Epithelial Mesenchymal Transition in Cancer Progression:

Preventive Phytochemicals

Soorya Parathodi Illam 1, Arunaksharan Narayanankutty 2, Shaji Edappilly Mathew 3, Remya

Valsalakumari 4, Rosemol M. Jacob 5 and Achuthan C. Raghavamenon*

Dept. of Biochemistry, Amala Cancer Research Centre, Amala Nagar P.O., Thrissur, Kerala- 680555

Running title: Phytochemicals in prevention of pathologic EMT

*Corresponding author,
Dr. Achuthan C. Raghavamenon,
Associate Professor, Dept. of Biochemistry,
Amala Cancer Research Centre, Amala Nagar P.O.,
Thrissur- 680 555, Kerala, India.
Fax: +91 487 2307950
Phone: +91- 9567 988570
Email: raghav@amalaims.org

1
Junior Research Fellow, Department of Biochemistry, Amala Cancer Research Centre,
Thrissur, Kerala, India; Email: pisoorya@amalaims.org
2
Senior Research Fellow, Department of Biochemistry, Amala Cancer Research Centre,
Thrissur, Kerala, India; Email: arunaksharan.n@amalaims.org
3
FDP fellow (UGC), Department of Biochemistry, Amala Cancer Research Centre, Thrissur,
Kerala, India; Email: shajiem007@gmail.com
4
Senior Research Fellow, Department of Immunology, Amala Cancer Research Centre,
Thrissur, Kerala, India; Email: remyachandran1986@gmail.com
5
M. Phil Scholar, Department of Biochemistry, Amala Cancer Research Centre, Thrissur,
Kerala, India; Email: acrcbiochemistry@gmail.com
Abstract

Background: Epithelial-Mesenchymal Transition (EMT) is the conversion of epithelial cells

into mesenchymal phenotype generally observed during embryogenesis and wound healing as

well as in malignant transformation. Several signaling pathways and transcription factors

associated with EMT have been explored. Dietary phytochemicals are multi-targeted agents

that interfere with these pathways, assume preventive potential against pathologic EMT.

Objective: Present review aims to provide a detailed description on the nature, characteristics

of EMT in physiological and pathophysiological conditions and the scope of phytochemicals

in its prevention.

Method: Details regarding the initiation, progression as well as prevention of pathologic

EMT and metastasis and recent patents on preventive phytochemicals are obtained from

PubMed literatures and patent databases.

Results: The phenotypic changes during EMT are regulated by transcription factors like

Snail, Slug, Twist and Zeb, which are activated through diverse signaling pathways of TGF-

β, NF-κB, Wnt and Notch. Scientific documentations till date have identified numerous

phytocompounds that are potent enough to interfere with these signaling pathways, which in

turn prevent pathological implications of EMT. Present review also discusses 28 recent

patents on those phytocompounds.

Conclusion: EMT is a significant pharmacological target for developing preventive agents to

combat pathological conditions like malignancy. Many of the phytochemicals cited in this

review are being enrolled for different phases of clinical trials for their efficacy. In spite of

the major limitations regarding bioavailability, sensitivity and tolerance of these compounds,

their synthetic analogs, formulations and efficient drug delivery systems are also being

attempted which will hopefully generate productive and promising results in near future.

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Keywords: Cancer metastasis; epithelial mesenchymal transition; natural products; patents;

phytochemicals; signaling pathways; transcription factors.

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1. Introduction

Epithelial cells show their apical–basal polarity, adhere and communicate with each other

through specialized intercellular junctions and position on a basement membrane that helps to

define their physiology. On the other hand, mesenchymal cells can invade and migrate

through the extra cellular matrix (ECM) to create dramatic cell transpositions [1]. Epithelial

mesenchymal transition (EMT) is a process in which epithelial cells show characteristic

alterations in gene expression pattern and increased potential for motility, enabling them to

break through the basal membrane and migrate over a long distance [2, 3]. It makes a

polarized epithelial cell, which usually interacts with basement membrane via its basal

surface, to experience multiple biochemical changes that allow the cell to assume

mesenchymal cell morphology (Fig. 1). These mesenchymal cells are characterized by

enhanced migratory capacity, invasiveness, high resistance to apoptosis, and significantly

increased production of ECM components [4]. EMT is important for generating multiple

tissues during organogenesis and plays important role in cellular reorganization during

wound healing. In addition EMT also occurs in pathological conditions, including

carcinogenesis and fibrosis (tumorigenic EMT). In contrast to the embryonic EMT,

tumorigenic EMT produces genetically abnormal cells that are insensitive to normal growth

regulatory signals [5]. Immune privilege might be essential for EMT orchestrated during

embryo development, while inflammation and epigenetics are likely the key inducers of

tumorigenic EMT [6]. Based on the non-pathogenic and pathogenic conditions, three EMT

types are recognized. Type 1 EMT, which is associated with embryogenesis and organ

development, mainly designed to generate the primary mesenchyme [7]. Type 2 EMT

includes non-cancerous processes that involve inflammatory changes associated with

movement of fibroblasts during tissue repair and regeneration, wound healing and fibrosis [8-

4
10]. Type- 3 EMT is described in metastatic malignancy, where loss of inter cellular adhesion

and epithelial polarity resulting in the cytoskeletal changes are visible [11-13].

EMT is becoming a major concern in the arena of medical and radiation oncology, as both

therapeutic drugs as well as radiations are known inducers of EMT in various cancer cells.

Drug resistant cancer cells have shown to acquire various growth, survival and invasive

capability due to changes in the expression of molecules associated with EMT and thus

become a primary target for drug development. Recently, several natural products, especially

of plant origin have been investigated for their ability to inhibit pathologic EMT. Among

these compounds, the most important ones are dietary phytochemicals, as they confer

therapeutically safe doses and nutritively beneficial.

2. EMT and Cancer Progression

Increased rate of epithelial cell proliferation and angiogenesis are strong indications of the

initiation and early growth of primary epithelial cancers [14]. Many studies have reported that

carcinoma cells can acquire a characteristic mesenchymal phenotype and express

mesenchymal markers such as α- smooth muscle actin (α-SMA, an actin isoform

characteristic of smooth muscle cells and increased expression of this leads to increase

fibroblast contractile activity), Fibroblast-specific protein 1 (FSP1, also called S100A4,

which is considered as a marker of fibroblasts in different organs undergoing tissue

remodeling and is capable of modulating the activities of other proteins such as components

of cytoskeleton by interacting with them [15]), vimentin (a major constituent of the

intermediate filament family of proteins) and desmin (a muscle-specific protein which is

essential for the maintenance of structural integrity) [16, 17]. These cells are usually present

at the invasive front of primary tumors and they can enter into the metastasis cascade which

involves sequential steps of intravasation, transport through the circulation, extravasation,

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arrest at physiologically favorable sites leading to the formation of micro metastases and

colonization leading to establishment of secondary tumors. During local invasion of the

epithelial primary tumor cells to the nearby tissues, the cells lose their polarity, become

motile and degrade the underlying basement membrane and ECM to escape from the primary

site. This is followed by the traverse of tumor cells across the endothelial lamina into the

blood or lymphatic vessels and thus entering the systemic circulation (intravasation) where

the cells should survive by resisting the shear forces, anoikis alarms and detection by immune

cells, referred to as systemic transport. Thus only a small number of cells that could resist

these oxidative insults will only be get arrested at the capillary beds of particular subsets of

target tissues. Moreover, action of certain tissue-specific proteins in the microenvironment

will determine the fate of the disseminated circulating tumor cells (CTCs) in order to decide

the colonization site. Subsequently, the extravasation of these cells through the capillary

endothelium into the parenchyma of distant organs is not a passive process but involves the

release of various growth factors and proteins by the tumor cells to increase the permeability

of endothelial and pericyte layers of blood vessels. Thereafter, the initial survival of these

CTCs in the foreign environment and further colonization depends on the hospitability of the

host tissue whose ECM components and micro-architecture differ ostensibly. Concomitantly,

the tumor cells will deploy heterotypic signaling in order to modify the foreign

microenvironment and also initiate cell autonomous mechanisms in order to survive there for

successfully establishing micro metastases. The final step of metastatic cascade is the

metastatic colonization, where, only those disseminated tumour cells, which could overcome

the robust microenvironment stresses and synchronously activated self-renewal mechanisms,

establish at the metastatic sites to form malignant macro metastases that are clinically evident

and ultimately life-threatening along with the assistance of pleiotropically acting regulatory

molecules [16, 18-20].

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The surrounding environments of metastasizing tumor masses usually abide low oxygen

concentrations, generally termed as hypoxic. Hypoxia induces tumour progression which is

mainly mediated through the hypoxia inducing factor-1 (HIF-1), a dimeric protein complex

that plays an integral role in the body's response to hypoxia, by the induction of alternative

metabolic pathways within cancer cells mainly by regulating anaerobic metabolic pathways.

Most aerobic cells usually depend on oxidative phosphorylation for their energy requirements

under sufficient oxygen supply. However, in hypoxic environments, there occurs a shift to

anaerobic metabolism for the purpose and HIF-1 is one of the principal genes to coordinate

this change by inducing a number of glycolytic enzymes such as aldolase A and pyruvate

kinase M and other glucose transporters, which then help the cells for energy production [21,

22]. Some of the recent reports revealed the distinguished roles of HIF-1 and their target

molecules associated with the regulation of EMT. For instance, HIF-1α has been reported to

play crucial role in hypoxia-induced stimulation of hepatocyte EMT [23]. Moreover, the

Snail family of zinc finger transcription factors which suppress E-cadherin, the calcium-

dependent cell-cell adhesion molecule at the adherence junction of epithelial cells, has been

proved to be targeted by HIF [24]. Besides, Snail also regulates EMT during embryonic

development [25].

