can modulate inflammatory anti-carcinogenic activities on cell transformation, pathways and tumor progression and metastasis, af- proliferation, apoptosis, survival, invasion, metastasis, fecting tumor cell survival, proliferation, and invasiveness adhesion as well as angiogenesis. The anti-carcinogenic (Gupta et al. 2010). Curcumin as well as other plant-derived effects of curcumin have been demonstrated in different natural polyphenols such as EGCG or resveratrol, induce studies on hematogenous, multiple myeloma, glioblastoma, epigenetic changes (inhibition of DNA methyltransfer- skin, head and neck, lung, colon, prostate, breast, and other ases (DNMTs), regulation of histone acetyltransferases types of cancer (Bachmeier et al. 2007; Kuo et al. 1996;Sung (HATs) and HDACs, or microRNA modulation) et al. 2009;Dhandapani etal. 2007; Limtrakul et al. 1997; (Gonwa et al. 1989)thatlead to suppressionof EMT Wilken et al. 2011; Moghaddam et al. 2009;Chenetal. and metastasis (Bandyopadhyay 2014; Bachmeier et al. 1999; Kawamori et al. 1999; Johnson & Mukhtar 2007; 2007; Kunnumakkara et al. 2008). Chendil et al. 2004; Mehta et al. 1997; Huang et al. 1998; The anti-metastatic action of curcumin involves Killian et al. 2012). inhibition of MMP-2, − 9, and MT1-MMP (Ohashi et Curcumin is poorly metabolized and extensively ex- al. 2003; Kim et al. 2012)(Fig. 4). Curcumin acts as spe- creted. It can be found in low concentrations in plasma cific supressor of p300/CREB-binding protein and affects and variety of tissues (Anand et al. 2007). Despite its lower major signalling pathways, protein tyrosine kinases and bioavailability, curcumin in low concentrations has been cytokines such as MAPK (Kim et al. 2012), JAK2/STAT3, shown to possess toxicity selectively to cancer, but not to Src/Akt (Saini et al. 2011), c-Jun/AP-1 (Collett & untransformed cells (Syng-Ai et al. 2004). For example, Campbell 2004), PKC (Garg et al. 2008), sonic hedgehog experimental data showed that human multidrug-resistant (Elamin et al. 2010), CXCL1 and 2 (Killian et al. 2012), etc. breast cancer MCF-7/TH cells are approximately 3.5-fold It also inhibits HDACs 1, 3, and 8 and HATs enzyme Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 10 of 17 Fig. 4 Effects of curcumin on breast cancer metastasis activities and modulates chromatin modification By inhibiting NF-κB signaling, curcumin suppresses me- (Balasubramanyam et al. 2004;Reuteret al. 2011). In tastasis in the very early stages of EMT. In lipopolysacchar- addition, curcumin suppresses NF-κB signaling by ide (LPS)-induced EMT in MCF-7 and MDA-MB-231 negative modulation of IKK, either directly or through cells, curcumin downregulated the expression of vimentin action of its upstream activators (Bharti et al. 2003; and upregulated those of E-cadherin as well as inhibited Jobin et al. 1999), preventing in such a way phos- LPS-induced morphological transformation of the cells phorylation of IκB (Plummer et al. 1999). Curcumin through inactivation of NF-κB-SNAIL signaling pathway abolishes the DNA binding of NF-κBand inhibits re- (Huang et al. 2013). porter gene expression in H1299 non-small cell lung Curcumin acts also as a phytoestrogen (Bachmeier carcinoma cell line, thus downregulating MMP-9 et al. 2010). The anti-proliferative effects of curcumin activation (Shishodia et al. 2003). In mice, where were found to be estrogen-dependent in ER-positive MDA-MB-231 breast cancer cells were injected intra- MCF-7 counteracting the estrogen responsive element cardiac, oral curcumin administration significantly re- (ERE)-CAT activities of estradiol (Shao et al. 2002). duced the number of lung metastases (Bachmeier et HER2/neu-positive or tamoxifen-resistant breast tu- al. 2007). This effect was most likely a result of in- mors are associated with specific microRNA signa- hibition of NF-κB activity and transcriptional down- ture, including overexpression of miR-181 (Miller et regulation of AP-1 and downregulation of cyclin D1, al. 2008;Loweryetal. 