3. EMT Marker proteins

Changes from an epithelial phenotype to mesenchymal are aided by characteristic expression

patterns of several proteins, assisted with up regulation of molecules which helps in cell

motility and down regulation of those cell adhesion molecules which maintain cell-cell

interactions, thus assigning these molecules as remarkable markers of EMT. This

understanding has led to scientific search and resulting recognition of a number of proteins

involved in EMT regulation such as N-cadherin (Neural cadherin), β6 integrin, FSP-1,

7
vimentin, fibronectin, smooth muscle actin (SMA), desmin, Sox (a DNA binding protein),

SNAIL1/SNAIL, SNAIL2/SLUG, zinc finger E-box-binding homeobox 1 (ZEB1), Notch-1

(a trans membrane protein that act as a receptor for membrane-bound ligands Jagged1,

Jagged2 and Delta1 to regulate cell-fate determination), FLT-1 (Feline McDonough

Sarcoma- related tyrosine kinase 1, a vascular endothelial growth factor receptor),

stromelysin-3 (ST3; a metalloproteinase), Twist (an embryonic transcription factor), FOXC2

(Fork head box protein C2, a transcription factor associated with a number of cellular and

developmental differentiation processes), HOXB7 (Homeo box protein Hox-B7, transcription

factor involved in cell differentiation and proliferation), ACTA2 (Alpha- actin-2, involved

in cell motility, structure and integrity), platelet derived growth factor (PDGF) etc [26].

E-cadherin is referred to as a prototypical epithelial cell marker of EMT. This is because; E-

cadherin is consecutively expressed in epithelial cells whose down regulation is associated

with EMT during embryonic development, tissue fibrosis, and cancer [27]. The differential

expression patterns of different cadherins, the so-called cadherin switches, have been used to

screen EMT. In fact the significant cadherin switch from E-cadherin to N-cadherin, which is

expressed mostly in mesenchymal cells, fibroblasts, cancer cells, and neural tissue, has often

been used to monitor the progress of EMT during embryonic development and cancer

progression [28]. VE-cadherin is yet another kind expressed specifically by the endothelial

cells and found at the junctional complex, where cancer cells interact with them by means of

N-cadherins during transendothelial migration (TEM). Thus both the cadherins mediate cell

to cell bonding by holding the catenins in between which in turn connect the actin

cytoskeleton of the cells. The eventual detachment of this bonding is mainly assisted by up

regulation of Src kinase pathway which stimulates phosphorylation of β-catenin linked to

VE-cadherin and N-cadherin which in turn disrupt the VE cadherin-mediated bonds holding

endothelial cells leading to effect the trans-endothelial migration of cancer cells [29].

8
Caveolins are another class of structural proteins, which are necessary for caveolae

formation. Caveolin-1 is one among them which has been significantly implicated in cancer

initiation and progression stages [30]. Supporting evidence has been reported by Zhang et al.

[31] where they have shown that Cav-1 and E-cadherin expression is down regulated during

gastric cancer progression and metastasis.

The alterations in cell-ECM interactions is another characteristic feature of EMT and are

generally reflected by the changes in the expression of different integrins. Integrins mediate

signaling pathways that can promote EMT [32, 33] and some of the integrins are expressed

differentially upon both epithelial and mesenchymal cells. For instance, in colon carcinoma,

only those cells that have undergone type 3 EMT express high levels of β6 integrin while

normal epithelial cells as well as noninvasive cancer cells express low-levels of the same

[34]. Another EMT marker that reflects adaptation to the altered ECM microenvironment

associated with EMT is the collagen-specific receptor tyrosine kinase DDR2 (discoidin

domain receptor tyrosine kinase 2) [35]. DDR2 mediates up regulation of matrix

metalloproteinase 1 (MMP1) and cell motility upon binding to type I or type X collagen [35,

36]. It has also documented that ectopic expression of FSP1, a member of Ca2+ binding S100

family of proteins itself facilitates EMT in adult epithelial cells and cancer cells. Studies have

proved that as part of the molecular program of type 3 EMT, metastatic cells often express

FSP1 [28, 37, 38]. Furthermore vimentin is a mesenchymal marker that can be acquired

during EMT and have a positive correlation with increased invasiveness and metastasis. But

its expression is usually found low below detectable limits and most difficult to be quantified,

as compared with other EMT markers that indicate a mesenchymal-like phenotype [12, 39]. It

has also been reported that type 3 EMT is associated with α-SMA, whose expression is

mostly confined to breast cancer [40] and clinically evident in breast tumors of the “basal

phenotype” [41]. In addition, β-Catenin, a cytoplasmic plaque protein, has dual role in EMT:

9
it associates cadherins to the cytoskeleton and act as a co- transcriptional activator jointly

with TCF/LEF (T-cell factor-1 and lymphoid enhancing factor-1, a transcription factor family

protein which transmits Wnt signals by binding to beta-catenin and recruiting it to target

genes for activation) [42]. Even though β-catenin is localized to cell membranes in normal

epithelial cells and noninvasive tumor cells, it is located either in the cytoplasm or in the

nucleus in cells that undergo EMT [43].

Fibronectin, a glycoprotein that assist in scaffolding fibrillar ECM, is considered as another

marker protein involved in EMT [44]. Reports have shown that both type 2 and type 3 EMT

are associated with increased fibronectin expression in vitro [28, 45]. Of the principal

basement membrane constituents (type IV collagens, laminin and sulfated proteoglycans) that

are down regulated during EMT, laminin is identified as a biomarker of the process. Laminin,

a heterotrimeric glycoproteins present in ECM influence cell differentiation, migration and

adhesion [46] and it is reported that the up regulation of laminin 5 is associated with type 3

EMT in cancer and type 2 EMT in tissue fibrosis. Evidences suggest that laminin 5 is over

expressed in type 3 EMT associated with breast carcinomas of the ductal type [47] and

hepatocellular carcinoma [48]. In addition, matrix metalloproteinases (MMP-2, MMP-3, and

MMP-9) also influences the dismantling of epithelial cell membrane and remodeling of

extracellular matrix. These proteolytic enzymes may link the EMT with increased invasion

and metastasis, and shortened survival time in almost all types of human cancers [4, 49].

4. Complex Signaling Pathway

EMT is a multistep event which is linked to various signaling pathways including TGF-β, NF

КB, Wnt, Notch, and others [50]. TGF-β signaling pathway is a key player in promoting

tumor progression and metastasis [51, 52]. The major pathways involved in TGF- β induced

tumor EMT are Smad-dependent and Smad-independent transcriptional pathways. TGF- β

10
also activates various types of non-Smad signaling in certain types of cells and it has been

reported that Ras/Erk, c-Jun N-terminal kinase (JNK), phosphatidyl insitol-3 (PI3) kinase, Par

6, and Cdc 42 GTPases play important roles in TGF-β induced EMT [53, 54]. An elevated

expression level of the inflammatory cytokines (TNF-a, IL-6) and ROS (Reactive Oxygen

Species) generated crucially under oxidative stress can induce the activation of NF-КB

pathway in the tumor environment. NF-КB can then activate the expression of certain

transcription factors such as Snail and ZEB which induce EMT [55]. Moreover, Wnt/ β -

catenin and Notch pathway can significantly regulate the EMT in carcinoma cell lines [56].

There are also reports suggesting that the loss of E-cadherin caused by translocation of β-

catenin to the nucleus to induce EMT and subsequent β-catenin signaling maintain the

stemness properties of CSCs; (Cancer Stem Cells) in skin cancer [57].

5. Transcription Factors

The major group of transcription factors appear to affect many of the changes seen in EMT

include Snail, Slug, Twist, ZEB1 & 2 and the Smad proteins. During EMT, Snail is generally

renowned as a Wnt (Wingless-related integration site, coined from Drosophila melanogaster

wingless gene int-1) dependent suppressor of E-cadherin during EMT. It is also known to

regulate several other characteristics of the EMT phenotype, including elevated levels of

mesenchymal markers such as fibronectin and vitronectin (an ECM glycoprotein that

possesses binding sites integrins thus helping anchorage of cells to ECM), reduction in the

expression pattern of various epithelial cell markers (claudins, occludins, and cytokeratin),

regulation of cellular proliferation by negatively modulating the expression of cyclin D -

cyclin-dependent kinase 4 (CDK4), increased MMP expression and inhibition of cellular

apoptosis mediated by down regulation of caspases, DNA fragmentation factor, and the BID

(Bcl interacting death agonists) pro-apoptotic component of blc-2 family [58]. Twist is

11
another protein usually involved in the cellular lineage determination and differentiation, is

over expressed during cancer metastasis [2, 45, 59]. Twist can act without the aid of Snail to

repress E-cadherin during the progression of tumor metastasis [2] and to up regulate

fibronectin and N-cadherin [45]. Another transcription factor is Forkhead box C2 (FOXC2)

that acts as a pleiotropic inducer of EMT. Over expression of any one of the EMT inducers

TGF-β1, Snail, or Twist up regulate FOXC2 expression and can lead to the induction of

EMT, indicating an essential role for FOXC2 in pathological EMT [60]. ZEB 1& 2 are the

two highly conserved zinc finger proteins which down regulate the expression of E-cadherin

and some of the epithelial markers by directly binding to the promoter regions of target genes

[61] and up regulation of the expression of vimentin and a number of other mesenchymal

markers [62]. ZEB 1 and 2 are induced by TGF-β, hypoxic conditions and inflammatory

cytokines which then cause initiation of EMT. ZEBs play a major role in normal embryonic

development as well as they are found up regulated in many tumors [63].

6. Natural products in prevention of EMT

As EMT is a complex process mediated through the involvement of diverse cell signaling

pathways, there are multiple target sites having therapeutic scope. Any molecule which can

interfere with crucial target molecules that can modulate these signaling events associated

with the progression of EMT will be a good choice for anti-EMT drug development,

providing a better multi-targeted therapeutic approach in the treatment of cancer progression

and metastasis. Among the vast number of natural or synthetic compounds studied till date,

phytochemicals and dietary nutraceuticals, are in the limelight of anti-EMT drug

development.

Several anticancer drugs that are now being used clinically or undergoing phase trials are

focusing the pivotal signaling pathways of EMT, which include inhibitors of DNA methyl

12
transferase [64], protein kinase CK2 [65], TGF-β1 signaling [66] and expressions of

molecular targets such as snail, slug, twist and Zeb [67, 68]. Though these molecules are

found to be potent antimetastatic or anti-EMT agents, their actions likely to be mono-targeted

that are specific to certain pathways or molecules [69]. In comparison with the synthetic

molecules, natural phytochemicals such as curcumin and resveratrol are broad spectrum

agents with multi-targeted anticancer and anti-EMT effects [70, 71]. Compared to mono-

targeted synthetic molecules, multi-targeted natural products have potential to overcome

multidrug resistance, which makes them better candidate for anticancer and anti-EMT drug

development.

6.1 Curcumin

Curcumin is well known for its anticancer and anti angiogenic properties. Apart from these

effects, it also contributes to tumor reduction by means of inhibition of metastatic cascade

[72]. As EMT is an inevitable phenomenon involved in the metastatic conversion of

neoplastic cells, the associated pathways remains the primary target of curcumin. In breast

cancer cells, curcumin inhibits lipopolysaccharide (LPS) induced inflammatory changes and

subsequent EMT (Fig. 2a) through down regulation of NF-κB and Snail pathway and

reducing the vimentin levels [73]. In pancreatic cancer cells, curcumin shows inhibition of

transforming growth factor beta (TGF- β) as well as hypoxia induced EMT, up regulating

epithelial marker proteins such as E- Cadherin or down regulating hedgehog signaling and

vimentin [74, 75]. Furthermore, inhibition of TGF-β/Smad pathway has shown in a

chemically (cobalt chloride) induced model of EMT in hepatocytes [76]. Studies by Lee et al.

[77] show that curcumin inhibits the invasive potentials of oral cancer cell (SCC-25). The

effects are mediated by reducing the levels of matrix metalloproteinase (MMP 2 and 9), Snail

and Twist; modulation of p53-E-Cadherin axis is also observed under the same conditions

13
[77]. In phthalate induced model of EMT, curcumin exerts inhibitory effects by blocking the

ERK/SK1 pathway and reduces the stemness properties in cells [78]. Inhibition of Wnt

signaling by curcumin demonstrates another mechanism of EMT prevention in lung cancer

cells [79]. Curcumin also inhibits radiation induced EMT in both triple positive and triple

negative breast cancer cells by reducing mesenchymal characters [80]. MAP kinase and

PI3K/Akt inhibition by curcumin is also reported in prostate cancer cell, DU-145 [81] and it

has been suggested that the inhibitory effect of curcumin on the MPAK/Akt axis is modulated

by hepatocyte growth factor and c-Met repressions. Similar observations are also reported in

non-small cell lung cancer [82], thyroid cancer [83], and colon cancer [84] cells which again

confirm the inhibitory effect of curcumin on EMT induced cancer cell invasion and

metastatic properties. Above all, curcumin is proposed to be exceptionally different from

synthetic mono targeted drugs since it is a natural multi-targeted agent with differential effect

specifically on most of the cancer cells and its potential to overcome drug resistance of

cancer cells along with its chemo-sensitizing property [70].

With respect to the widely accepted pharmacological properties of curcumin, it also made

important leading patents than any other natural compounds studied. Curcumin analogs that

possess antitumor and anti-angiogenic properties are now patented [85, 86]. Moreover,

curcumin in its raw form as well as chemically modified curcuminoids which possess

antimetastatic and anti-angiogenic potentials have also been patented. Other relevant patents

include curcuminoids in combination with docetaxel [87], which is now being used in

treatment of various metastatic cancers and a novel curcuminoid- factor VIIa complex, which

is constructed as a cytotoxic compound that delivers curcuminoid, specifically to tumor

vasculature [88].

6.2 Sulforaphane

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Sulforaphane (SFN) is a potent phytochemical commonly found in cruciferous vegetables

such as broccoli, Brussels sprouts and cabbages [89]. Emerging evidences have shown that

intake of SFN as a dietary supplement can interfere with the process of various signaling

pathways associated with pathologic EMT. In human bladder cancer cells, SFN down

regulated the expression of COX-2/MMP2, 9/Snail, ZEB1 and miR-200c/ZEB1 pathways

involved in EMT [90], whereas in thyroid cancer, hepatocellular carcinoma and non-small

cell lung carcinoma, it reduces EMT by regulating ROS dependent pathways [91, 92] and

GSK3β/β-catenin pathways [93]. In addition, other pathological implications of EMT such as

angiogenesis [94] and cancer stemness [95, 96] in various cancers have been targeted by

SFN, which is partially being mediated by epigenetic modulations [97]. Antimetastatic

combinations comprising of sulforaphane with ursolic acid [98] and with mushroom powder

(maitake, shiitake, or reishi mushrooms) [99] have also been patented.

6.3 Grape compounds and resveratrol

Grapes are rich sources of several bioactive compounds such as phenolic acids, flavonoids

and peculiarly the stilbenes [100]. These phytochemicals are known to inhibit the process of

EMT by means of several mechanisms. Studies have reported the inhibitory effect of grape

seed proanthocyanidins on invasion and migration properties of head and neck squamous cell

carcinoma cells by means of down regulating NF-kB signaling and EGFR levels [101, 102].

Anthocyanins from Vitis coignetiae is also shown to have anti-EMT properties in human

uterine cervical cancer cells [103]. Recent studies have shown the inhibitory effect of

Muscadine grape skin extract on prostate cancer cell invasion by regulating Snail and STAT

3 expression [104-106]. Another flavonol widely present in grapes is Fisetin which could

prevent metastasis by targeting MAP kinase and NF-KB signaling in melanoma cells [107].

15
Among the bioactive compounds of grapes, resveratrol, a phytoalexin belonging to the class

of stilbenes, has gained much popularity. It is known to inhibit the process of carcinogenesis

in different ways including the inhibition of metastasis. Resveratrol and its synthetic

analogues exert its biological effects by regulating several cellular signaling pathways of

inflammation, cell proliferation and cell death [108]. Several of these pathways are interlined

with the process of cancer cell motility and metastasis by means of EMT. Studies have

reported that resveratrol inhibits the EMT associated with metastasis induced by hypoxia

[109], epidermal growth factor [110], LPS [111, 112], TGF-β1 [113] and Cisplatin [114]

(Fig. 2a). It has been shown that resveratrol modulates different mesenchymal characteristic

signaling pathways such as hedgehog [115], TGF-β1/Smad [116] and PI3K/Akt [117]. In

addition, it reduces stem cell like properties in pancreatic cancer cells [118] and tamoxifen

resistance in breast cancer cells [119].

Lycopene along with resveratrol is a patented dietary formulation that is proved to have

preventive effects on metastasis and angiogenesis in vitro [120]. Above mentioned

combination is also used for NK cell activation leading to anti-neoplastic [121]. This has led

to the development of newer combination comprising lycopene for the treatment and

prevention of angiogenesis associated pathologies [122]. Also stilbene analogs are patented

for its vascular damaging effect that helps to treat cancers [123].

6.4 Tea polyphenols and epigallocatechin gallate

Tea polyphenols have been recognized for their varied pharmacological properties such as

antioxidant, anti-inflammatory and anticancer effects. Based on the method of preparation,

individual quantities of each polyphenols may vary among different preparations, but all

those contain similar phenolic profile such as catechins, epigallocatechin gallate (EGCG) and

epigallocatechin. Green tea contains high amounts of these compounds, in particular, EGCG.

16
Inhibitory effect of both green tea and black tea polyphenols have been reported against skin

and oral cancer cells [124, 125]. These effects are mediated by the down regulation of

inflammatory signaling, especially the levels of prostaglandin and NF-κB (Fig. 2b). Among

the bioactive compounds, EGCG is reported to prevent TGF-β induced EMT by effectively

down regulating the phosphorylation cascade of Smad and Erk proteins, as well as reducing

the levels of various transcription factors such as Zeb1, Twist and slug [126]. Simultaneous

with these, EGCG causes up regulation of cell adhesion molecule E-Cadherin which leads to

inhibition of EMT. EGCG alone [127] and in combination with quercetin [128] is found to

reduce cancer stemness in prostate as well as nasopharyngeal cancer cells. Cancer stemness is

also reduced by EGCG in prostate as well as nasopharyngeal cancers. Apart from cancer,

EMT is also involved in the fibrotic damages to kidney cells, where EGCG found to exert its

protective effect by modulating Nrf2 pathway [129]. Latest studies conducted by Lu et al.

[130] has shown the protective effect of EGCG against tobacco smoke induced epithelial

mesenchymal transition by repressing the expression of Erk and its downstream target genes.

Several lines of experiments shows that intake of tea inhibits several type of tumors including

cancers of lungs and esophagus [131]. Such studies have led to the patency of

epigallocatechin- 3 gallate, the bioactive component, as inhibitor of angiogenesis [132]. In

addition, Chinese blackberry (Rubus suavissimus) extract and its major bioactive component

gallic acid which is found to possess anti-angiogenic potential has also been recently patented

[133].

6.5 Luteolin and kaempferol

Luteolin and kaempferol are the two common flavonoids present in a variety of edible items

such as peppers, broccoli and citrus fruits. Similar to other flavonoids, luteolin and

kaempferol are reported to have anticancer effects. As shown in Fig. 2b, luteolin inhibit EMT

17
in melanoma cells A431 [134] and B16F10 [135] melanoma cell lines. These effects are

mediated by down regulating the expression of matrix metalloproteinase and β3 integrin.

Other pathways that are found repressed by luteolin include PI3K/Akt/NF-KB axis [136] as

well as STAT3 signaling [137]. Compared to luteolin, dietary kaempferol is mainly act

against the EMT changes associated with respiratory epithelial cancers. Studies by Gong et

al. [138] has indicated that kaempferol efficiently block the EMT changes induced by LPS in

bronchial epithelial cells by impeding levels of N-Cadherin and smooth muscle actin.

Kaempferol is also shown to inhibit TGF- β induced EMT and invasiveness in lung cancer

cells by repressing the phosphorylation of Smad proteins by Akt, thereby reducing their

metastatic potentials [139].

6.6 Genistein

Genistein is an isoflavone present in a variety of edible vegetables especially those of

legumes. It has been shown that genistein reverses the EMT changes in prostate cancer cells

[140]. Similar results are also observed in studies conducted by Han et al. [141], where TGF-

β induced EMT is reduced by down regulating Erk/MMP expression. Further, in

hepatocellular cancer cells, genistein reduces the invasiveness by nuclear factor of activated

T cells 1 (NFAT1, member of NFAT family), which play a key role in the transcription of

cytokine and other immune responsive genes [142, 143]. In hormone responsive cancer cells,

a wide variety of environmental estrogens are reported to induce EMT. Under those

circumstances, genistein is reported to prevent the progression of EMT by inhibiting estrogen

receptor and TGF-β signaling [144].