2009). In breast cancer, curcu- COX-2, and MMP-9, which further leads to inhibition min was shown to inhibit metastasis by inducing the of the breast cancer cell metastasis (Aggarwal et al. expression of miR-181b and downregulatinng those of 2005; Kim et al. 2012). CXCL-1 and -2 (Kronski et al. 2014). Chronic inflammation is considered to be a major factor A variety effects on tumor microenvironment were de- in tumor progression. For example, chronic prostatitis, scribed after curcumin treatment. In colon cancer, curcu- chronic obstructive pulmonary disease, inflammatory min interacts with the stromal fibroblasts in the colon bowel disease or chronic pancreatitis – all represent risk tumor microenvironment thus suppressing their crosstalk factors for developing prostate, lung, colon or pancreatic with CSCs (Buhrmann et al. 2014). Treatment with cancer. Curcumin inhibits chronic inflammation by dis- curcumin-polyethylene glycol conjugate (an amphiphilic rupting the feedback loop between NF-κB and the curcumin-based micelle) suppressed the percentage of pro-inflammatory cytokines, CXCL-1 and -2 (reviewed by myeloid-derived suppressor cells (MDSCs), which was Bandyopadhyay (Bandyopadhyay 2014)). suggested to be the reason behind the observed Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 11 of 17 inhibition of Treg and the activation of the effector T-cells anti-angiogenic effects, and inhibition of cancer metasta- (Lu et al. 2016). Combination of curcumin and ECGC in- sis incidence by effects on tumor proliferation, migration hibits colorectal carcinoma microenvironment-induced and invasion. These properties have been demonstrated angiogenesis by activating JAK/STAT3/IL-8 signaling in various cancer types such as sarcoma (Nagase et al. pathway (Jin et al. 2017). Curcumin downregulates 2001; Su et al. 2013), multiple melanoma (Ishitsuka et al. the expression of VEGF as shown in prostate cancer 2005), leukemia (Hirano et al. 1994; Hibasami et al. cells (Gupta et al. 2013) and blocked IL-1 and VEGF 1998; Battle et al. 2005), lung (Yang et al. 2002; Singh & expression in chondrosarcoma cells (Kalinski et al. 2014). Katiyar 2013), skin (Konoshima et al. 1991), pancreas Currently, curcumin is an object of more than 120 (Bai et al. 2003), ovary (Li et al. 2008), prostate clinical trials evaluating its effects against different (Shigemura et al. 2007), colorectal (Wang et al. 2004), maladies including cancer. breast (Nagalingam et al. 2012; Avtanski et al. 2014), and other cancers (Nagase et al. 2001; Garcia et al. 2008; Honokiol Deng et al. 2008; Chen et al. 2011; Chang et al. 2013). Honokiol is a biphenolic lignan with bioactive para-allyl One important characteristic of honokiol is that it easily and ortho-allyl phenolic groups, a product of Magnolia crosses the blood-brain barrier and achieves significant sp. (M. biondii, M. obovate, and M. officinalis) that dem- serum concentrations because of its hydrophobic and onstrates promising actions on tumor metastases. Bark lipophilic properties (Wang et al. 2011; Lin et al. 2012; or seed cones of magnolia plants has been used for Woodbury et al. 2013). centuries in the traditional Asian medicine for its Honokiol has pleiotropic effects in the cells (Fig. 5), anti-inflammatory, antithrombotic, anxiolytic, anti- including modulation of NF-κB(Tseetal. 2005;Lee depressant, antispasmodic, antioxidant, and antibacterial et al. 2005; Ahn et al. 2006;Sheuetal. 2008;Arora effects and its protective action against hepatotoxicity, et al. 2011), MAPK (Kim et al. 2012; Zhang et al. neurotoxicity and angiopathy (Fried & Arbiser 2009; Lee 2014), STAT3 (Rajendran et al. 2012;Avtanskiet al. et al. 2011). The anti-carcinogenic activities of honokiol 2014), Akt [238,], VEGF (Wen et al. 2015), ERK (Zhu et range from tumor suppression, pro-apoptotic and al. 2014; Yeh et al. 2016), s-Scr (Park et al. 2009), and Fig. 5 Effects of honokiol on breast cancer metastasis Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 12 of 17 other major signaling pathways (Fried & Arbiser 2009). metastasis initiation and progression by targeting both, For example, in SVR angiosarcoma cells, honokiol induces cancer cells and cancer microenvironment. Novel strat- apoptosis by suppressing the phosphorylation of ERK, egies for targeting metastasis aim to modulate the levels Akt, and c-Src (Bai et al. 2003). In addition to its of specific microRNAs that play a role