6.7 Other compounds with anti-EMT activity

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Other than the aforesaid phytomolecules, several other nutraceuticals are also reported to

have protective effects against EMT and subsequent invasiveness of various cancers (Table

1). Citrus fruits are the well-studied among many fruit yielding plants, which contain

compounds such as naringenin, tangeretin and nobiletin are reported to inhibit Notch-1 as

well as TGF-β signaling and thereby reducing the invasive potentials of various cancers [145-

147]. Cruciferous vegetables are another source of anti-EMT compounds, which include

Indole-3-carbinol, indole [3, 2-b] carbazole and their derivative 3,3′-Diindolylmethane [148,

149], which are known to inhibit FAK signaling which controls cytoskeletal components and

integrin. Secoiridoids and oleanolic acids from olive [150, 151], mangostin [152], deguelin

[153], pinocembrin [154], and morusin [155] are other dietary nutraceutical components that

possess anti-EMT activities.

Another group of plant products, chalcones, of polyphenolic family have been described to

possess biological activities including antioxidant, anti-inflammatory and anticancer potential

[156]. Chalcone and its analogues have recently been patented as anti-angiogenesis agents

[157]. Pharmaceutical preparations containing chalcones or its derivative are also patented for

its matrix metalloproteinase inhibitory activities [158]. Yet another citable example includes

the use of apigenin in combination with chemotherapeutic agents for cancer prevention [159].

Further, different combinations of several plant phenols are presently being tested for their

antimetastatic activities. The combination of gallic acid, ellagic acid, and rubusoside are

patented as inhibitors of angiogenesis by interfering pro-angiogenic factors [160].

Development of a new method of administering luteolin, ellagic acid and punicic acid,

specific components of pomegranate juice, in an effective amount has been introduced

against the advancement of cancer progression and migration [161].

19
Pharmaceutical compositions comprising soluble extracts or isolated polypeptides from the

edible roots of the plant Colocasia esculenta and Xanthosoma sagittifolium are reported to

inhibit metastasis of breast and prostate cancer cells [162]. Similar antimetastatic activity is

reported for a combination that contains a bioactive saponin from Anemarrhena

asphodeloides, Timosaponin AIII [163]. Black garlic extract is also proven to inhibit growth

of breast cancer by enhancing adhesiveness among cancer cells [164].

6.8 Patented combinations of natural products for treating EMT

Several combinations naturally occurring phytochemicals and plant extracts are being used to

treat cancers and its secondary complications, among which a good number are being

patented. A combination comprising of turmeric and fish oil has been found to improve the

anticancer potential of paclitaxel [165]. Another investigation by Xu et al. [166], [167]

reveals anticancer and antimetastatic potential of a composition consisting of polyprenylated

acylphloroglucinol (PPAP) compound Guttiferone K against esophageal cancer. Traditional

Chinese medicines (TCM) are always been on the top among the formulations being

patented; some of them are mentioned as follows. A composition that comprises of TCM

plants including Rhizoma pinelliae, R. gastrodiae and R. arisaematis is used against various

late stage cancers with liver and lymphatic metastasis [168]. Another combination comprising

of Rhizoma plant species together with Astragalus root, lotus and Chinese date is found to be

promising against brain metastasis of lung cancer [169]. Other than these combinations,

numerous numbers of traditional Chinese combinations are patented, which have proven anti-

metastatic properties [170, 171].

7. Current and future developments

Epithelial mesenchymal transition associated with metastasis, angiogenesis and drug

resistances as well as stemness in cancer cells are the major areas in chemotherapeutic drug

20
development. Several different approaches such as combination and adjuvant chemotherapy

are currently employed as therapeutic options. In addition to these, RNAi technology is also

used to selectively down regulate the genes related to EMT process. However, these

treatment strategies are rather specific or mono-targeted. In contrast, the natural products

such as curcumin and resveratrol, that have promising anti-EMT in activity, are multi

targeted in nature. They interact with the cancer cells in many different ways such as

modulation of various survival/ apoptosis signaling pathways and their downstream targets,

reducing several kinase activities related to cell proliferation, inflammatory responses and

epigenetic regulation thereby mediating anti-EMT and anti-angiogenic effects.

Though preclinical evidences are supportive to anti-EMT properties of these natural products,

clinical studies are still in the start-up stage. Most of the clinical studies are limited to the use

of curcumin and resveratrol as an adjuvant to the classical chemotherapeutic drugs.

Significant improvement in the anticancer potential of chemotherapeutic drugs such as

gemcitabine, docetaxel, paclitaxel and 5FU, in conjugation with these natural products has

been achieved.

Compounds such as curcumin and resveratrol having anticancer potential are now in clinical

trials against cancer progression and metastasis. Some of these phytocompounds or their

derivatives are patented for its effectiveness in prevention and treatment of metastasis and

associated events. Nevertheless, it is unlikely that a single phytomolecule prevents cancer

progression and metastasis but a combination of these molecules that differentially modulate

EMT signaling can prevent. Future developments in these aspects may pave way to new drug

discovery for modern strategies of anticancer therapy, especially related to cancer metastasis.

Abbreviations:

Akt: protein kinase B

21
ALDH: Aldehyde dehydrogenase

ECM: Extracellular Matrix

ERK: Extracellular signal–regulated kinase

FAK: focal adhesion kinase

FZD: Frizzled

ILK: Integrin-Linked Kinase

MKK: MAPK Kinase

MMP: Matrix metalloproteinase

mTOR: Mechanistic target of rapamycin

NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells

Notch-1: Notch homolog 1, translocation-associated

PI3K: Phosphoinositide 3-kinase

PTCH1: Patched 1

SHH: Sonic Hedge Hog

Smad-3: Mothers against decapentaplegic homolog-3

SMO: Smoothened

STAT: Signal transducer and activator of transcription 3

TGF-β: Transforming growth factor beta

Wnt: vertebrate homolog integrated

Zeb-1: Zinc finger E-box-binding homeobox 1

Conflict of Interest

The authors declare no conflict of interest in this study.

Acknowledgement

22
Soorya P I and Arunaksharan N acknowledge the receipt of junior and senior research

fellowships from Kerala State Council for Science Technology and Environment (No.

01/FSHP-MAIN/2014/KSCSTE) and Council of Scientific and Industrial Research (File No.

09/869(0012)/2012 EMR-I).

Reference

[1] Hay ED. An Overview of Epithelio-Mesenchymal Transformation. Cells Tissues

Organs 1995; 154(1): 8-20

[2] Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a

master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell

2004; 117(7): 927-39

[3] Pardali K and Moustakas A. Actions of TGF-beta as tumor suppressor and pro-

metastatic factor in human cancer. Biochimica et Biophysica Acta 2007; 1775(1): 21-

62

[4] Kalluri R and Neilson EG. Epithelial-mesenchymal transition and its implications for

fibrosis. J Clin Invest 2003; 112(12): 1776-84

[5] Polyak K and Weinberg RA. Transitions between epithelial and mesenchymal states:

acquisition of malignant and stem cell traits. Nature Reviews Cancer 2009; 9(4): 265-

73

[6] Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J

Clin Invest 2009; 119(6): 1417-9

[7] Kalluri R and Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin

Invest 2009; 119(6): 1420-8

[8] Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et

al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature

Medicine 2007; 13(8): 952-61

23
[9] Bataille F, Rohrmeier C, Bates R, Weber A, Rieder F, Brenmoehl J, et al. Evidence

for a role of epithelial mesenchymal transition during pathogenesis of fistulae in

Crohn's disease. Inflammatory and Bowel Diseases 2008; 14(11): 1514-27

[10] Zeisberg M and Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J

Clin Invest 2009; 119(6): 1429-37

[11] Whipple RA, Matrone MA, Cho EH, Balzer EM, Vitolo MI, Yoon JR, et al.

Epithelial-to-mesenchymal transition promotes tubulin detyrosination and

microtentacles that enhance endothelial engagement. Cancer Res 2010; 70(20): 8127-

37

[12] Liu F, Zhou Y, Zhou D, Kan M, Niu X, Zhang Z, et al. Whole DNA methylome

profiling in lung cancer cells before and after epithelial-to-mesenchymal transition.

Diagnostic Pathology 2014; 9(66): 1746-596

[13] Zhang JX, Mai SJ, Huang XX, Wang FW, Liao YJ, Lin MC, et al. MiR-29c mediates

epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via

PTP4A and GNA13 regulation of beta-catenin signaling. Annals of Oncology 2014;

25(11): 2196-204

[14] Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1): 57-70

[15] Mazzucchelli L. Protein S100A4: Too Long Overlooked by Pathologists? The

American Journal of Pathology 2002; 160(1): 7-13

[16] Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nature Reviews

Cancer 2002; 2(6): 442-54

[17] Paulin D and Li Z. Desmin: a major intermediate filament protein essential for the

structural integrity and function of muscle. Exp Cell Res 2004; 301(1): 1-7

24
[18] Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, et al. Variable

beta-catenin expression in colorectal cancers indicates tumor progression driven by

the tumor environment. Proc Natl Acad Sci U S A 2001; 98(18): 10356-61

[19] Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis

revisited. Nat Rev Cancer 2003; 3(6): 453-8

[20] Valastyan S and Weinberg RA. Tumor metastasis: molecular insights and evolving

paradigms. Cell 2011; 147(2): 275-92

[21] Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, et al.

Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour

angiogenesis. Nature 1998; 394(6692): 485-90

[22] Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist 2004;

9(Suppl 5): 10-7

[23] Copple BL. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by

hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms.

Liver Int 2010; 30(5): 669-82

[24] Luo D, Wang J, Li J and Post M. Mouse snail is a target gene for HIF. Mol Cancer

Res 2011; 9(2): 234-45

[25] Wu Y and Zhou BP. Snail: More than EMT. Cell Adh Migr 2010; 4(2): 199-203

[26] Wu ZQ, Li XY, Hu CY, Ford M, Kleer CG and Weiss SJ. Canonical Wnt signaling

regulates Slug activity and links epithelial-mesenchymal transition with epigenetic

Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci U S A 2012;

109(41): 16654-9

[27] Hay ED and Zuk A. Transformations between epithelium and mesenchyme: normal,

pathological, and experimentally induced. Am J Kidney Dis 1995; 26(4): 678-90

25
[28] Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, et al. Role of

basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int

2002; 61(5): 1714-28

[29] Ignacio R-C, Mark AJC, Alexander RAA and Dirk D. Multi-scale modelling of

cancer cell intravasation: the role of cadherins in metastasis. Physical Biology 2009;

6(1): 016008

[30] Williams TM and Lisanti MP. Caveolin-1 in oncogenic transformation, cancer, and

metastasis. Am J Physiol Cell Physiol 2005; 288(3): C494-506

[31] Zhang K, Yang G, Wu W, Zhang J, Xia X, Jiang T, et al. Decreased Expression of

Caveolin-1 and E-Cadherin Correlates with the Clinicopathologic Features of Gastric

Cancer and the EMT Process. Recent Pat Anticancer Drug Discov 2016; 11(2): 236-

44

[32] Li Y, Yang J, Dai C, Wu C and Liu Y. Role for integrin-linked kinase in mediating

tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin

Invest 2003; 112(4): 503-16

[33] Li Y, Yang J, Luo JH, Dedhar S and Liu Y. Tubular epithelial cell dedifferentiation is

driven by the helix-loop-helix transcriptional inhibitor Id1. J Am Soc Nephrol 2007;

18(2): 449-60

[34] Bates RC. Colorectal cancer progression: integrin alphavbeta6 and the epithelial-

mesenchymal transition (EMT). Cell Cycle 2005; 4(10): 1350-2

[35] Vogel W, Gish GD, Alves F and Pawson T. The discoidin domain receptor tyrosine

kinases are activated by collagen. Molecular Cell 1997; 1(1): 13-23

[36] Leitinger B and Kwan AP. The discoidin domain receptor DDR2 is a receptor for type

X collagen. Matrix Biol 2006; 25(6): 355-64

26
[37] Xue C, Plieth D, Venkov C, Xu C and Neilson EG. The gatekeeper effect of

epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis.

Cancer Res 2003; 63(12): 3386-94

[38] Iwano M, Plieth D, Danoff TM, Xue C, Okada H and Neilson EG. Evidence that

fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110(3):

341-50

[39] Raymond WA and Leong AS. Vimentin--a new prognostic parameter in breast

carcinoma? J Pathol 1989; 158(2): 107-14

[40] Damonte P, Gregg JP, Borowsky AD, Keister BA and Cardiff RD. EMT

tumorigenesis in the mouse mammary gland. Lab Invest 2007; 87(12): 1218-26

[41] Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G and

Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like

phenotype. Cancer Res 2008; 68(4): 989-97

[42] Bienz M. beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol

2005; 15(2): R64-7

[43] Brabletz T, Jung A, Hermann K, Gunther K, Hohenberger W and Kirchner T. Nuclear

overexpression of the oncoprotein beta-catenin in colorectal cancer is localized

predominantly at the invasion front. Pathol Res Pract 1998; 194(10): 701-4

[44] Hynes RO and Yamada KM. Fibronectins: multifunctional modular glycoproteins. J

Cell Biol 1982; 95(2 Pt 1): 369-77

[45] Yang Z, Zhang X, Gang H, Li X, Li Z, Wang T, et al. Up-regulation of gastric cancer

cell invasion by Twist is accompanied by N-cadherin and fibronectin expression.

Biochem Biophys Res Commun 2007; 358(3): 925-30

[46] Colognato H and Yurchenco PD. Form and function: the laminin family of

heterotrimers. Dev Dyn 2000; 218(2): 213-34

27
[47] Carpenter PM, Wang-Rodriguez J, Chan OT and Wilczynski SP. Laminin 5

expression in metaplastic breast carcinomas. Am J Surg Pathol 2008; 32(3): 345-53

[48] Giannelli G, Bergamini C, Fransvea E, Sgarra C and Antonaci S. Laminin-5 with

transforming growth factor-beta1 induces epithelial to mesenchymal transition in

hepatocellular carcinoma. Gastroenterology 2005; 129(5): 1375-83

[49] Wang J, Chen L, Li Y and Guan X-Y. Overexpression of Cathepsin Z Contributes to

Tumor Metastasis by Inducing Epithelial-Mesenchymal Transition in Hepatocellular

Carcinoma. PLoS One 2011; 6(9): e24967

[50] Ouyang G, Wang Z, Fang X, Liu J and Yang CJ. Molecular signaling of the epithelial

to mesenchymal transition in generating and maintaining cancer stem cells. Cell Mol

Life Sci 2010; 67(15): 2605-18

[51] Massague J. TGFbeta in Cancer. Cell 2008; 134(2): 215-30

[52] Derynck R, Akhurst RJ and Balmain A. TGF-beta signaling in tumor suppression and

cancer progression. Nature Genetics 2001; 29(2): 117-29

[53] Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y and Wrana JL.

Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell

plasticity. Science 2005; 307(5715): 1603-9

[54] Miyazono K. Transforming growth factor-beta signaling in epithelial-mesenchymal

transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci 2009; 85(8):

314-23

[55] Min C, Eddy SF, Sherr DH and Sonenshein GE. NF-kappaB and epithelial to

mesenchymal transition of cancer. J Cell Biochem 2008; 104(3): 733-44

[56] Jing Y, Han Z, Zhang S, Liu Y and Wei L. Epithelial-Mesenchymal Transition in

tumor microenvironment. Cell Bioscience 2011; 1(29): 2045-3701

28
[57] Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, et al.

Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling.

Nature 2008; 452(7187): 650-3

[58] Boutet A, De Frutos CA, Maxwell PH, Mayol MJ, Romero J and Nieto MA. Snail

activation disrupts tissue homeostasis and induces fibrosis in the adult kidney. EMBO

J 2006; 25(23): 5603-13

[59] Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, et al. Direct regulation

of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 2008; 10(3): 295-305

[60] Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, et al. Mesenchyme

Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive

basal-like breast cancers. Proc Natl Acad Sci U S A 2007; 104(24): 10069-74

[61] Vandewalle C, Van Roy F and Berx G. The role of the ZEB family of transcription

factors in development and disease. Cell Mol Life Sci 2009; 66(5): 773-87

[62] Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noel A, et al.

Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene

2006; 25(36): 4975-85

[63] De Craene B and Berx G. Regulatory networks defining EMT during cancer initiation

and progression. Nature Reviews Cancer 2013; 13(2): 97-110

[64] Yang P-M, Lin Y-T, Shun C-T, Lin S-H, Wei T-T, Chuang S-H, et al. Zebularine

inhibits tumorigenesis and stemness of colorectal cancer via p53-dependent

endoplasmic reticulum stress. Scientific Reports 2013; 3(3219):

doi:10.1038/srep03219

[65] Kim J and Hwan Kim S. CK2 inhibitor CX-4945 blocks TGF-beta1-induced

epithelial-to-mesenchymal transition in A549 human lung adenocarcinoma cells.

PLoS One 2013; 8(9): e74342. doi:10.1371/journal.pone.0074342

29
[66] Hjelmeland MD, Hjelmeland AB, Sathornsumetee S, Reese ED, Herbstreith MH,

Laping NJ, et al. SB-431542, a small molecule transforming growth factor-beta-

receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol

Cancer Ther 2004; 3(6): 737-45

[67] Kothari AN, Mi Z, Zapf M and Kuo PC. Novel clinical therapeutics targeting the

epithelial to mesenchymal transition. Clinical and Translational Medicine 2014;

3(35): 35. doi: 10.1186/s40169-014-0035-0

[68] Iversen, P.L., Roy, H.K., Bestwick, R.K. Antisense composition and method for

treating cancer. WO2005089247A2 (2005).

[69] Zahorowska B, Crowe PJ and Yang J-L. Combined therapies for cancer: a review of

EGFR-targeted monotherapy and combination treatment with other drugs. Journal of

Cancer Research and Clinical Oncology 2009; 135(9): 1137-48

[70] Bordoloi D, Roy NK, Monisha J, Padmavathi G and Kunnumakkara AB. Multi-

Targeted Agents in Cancer Cell Chemosensitization: What We Learnt from Curcumin

Thus Far. Recent Pat Anticancer Drug Discov 2016; 11(1): 67-97

[71] Teiten M-H, Eifes S, Dicato M and Diederich M. Curcumin―The Paradigm of a

Multi-Target Natural Compound with Applications in Cancer Prevention and

Treatment. Toxins 2010; 2(1): 128-62

[72] Chen HW, Lee JY, Huang JY, Wang CC, Chen WJ, Su SF, et al. Curcumin inhibits

lung cancer cell invasion and metastasis through the tumor suppressor HLJ1. Cancer

Res 2008; 68(18): 7428-38

[73] Huang T, Chen Z and Fang L. Curcumin inhibits LPS-induced EMT through

downregulation of NF-kappaB-Snail signaling in breast cancer cells. Oncol Rep 2013;

29(1): 117-24

30
[74] Sun XD, Liu XE and Huang DS. Curcumin reverses the epithelial-mesenchymal

transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway.