in the transform- anti-proliferative properties, honokiol inhibits the migra- ation of the malignant cells. This approach could be tion and tube formation of human umbilical vein endothe- used against CSCs or cells undergoing EMT that are lial cells (HUVECs) and suppresses angiogenesis in typically drug resistant (Li et al. 2010). Importantly, zebrafish angiogenesis model (Zhu et al. 2011). Honokiol some phyto-polyphenolic compounds have been shown downregulates IKK activation and thus inhibits NF-κBsig- to exert beneficial effects through direct modulation of naling pathway and MMP-9, TNFα,IL-8, ICAM-1,and specific microRNAs at low concentrations. MCP-1 expression (Tse et al. 2005; Lee et al. 2005;Ahn et Natural polyphenolic compounds are usually charac- al. 2006;Sheu et al. 2008). It also inhibits the migration terized by low level of toxicity, but main disadvantage is and invasion of MCF-7 and MDA-MB-231 cells by upreg- their poor bioavailability and weak resorption reaching. ulating the activity of liver kinase B1 (LKB1) leading to ac- In this regard, new strategies for target-specific delivery tivation of AMP-activated protein kinase (AMPK) have been experimentally developed and proven to be ef- (Nagalingam et al. 2012). In vivo, honokiol inhibited fective. Recent advances in nano-medicine open the tumor growth of MDA-MB-231 cells-xenografted nude doors for the development of vehicles for drug delivery mice by blocking breast cancer cellular proliferation with long-circulation that can be used to target trans- (Nagalingam et al. 2012). Our in vitro and in vivo studies formed cells. Polyphenolic compounds administered by revealed that honokiol inhibits EMT of breast cancer cells traditional methods are not always effective because of by suppressing STAT3 signaling resulting in repression of they are poorly absorbed and extensively excreted. But ZEB1 expression and its recruitment on the E-cadherin pro- the chemopreventive efficacy of these polyphenols can moter (Avtanski et al. 2014). Honokiol modulated micro- be significantly improved by encapsulating them into RNA profile in the breast cancer cell, specifically amplifying nonoparticles. Thus, integration of various disciplines miR-34a expression in a STAT3-dependent manner, inhibit- such as biochemistry, molecular biology, chemistry, and ing Wnt1-metastatic-associated protein 1 (MTA1)-β-catenin nanotechnology could contribute to the development of signaling axis (Avtanski et al. 2015a). The mechanism be- novel therapies against breast cancer methastasis. hind the effects of honokiol on EMT and breast cancer mi- This paper is dedicated to the memory of Rumiana gration involves induction of SirT1, SirT3 and miR-34a Cherneva, who lost the battle with breast cancer. expression and cytoplasmic localization of LKB1 (Avtanski Abbreviations et al. 2015b). 67LR: 67-kDa Laminin Receptor; AMF: Autocrine Motility Factor; AMPK: 5’ Aside from directly targeting tumor cells, honokiol AMP-Activated Protein Kinase; AP-1: Activator Protein-1; BCL: B-Cell was also demonstrated to have effects on tumor micro- Lymphoma; C/EBPα: CCAAT-Enhancer Binding Protein-Alpha; CAA: Cancer- Associated Adipocyte; CAF: Cancer-Associated Fibroblast; CAM: Cell Adhesion environment. Honokiol decreased desmoplasia in pan- Molecule; CCL2: Chemokine (C-C motif) Ligand 2; COX: Cyclooxygenase; creatic tumor xenografts, as characterized by reduced CSC: Cancer Stem Cells; CXCR4: C-S-C chemokine Receptor type 4; secretion of extracellular matrix protein (collagen I) and DNMT: DNA Methyltransferase; EC: Epicatechin; ECG: Epicathechin Gallate; ECM: Extracellular Matrix; EGC: Epigallocatechin; EGCG: Epigallocatechin-3- suppressed myofibroblast marker α-smooth muscle actin Gallate; EGF: Epidermal Growth Factor; EGFR: Epidermal Growth Factor (α-SMA) immunostaining (Averett et al. 2016). Findings Receptor; EMT: Epithelial-to-Mesenchymal Transition; ER: Estrogen Receptor; from the same study revealed an inhibitory effect of ERE: Estrogen Responsive Element; ERK: Extracellular-Signal-Regulated Kinase; EZH: Enhancer of Zeste Homolog; FAK: Focal Adhesion Kinase; FGFR: Fibroblast honokiol on C-S-C chemokine receptor type 4 (CXCR4) Growth Factor Receptor; FOXO1: Forkhead Box O1 Protein; GC: Gallocatechin; signaling, which is known to play an important role in GCG: Gallocatechin Gallate; HAT: Histone Acetyltransferase; HDAC: Histone the crosstalk between the tumor and the stromal cells. Deacetylase; HER2: Human Epidermal Growth Factor Receptor 2; HUVEC: Human Umbilical Vein Endothelial Cells; IFNγ: Interferon-Gamma; IkB: Inhibitors of kappa B; IKK: Inhibitors of kappa B Kinase Kinases; IL: Interleukin; LKB1: Liver Kinase B1; Conclusions LPS: Lipopolysaccharide; α-SMA: Alpha-Smooth Muscle Actin; MAPK: Mitogen- Nature is abundant in chemicals with potential thera- Activated Protein Kinases; MAPKK: Mitogen-Activated Protein Kinase Kinase; M-CSF: Macrophage Colony-Stimulating Factor; MDSC: Myeloid-Derived peutic effects that are worth studying. A variety of poly- Suppressor Cells; MEKK: MAPK/ERK Kinase Kinase; miR: MicroRNA; MMP: Matrix phenols from plant origin demonstrate pleiotropic Metalloproteinase; MSP: Motility-Stimulating Protein; mTOR: Mammalian Target therapeutic properties against a broad range of patho- of Rapamycin; NF-κB: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells; NIK: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B logical conditions, including different types of cancer. Cells-Inducing Kinase; NFKBIA: Nuclear Factor of Kappa Light Polypeptide Such polyphenolic compounds can be viewed as promis- Gene Enhancer in B-Cells Inhibitor-Alpha; ODC: Ornithine Dacarboxylase; ing candidates for supplements to the traditional cancer PAI: Plasminogen Activator Inhibitor; PARP: Poly [ADP-Ribose] Polymerase; PDGFR: Platelet-Derived Growth Factor Receptor; PI3K: Phosphatidylinositol-3- prevention and treatment modalities as well as a basis Kinase; PKC: Protein Kinase C; PR: Progesterone Receptor; RAF: Rapidly for designing novel synthetic drugs. Naturally derived Accelerated Fibrosarcoma Kinase; ROS: Reactive Oxygen Species; RTK: Receptor plant polyphenols have been demonstrated to inhibit Tyrosin Kinase; SERM: Selective Estrogen Receptor Modulators; TEC: Tumor Avtanski and Poretsky Molecular Medicine (2018) 24:29 Page 13 of 17 Endothelial Cells; TIL: Tumor-Infiltrating Lymphocyte; TIMP: Tissue Inhibitors of Azios NG, Dharmawardhane SF. Resveratrol and estradiol exert disparate effects Metalloproteinases; TNFα: Tumor Necrosis Factor-Alpha; uPA: Urokinase-Type on cell migration, cell surface actin structures, and focal adhesion assembly Plasminogen Activator; VEGF: Vascular Endothelial Growth Factor; XIAP: X-linked in MDA-MB-231 human breast cancer cells. Neoplasia. 2005;7:128–40. Inhibitor of Apoptosis Protein Bachmeier BE, et al. The chemopreventive polyphenol curcumin prevents hematogenous breast cancer metastases in immunodeficient mice. Cell Physiol Biochem. 2007;19:137–52. Availability of data and materials Bachmeier BE, et al. Reference profile correlation reveals estrogen-like Data sharing not applicable to this article as no datasets were generated or trancriptional activity of curcumin. Cell Physiol Biochem. 2010;26:471–82. analyzed during the current study. BaiX,et al. Honokiol,a smallmolecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem. 2003;278:35501–7. Authors’ contributions Balasubramanyam K, et al. Curcumin, a novel p300/CREB-binding protein-specific DA drafted the manuscript. LP revised the manuscript critically. Both authors inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone read and approved the final manuscript. proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 2004;279:51163–71. Ethics approval and consent to participate Baliga MS, Meleth S, Katiyar SK. Growth inhibitory and Antimetastatic effect of Not applicable. green tea polyphenols on metastasis-specific mouse mammary carcinoma 4T1 cells in vitro and in vivo systems. Clin Cancer Res. 2005;11:1918–27. Bandyopadhyay D. Farmer to pharmacist: curcumin as an anti-invasive and Competing interests antimetastatic agent for the treatment of cancer. Front Chem. 2014;2:113. The authors declare that they have no competing interests. Banerjee S, Bueso-Ramos C, Aggarwal BB. 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Molecular MedicineSpringer Journals

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