Oncol Rep 2013; 29(6): 2401-7

[75] Cao L, Xiao X, Lei J, Duan W, Ma Q and Li W. Curcumin inhibits hypoxia-induced

epithelialmesenchymal transition in pancreatic cancer cells via suppression of the

hedgehog signaling pathway. Oncol Rep 2016; 35(6): 3728-34

[76] Kong D, Zhang F, Shao J, Wu L, Zhang X, Chen L, et al. Curcumin inhibits cobalt

chloride-induced epithelial-to-mesenchymal transition associated with interference

with TGF-beta/Smad signaling in hepatocytes. Lab Invest 2015; 95(11): 1234-45

[77] Lee AY, Fan CC, Chen YA, Cheng CW, Sung YJ, Hsu CP, et al. Curcumin Inhibits

Invasiveness and Epithelial-Mesenchymal Transition in Oral Squamous Cell

Carcinoma Through Reducing Matrix Metalloproteinase 2, 9 and Modulating p53-E-

Cadherin Pathway. Integr Cancer Ther 2015; 14(5): 484-90

[78] Tsai CF, Hsieh TH, Lee JN, Hsu CY, Wang YC, Kuo KK, et al. Curcumin Suppresses

Phthalate-Induced Metastasis and the Proportion of Cancer Stem Cell (CSC)-like

Cells via the Inhibition of AhR/ERK/SK1 Signaling in Hepatocellular Carcinoma. J

Agric Food Chem 2015; 63(48): 10388-98

[79] Xu JH, Yang HP, Zhou XD, Wang HJ, Gong L and Tang CL. Role of Wnt Inhibitory

Factor-1 in Inhibition of Bisdemethoxycurcumin Mediated Epithelial-to-

Mesenchymal Transition in Highly Metastatic Lung Cancer 95D Cells. Chin Med J

2015; 128(10): 1376-83

[80] Gallardo M and Calaf GM. Curcumin inhibits invasive capabilities through epithelial

mesenchymal transition in breast cancer cell lines. Int J Oncol 2016; 49(3): 1019-27

31
[81] Hu HJ, Lin XL, Liu MH, Fan XJ and Zou WW. Curcumin mediates reversion of

HGF-induced epithelial-mesenchymal transition via inhibition of c-Met expression in

DU145 cells. Oncol Lett 2016; 11(2): 1499-505

[82] Jiao D, Wang J, Lu W, Tang X, Chen J, Mou H, et al. Curcumin inhibited HGF-

induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR

signaling pathways in lung cancer. Mol Ther Oncolytics 2016; 3(16018): doi

10.1038/mto.2016.18

[83] Zhang L, Cheng X, Gao Y, Zhang C, Bao J, Guan H, et al. Curcumin inhibits

metastasis in human papillary thyroid carcinoma BCPAP cells via down-regulation of

the TGF-beta/Smad2/3 signaling pathway. Exp Cell Res 2016; 341(2): 157-65

[84] Zhang Z, Chen H, Xu C, Song L, Huang L, Lai Y, et al. Curcumin inhibits tumor

epithelialmesenchymal transition by downregulating the Wnt signaling pathway and

upregulating NKD2 expression in colon cancer cells. Oncol Rep 2016; 35(5): 2615-23

[85] Bisht S, Schlesinger M, Rupp A, Schubert R, Nolting J, Wenzel J, et al. A liposomal

formulation of the synthetic curcumin analog EF24 (Lipo-EF24) inhibits pancreatic

cancer progression: towards future combination therapies. Journal of

Nanobiotechnology 2016; 14(1): 57

[86] Snyder, J., Davis, M., Adams, B., Shoji, M., Liotta, D., Ferstl, E., Sunay, U.

Curcumin analogs with anti-tumor and anti-angiogenic properties. US20020019382

(2002)

[87] Barthomeuf, C., Chollet, P., Bayet-Robert, M. Curcuminoids in Combination

Docetaxel for the Treatment of Cancer and Tumour Metastasis. US20140128337

(2014)

[88] Shoji, M., Snyder, J., Liotta, D., Sun, A. Novel curcuminoid-factor VIIa constructs as

suppressors of tumor growth and angiogenesis. US20090011991 (2006)

32
[89] de Figueiredo SM, Binda NS, Nogueira-Machado JA, Vieira-Filho SA and Caligiorne

RB. The antioxidant properties of organosulfur compounds (sulforaphane). Recent Pat

Endocr Metab Immune Drug Discov 2015; 9(1): 24-39

[90] Shan Y, Zhang L, Bao Y, Li B, He C, Gao M, et al. Epithelial-mesenchymal

transition, a novel target of sulforaphane via COX-2/MMP2, 9/Snail, ZEB1 and miR-

200c/ZEB1 pathways in human bladder cancer cells. J Nutr Biochem 2013; 24(6):

1062-9

[91] Wu J, Han J, Hou B, Deng C, Wu H and Shen L. Sulforaphane inhibits TGF-beta-

induced epithelial-mesenchymal transition of hepatocellular carcinoma cells via the

reactive oxygen species-dependent pathway. Oncol Rep 2016; 35(5): 2977-83

[92] Wang L, Tian Z, Yang Q, Li H, Guan H, Shi B, et al. Sulforaphane inhibits thyroid

cancer cell growth and invasiveness through the reactive oxygen species-dependent

pathway. Oncotarget 2015; 6(28): 25917-31

[93] Wang D-x, Zou Y-j, Zhuang X-b, Chen S-x, Lin Y, Li W-l, et al. Sulforaphane

suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated

GSK3[beta]/[beta]-catenin signaling pathways. Acta Pharmacol Sin 2016;

[94] Davis R, Singh KP, Kurzrock R and Shankar S. Sulforaphane inhibits angiogenesis

through activation of FOXO transcription factors. Oncol Rep 2009; 22(6): 1473-8

[95] Li Y and Zhang T. Targeting cancer stem cells with sulforaphane, a dietary

component from broccoli and broccoli sprouts. Future Oncol 2013; 9(8): 1097-103

[96] Liu C-M, Peng C-Y, Liao Y-W, Lu M-Y, Tsai M-L, Yeh J-C, et al. Sulforaphane

targets cancer stemness and tumor initiating properties in oral squamous cell

carcinomas via miR-200c induction. Journal of the Formosan Medical Association

2017; 116(1): 41-8

33
[97] Tortorella SM, Royce SG, Licciardi PV and Karagiannis TC. Dietary Sulforaphane in

Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition.

Antioxidants & Redox Signaling 2015; 22(16): 1382-424

[98] Cornblatt B, Cornblatt G, Bzhelyansky A and Henderson RW. Compositions

comprising sulforaphane or a sulforaphane precursor and ursolic acid.

WO2014008353 (2014)

[99] Cornblatt B, Cornblatt G, Bzhelyansky A and Henderson RW. Compositions

comprising sulforaphane or a sulforaphane precursor and a mushroom extract or

powder. WO2014008353 (2014)

[100] Lorrain B, Ky I, Pechamat L and Teissedre PL. Evolution of analysis of polyhenols

from grapes, wines, and extracts. Molecules 2013; 18(1): 1076-100

[101] Sun Q, Prasad R, Rosenthal E and Katiyar SK. Grape seed proanthocyanidins inhibit

the invasive potential of head and neck cutaneous squamous cell carcinoma cells by

targeting EGFR expression and epithelial-to-mesenchymal transition. BMC

Complement Altern Med 2011; 11(134): 1472-6882

[102] Sun Q, Prasad R, Rosenthal E and Katiyar SK. Grape Seed Proanthocyanidins Inhibit

the Invasiveness of Human HNSCC Cells by Targeting EGFR and Reversing the

Epithelial-To-Mesenchymal Transition. PLoS One 2012; 7(1): e31093

[103] Lu JN, Lee WS, Yun JW, Kim MJ, Kim HJ, Kim DC, et al. Anthocyanins from Vitis

coignetiae Pulliat Inhibit Cancer Invasion and Epithelial-Mesenchymal Transition, but

These Effects Can Be Attenuated by Tumor Necrosis Factor in Human Uterine

Cervical Cancer HeLa Cells. Evidence-based Complementary and Alternative

Medicine : eCAM 2013; 2013(2013): 503043 doi:10.1155/2013/503043

[104] Burton LJ, Barnett P, Smith B, Arnold RS, Hudson T, Kundu K, et al. Muscadine

grape skin extract reverts snail-mediated epithelial mesenchymal transition via

34
 superoxide species in human prostate cancer cells. BMC Complementary and

Alternative Medicine 2014; 14(97): doi: 10.1186/1472-6882-14-97

[105] Burton LJ, Smith BA, Smith BN, Loyd Q, Nagappan P, McKeithen D, et al.

Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion,

migration and osteoclastogenesis in prostate and breast cancer cells. Carcinogenesis

2015; 36(9): 1019-27

[106] Odero-Marah, V. Muscadine grape skin extract as treatment for bone metastatic

cancer. US20160067298 (2016)

[107] Pal HC, Sharma S, Strickland LR, Katiyar SK, Ballestas ME, Athar M, et al. Fisetin

Inhibits Human Melanoma Cell Invasion through Promotion of Mesenchymal to

Epithelial Transition and by Targeting MAPK and NFκB Signaling Pathways. PLoS

One 2014; 9(1): e86338

[108] Xiao Y, Chen H, Song C, Zeng X, Zheng Q, Zhang Y, et al. Pharmacological

activities and structure-modification of resveratrol analogues. Pharmazie 2015;

70(12): 765-71

[109] Wu H, Liang X, Fang Y, Qin X, Zhang Y and Liu J. Resveratrol inhibits hypoxia-

induced metastasis potential enhancement by restricting hypoxia-induced factor-1α

expression in colon carcinoma cells. Biomedicine & Pharmacotherapy 2008; 62(9):

613-21

[110] Vergara D, Valente CM, Tinelli A, Siciliano C, Lorusso V, Acierno R, et al.

Resveratrol inhibits the epidermal growth factor-induced epithelial mesenchymal

transition in MCF-7 cells. Cancer Letters 2011; 310(1): 1-8

[111] Chen MC, Chang WW, Kuan YD, Lin ST, Hsu HC and Lee CH. Resveratrol inhibits

LPS-induced epithelial-mesenchymal transition in mouse melanoma model. Innate

Immun 2012; 18(5): 685-93

35
[112] Li J, Chong T, Wang Z, Chen H, Li H, Cao J, et al. A novel anticancer effect of

resveratrol: reversal of epithelialmesenchymal transition in prostate cancer cells. Mol

Med Rep 2014; 10(4): 1717-24

[113] Wang H, Zhang H, Tang L, Chen H, Wu C, Zhao M, et al. Resveratrol inhibits TGF-

β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion

and metastasis. Toxicology 2013; 303: 139-46

[114] Baribeau S, Chaudhry P, Parent S and Asselin É. Resveratrol Inhibits Cisplatin-

Induced Epithelial-to-Mesenchymal Transition in Ovarian Cancer Cell Lines. PLoS

One 2014; 9(1): e86987

[115] Gao Q, Yuan Y, Gan H-Z and Peng Q. Resveratrol inhibits the hedgehog signaling

pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion

and metastasis. Oncology Letters 2015; 9(5): 2381-7

[116] Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, et al. Resveratrol suppresses epithelial-to-

mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling

pathway mediated Snail/E-cadherin expression. BMC Cancer 2015; 15(97): doi:

10.1186/s12885-015-1119-y

[117] Li W, Ma J, Ma Q, Li B, Han L, Liu J, et al. Resveratrol inhibits the epithelial-

mesenchymal transition of pancreatic cancer cells via suppression of the PI-

3K/Akt/NF-kappaB pathway. Curr Med Chem 2013; 20(33): 4185-94

[118] Shankar S, Nall D, Tang S-N, Meeker D, Passarini J, Sharma J, et al. Resveratrol

Inhibits Pancreatic Cancer Stem Cell Characteristics in Human and Kras(G12D)

Transgenic Mice by Inhibiting Pluripotency Maintaining Factors and Epithelial-

Mesenchymal Transition. PLoS One 2011; 6(1): e16530

[119] Shi X-P, Miao S, Wu Y, Zhang W, Zhang X-F, Ma H-Z, et al. Resveratrol Sensitizes

Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-

36
 Mesenchymal Transition Features. International Journal of Molecular Sciences 2013;

14(8): 15655-68

[120] Hsieh, K.L. Lycopene and resveratrol dietary supplement. US20150132373 (2015)

[121] Hsieh, K.L. Lycopene and resveratrol compositions for nk cell activation resulting in

anti-neoplastic effect. EP2429509 (2016)

[122] Barella, L., Goralczyk, R., Jung, K., Lein, M., Siler, U., Stoecklin, E., Wertz, K.

Compositions comprising lycopene for the treatment and prevention of angiogenesis

associated pathologies. US20060020046 (2006)

[123] Davis, P.D. New stilbenes with vascular damaging activity. WO2001012579 (2001)

[124] Singh T and Katiyar SK. Green Tea Catechins Reduce Invasive Potential of Human

Melanoma Cells by Targeting COX-2, PGE(2) Receptors and Epithelial-to-

Mesenchymal Transition. PLoS One 2011; 6(10): e25224

[125] Chang Y-C, Chen P-N, Chu S-C, Lin C-Y, Kuo W-H and Hsieh Y-S. Black Tea

Polyphenols Reverse Epithelial-to-Mesenchymal Transition and Suppress Cancer

Invasion and Proteases in Human Oral Cancer Cells. Journal of Agricultural and Food

Chemistry 2012; 60(34): 8395-403

[126] Liu LC, Tsao TC, Hsu SR, Wang HC, Tsai TC, Kao JY, et al. EGCG inhibits

transforming growth factor-beta-mediated epithelial-to-mesenchymal transition via

the inhibition of Smad2 and Erk1/2 signaling pathways in nonsmall cell lung cancer

cells. J Agric Food Chem 2012; 60(39): 9863-73

[127] Lin C-H, Shen Y-A, Hung P-H, Yu Y-B and Chen Y-J. Epigallocathechin gallate,

polyphenol present in green tea, inhibits stem-like characteristics and epithelial-

mesenchymal transition in nasopharyngeal cancer cell lines. BMC Complementary

and Alternative Medicine 2012; 12(201): doi: 10.1186/1472-6882-12-201

37
[128] Tang S-N, Singh C, Nall D, Meeker D, Shankar S and Srivastava RK. The dietary

bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit

prostate cancer stem cell characteristics, invasion, migration and epithelial-

mesenchymal transition. Journal of Molecular Signaling 2010; 5(14): doi:

10.1186/1750-2187-5-14

[129] Kanlaya R, Khamchun S, Kapincharanon C and Thongboonkerd V. Protective effect

of epigallocatechin-3-gallate (EGCG) via Nrf2 pathway against oxalate-induced

epithelial mesenchymal transition (EMT) of renal tubular cells. Scientific Reports

2016; 6(30233): doi: 10.1038/srep30233

[130] Lu L, Chen J, Tang H, Bai L, Lu C, Wang K, et al. EGCG Suppresses ERK5

Activation to Reverse Tobacco Smoke-Triggered Gastric Epithelial-Mesenchymal

Transition in BALB/c Mice. Nutrients 2016; 8(7): 380

[131] Cao Y and Cao R. Angiogenesis inhibited by drinking tea. Nature 1999; 398(6726):

381 doi:10.1038/18793

[132] Cao, Y. Inhibition of angiogenesis with epigallocatechin-3-gallate. WO2000047193

(2000)

[133] Greenway, F.L., Liu, Z., Woltering, E.A. Anti-angiogenic extracts from pomegranate.

US8334000 (2012)

[134] Lin YS, Tsai PH, Kandaswami CC, Cheng CH, Ke FC, Lee PP, et al. Effects of

dietary flavonoids, luteolin, and quercetin on the reversal of epithelial-mesenchymal

transition in A431 epidermal cancer cells. Cancer Sci 2011; 102(10): 1829-39

[135] Ruan J-s, Liu Y-p, Zhang L, Yan L-g, Fan F-t, Shen C-s, et al. Luteolin reduces the

invasive potential of malignant melanoma cells by targeting β3 integrin and the

epithelial-mesenchymal transition. Acta Pharmacologica Sinica 2012; 33(10): 1325-

31

38
[136] Chen K-C, Chen C-Y, Lin C-J, Yang T-Y, Chen T-H, Wu L-C, et al. Luteolin

attenuates TGF-β1-induced epithelial–mesenchymal transition of lung cancer cells by

interfering in the PI3K/Akt–NF-κB–Snail pathway. Life Sciences 2013; 93(24): 924-

33

[137] Huang X, Dai S, Dai J, Xiao Y, Bai Y, Chen B, et al. Luteolin decreases invasiveness,

deactivates STAT3 signaling, and reverses interleukin-6 induced epithelial–

mesenchymal transition and matrix metalloproteinase secretion of pancreatic cancer

cells. OncoTargets and therapy 2015; 8: 2989-3001

[138] Gong JH, Cho IH, Shin D, Han SY, Park SH and Kang YH. Inhibition of airway

epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced

epithelial cells and ovalbumin-sensitized mice. Lab Invest 2014; 94(3): 297-308

[139] Jo E, Park SJ, Choi YS, Jeon WK and Kim BC. Kaempferol Suppresses Transforming

Growth Factor-beta1-Induced Epithelial-to-Mesenchymal Transition and Migration of

A549 Lung Cancer Cells by Inhibiting Akt1-Mediated Phosphorylation of Smad3 at

Threonine-179. Neoplasia 2015; 17(7): 525-37

[140] Zhang LL, Li L, Wu DP, Fan JH, Li X, Wu KJ, et al. A novel anti-cancer effect of

genistein: reversal of epithelial mesenchymal transition in prostate cancer cells. Acta

Pharmacol Sin 2008; 29(9): 1060-8

[141] Han L, Zhang HW, Zhou WP, Chen GM and Guo KJ. The effects of genistein on

transforming growth factor-beta1-induced invasion and metastasis in human

pancreatic cancer cell line Panc-1 in vitro. Chin Med J 2012; 125(11): 2032-40

[142] Dai W, Wang F, He L, Lin C, Wu S, Chen P, et al. Genistein inhibits hepatocellular

carcinoma cell migration by reversing the epithelial-mesenchymal transition: partial

mediation by the transcription factor NFAT1. Mol Carcinog 2015; 54(4): 301-11

39
[143] Rao A, Luo C and Hogan PG. Transcription factors of the NFAT family: regulation

and function. Annu Rev Immunol 1997; 15: 707-47

[144] Kim YS, Choi KC and Hwang KA. Genistein suppressed epithelial-mesenchymal

transition and migration efficacies of BG-1 ovarian cancer cells activated by

estrogenic chemicals via estrogen receptor pathway and downregulation of TGF-beta

signaling pathway. Phytomedicine 2015; 22(11): 993-9

[145] Lou C, Zhang F, Yang M, Zhao J, Zeng W, Fang X, et al. Naringenin Decreases

Invasiveness and Metastasis by Inhibiting TGF-β-Induced Epithelial to Mesenchymal

Transition in Pancreatic Cancer Cells. PLoS One 2012; 7(12): e50956

[146] Gao XJ, Liu JW, Zhang QG, Zhang JJ, Xu HT and Liu HJ. Nobiletin inhibited

hypoxia-induced epithelial-mesenchymal transition of lung cancer cells by

inactivating of Notch-1 signaling and switching on miR-200b. Pharmazie 2015; 70(4):

256-62

[147] Zhang X, Zheng L, Sun Y, Wang T and Wang B. Tangeretin enhances

radiosensitivity and inhibits the radiation-induced epithelial-mesenchymal transition

of gastric cancer cells. Oncol Rep 2015; 34(1): 302-10

[148] Ho JN, Jun W, Choue R and Lee J. I3C and ICZ inhibit migration by suppressing the

EMT process and FAK expression in breast cancer cells. Mol Med Rep 2013; 7(2):

384-8

[149] Wu T, Chen C, Li FEN, Chen ZHE, Xu Y, Xiao B, et al. 3,3′-Diindolylmethane

inhibits the invasion and metastasis of nasopharyngeal carcinoma cells in vitro and in

vivo by regulation of epithelial mesenchymal transition. Experimental and

Therapeutic Medicine 2014; 7(6): 1635-8

[150] Vazquez-Martin A, Fernandez-Arroyo S, Cufi S, Oliveras-Ferraros C, Lozano-

Sanchez J, Vellon L, et al. Phenolic secoiridoids in extra virgin olive oil impede

40
 fibrogenic and oncogenic epithelial-to-mesenchymal transition: extra virgin olive oil

as a source of novel antiaging phytochemicals. Rejuvenation Res 2012; 15(1): 3-21

[151] Guo G, Yao W, Zhang Q and Bo Y. Oleanolic Acid Suppresses Migration and

Invasion of Malignant Glioma Cells by Inactivating MAPK/ERK Signaling Pathway.

PLoS One 2013; 8(8): e72079

[152] Xu Q, Ma J, Lei J, Duan W, Sheng L, Chen X, et al. α-Mangostin Suppresses the

Viability and Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells by

Downregulating the PI3K/Akt Pathway. BioMed Research International 2014; 2014:

546353. doi: 10.1155/2014/546353

[153] Boreddy SR and Srivastava SK. Deguelin Suppresses Pancreatic Tumor Growth and

Metastasis by Inhibiting Epithelial to Mesenchymal Transition in an Orthotopic

Model(). Oncogene 2013; 32(34): 3980-91

[154] Chen K-S, Shi M-D, Chien C-S and Shih Y-W. Pinocembrin suppresses TGF-β1-

induced epithelial-mesenchymal transition and metastasis of human Y-79

retinoblastoma cells through inactivating αvβ3 integrin/FAK/p38α signaling pathway.

Cell & Bioscience 2014; 4:41

[155] Wang L, Guo H, Yang L, Dong L, Lin C, Zhang J, et al. Morusin inhibits human

cervical cancer stem cell growth and migration through attenuation of NF-κB activity

and apoptosis induction. Molecular and Cellular Biochemistry 2013; 379(1): 7-18

[156] Orlikova B, Tasdemir D, Golais F, Dicato M and Diederich M. Dietary chalcones

with chemopreventive and chemotherapeutic potential. Genes & Nutrition 2011; 6(2):

125-47

[157] Bowen, P.J., Robinson, T.P., Ehlers, T., Goldsmith, D., Arbiser, J. Chalcone and its

analogs as agents for the inhibition of angiogenesis and related disease states.

WO2001046110 (2001)

41
[158] Kim, M.Y., Park, B.Y., Kim, K.M., Sung, N.D., Myung, P.K. Pharmaceutical

composition containing chalcone or its derivatives for matrix metalloproteinase

inhibitory activity. WO2003037315 (2003)

[159] Jiang, B.H., Fang, J. Apigenin for chemoprevention, and chemotherapy combined

with therapeutic reagents. US8377918 (2013

[160] Liu, Z. Yang, P. Natural Composition for Anti-Angiogenesis and Anti-Obesity.

US20110039796 (2011)

[161] Martins-Green, M. Wang, L. Specific pomegranate juice compoments and inhibition

of prostate cancer progression/metastasis. WO2014165714 (2014)

[162] Fulton, A., Kundu, N. Natural plant products for control of cancer metastasis.

WO2011115651 (2011)

[163] Chae, S.W., Kim, G.M., Im, A., Kim, S.H. Composition for treating or inhibiting

metastasis of skin cancer. KR20150080777A (2015)

[164] Fan, S. Black garlic extract and application thereof in preventing and curing breast

cancer. CN105596674A (2016)

[165] Jacob, J.N. Formulations from natural products, turmeric, paclitaxel, and aspirin.

US20130029922 (2013)

[166] Xu, H., Lao, Y., Tan, H., Chen, K., Bian, Z., Yang, D., Chen, S., Lu, A., Chan, A.S.C.

Usage of guttiferone k, a natural compound from garcinia yunnanensis hu on treating

high metastatic esophageal cancer. US20150011646 (2015)

[167] Xu, H., Shen, K., Lao, Y., Tan, H., Chen, K., Bian, Z., Lin, C., Lu, A. Usage of

guttiferone k for treating high metastatic cancer. US20150231090 (2015)

[168] Xiao, M. Pharmaceutical composition for treating cancers and preparation method

therefor. US20150374778 (2015)

42
[169] Li, Z., Li, Y., Su, H., Cao, G., Chen, Z. A pharmaceutical preparation and method of

treatment of lung cancer with brain metastasis. CN105816767A (2016)

[170] Jia, D., Liu, H. and Chen H. Chinese medicine for inhibiting metastases from colon

cancer. CN105878930A (2016)

[171] Liang, Y., Wang, G.P. Chinese medicine for the treatment of breast cancer recurrence

and metastasis of preparation. CN105853933A (2016)

[172] Ahmad A, Sarkar SH, Bitar B, Ali S, Aboukameel A, Sethi S, et al. Garcinol

Regulates EMT and Wnt Signaling Pathways, Leading to Anticancer Activity against

Breast Cancer Cells. Molecular Cancer Therapeutics 2012; 11(10): 2193-201

[173] Liu Z, Zhang B, Liu K, Ding Z and Hu X. Schisandrin B attenuates cancer invasion

and metastasis via inhibiting epithelial-mesenchymal transition. PLoS One 2012; 7(7):

25

[174] Hsieh Y-S, Chu S-C, Hsu L-S, Chen K-S, Lai M-T, Yeh C-H, et al. Rubus idaeus L.

reverses epithelial-to-mesenchymal transition and suppresses cell invasion and

protease activities by targeting ERK1/2 and FAK pathways in human lung cancer

cells. Food and Chemical Toxicology 2013; 62(908-18

[175] Kang J, Kim E, Kim W, Seong KM, Youn H, Kim JW, et al. Rhamnetin and Cirsiliol

Induce Radiosensitization and Inhibition of Epithelial-Mesenchymal Transition

(EMT) by miR-34a-mediated Suppression of Notch-1 Expression in Non-small Cell

Lung Cancer Cell Lines. The Journal of Biological Chemistry 2013; 288(38): 27343-

57

[176] Kin R, Kato S, Kaneto N, Sakurai H, Hayakawa Y, Li F, et al. Procyanidin C1 from

Cinnamomi Cortex inhibits TGF-beta-induced epithelial-to-mesenchymal transition in

the A549 lung cancer cell line. Int J Oncol 2013; 43(6): 1901-6

43
[177] Zhang X, Li Y, Zhang Y, Song J, Wang Q, Zheng L, et al. Beta-Elemene Blocks

Epithelial-Mesenchymal Transition in Human Breast Cancer Cell Line MCF-7

through Smad3-Mediated Down-Regulation of Nuclear Transcription Factors. PLoS

One 2013; 8(3): e58719

[178] Avtanski DB, Nagalingam A, Bonner MY, Arbiser JL, Saxena NK and Sharma D.

Honokiol inhibits epithelial–mesenchymal transition in breast cancer cells by

targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis.

Molecular Oncology 2014; 8(3): 565-80

[179] Lin X, Yi Z, Diao J, Shao M, Zhao L, Cai H, et al. ShaoYao decoction ameliorates

colitis-associated colorectal cancer by downregulating proinflammatory cytokines and

promoting epithelial-mesenchymal transition. J Transl Med 2014; 12(105): 1479-5876

[180] Liu L, Salnikov AV, Bauer N, Aleksandrowicz E, Labsch S, Nwaeburu C, et al.

Triptolide reverses hypoxia-induced epithelial–mesenchymal transition and stem-like

features in pancreatic cancer by NF-κB downregulation. International Journal of

Cancer. Journal International du Cancer 2014; 134(10): 2489-503

[181] Yang B, Huang J, Xiang T, Yin X, Luo X, Huang J, et al. Chrysin inhibits metastatic

potential of human triple-negative breast cancer cells by modulating matrix

metalloproteinase-10, epithelial to mesenchymal transition, and PI3K/Akt signaling

pathway. Journal of Applied Toxicology 2014; 34(1): 105-12

[182] Aravindan S, Ramraj SK, Somasundaram ST, Herman TS and Aravindan N.

Polyphenols from marine brown algae target radiotherapy-coordinated EMT and

stemness-maintenance in residual pancreatic cancer. Stem Cell Research & Therapy

2015; 6(1): 182

[183] Sivasankar S, Lavanya R, Brindha P and Angayarkanni N. Aqueous and Alcoholic

Extracts of Triphala and Their Active Compounds Chebulagic Acid and Chebulinic

44
 Acid Prevented Epithelial to Mesenchymal Transition in Retinal Pigment Epithelial

Cells, by Inhibiting SMAD-3 Phosphorylation. PLoS One 2015; 10(3): e0120512

[184] Subramani R, Gonzalez E, Arumugam A, Nandy S, Gonzalez V, Medel J, et al.

Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated

apoptosis and inhibition of epithelial-to-mesenchymal transition. Scientific Reports

2016; 6(19819

45
Figure Legends

Figure 1 Process of conversion of an epithelial cell (a) get converted to a transition state (b)

and finally forming a mesenchymal phenotype (C).

Figure 2 a. Mechanism of curcumin induced inhibition of epithelial mesenchymal transition

in cancer cells. The red color star (*) mark indicates the pathways blocked by

curcumin and resveratrol, whereas yellow (*) and purple (*) colored star marks

indicates inhibition by curcumin or resveratrol alone. Figure 2 b. Mechanism of

EGCG, luteolin or kaempferol induced inhibition of epithelial mesenchymal transition

in cancer cells. The red color cross (x) mark indicates the pathways blocked by

EGCG, the red color star (*) marks indicate the pathways blocked by luteolin and

kaempferol.

46
 Table 1. Bioactive component from various plants and their effect on epithelial mesenchymal
transition and mode of action

Pathway/
Bioactive compound Food source Cancer Reference
Signaling
Garcinol Garcinia indica Breast Wnt [172]
Schisandrin B Schisandra chinensis Breast TGF-β [173]
Naringenin Citrus fruits& Tomato Pancreas TGF-β [145]
Secoiridoids Olive oil Kidney Smad/TGF-β [150]
Deguelin Legumes Balb/c mice NF-κB/ TGF-β [153]
Oleanolic acid Syzygium and Olive Glioma MAPK/ERK [151]
Indole-3-carbinol&
Cruciferous vegetables Breast FAK [148]
indole [3, 2-b] carbazole
Polyphenols Rubus idaeus Lung ERK/ FAK [174]
Rhamnetin and Cirsiliol Cloves Lung Notch-1 [175]
Procyanidin C1 Cinnamomi Cortex Lung TGF-β [176]
Morusin Mulberry Cervical NF-κB [155]
Beta-Elemene Curcuma zedoaria Breast Smad-3 [177]
Honokiol Magnolia grandiflora Breast STAT3/ Zeb-1 [178]
Pinocembrin Honey and Propolis Retinoblastoma Integrin/FAK [154]
ShaoYao decoction ShaoYao Colon Cytokines [179]
Triptolide Tripterygium wilfordii Pancreas NF-κB [180]
3,3′-Diindolylmethane Cruciferous vegetables Nasopharyngeal MMP [149]
α- Mangostin Garcinia mangostana Pancreas PI3K/ Akt [152]
Chrysin Passiflora species TNBC PI3K/ Akt/MMP [181]
Polyphenols Hormophysa triquerta Pancreas ALDH/Sox-2 [182]
Nobiletin Citrus peels Lung Notch-1 [146]
Chebulagic Acid, Triphala- Ayurvedic Retinal Pigment
Smad-3 [183]
Chebulinic Acid combination Epithelial
Tangeretin Citrus peels Gastric Notch-1/ Jagged1 [147]
Nimbolide Azadirachta indica Pancreas PI3K/AKT/mTOR [184]

47