Accepted Manuscript

Title: Dietary phytochemicals for possible preventive and

therapeutic option of uterine fibroids: signaling pathways as
target

Authors: Md. Soriful Islam James H. Segars Mario

Castellucci MD, PhD Pasquapina Ciarmela Ph.D

PII: S1734-1140(16)30297-3
DOI: http://dx.doi.org/doi:10.1016/j.pharep.2016.10.013
Reference: PHAREP 585

To appear in:

Received date: 20-7-2016

Revised date: 3-10-2016
Accepted date: 19-10-2016

Please cite this article as: Md.Soriful Islam, James H.Segars, Mario Castellucci,
Pasquapina Ciarmela, Dietary phytochemicals for possible preventive
and therapeutic option of uterine fibroids: signaling pathways as target,
http://dx.doi.org/10.1016/j.pharep.2016.10.013

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 1

FULL TITLE: Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids:

signaling pathways as target

SHORT TITLE: Dietary phytochemicals for uterine fibroids

Md Soriful Islam1, 2, James H. Segars3, Mario Castellucci1*, Pasquapina Ciarmela1, 4*

1
Department of Experimental and Clinical Medicine, Faculty of Medicine, Università Politecnica delle

Marche, Ancona 60020, Italy

2
Biotechnology and Microbiology Laboratory, Department of Botany, University of Rajshahi, Rajshahi

6205, Bangladesh;
3
Howard W. and Georgeanna Seegar Jones Division of Reproductive Sciences, Department of

Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
4
Department of Information Engineering, Università Politecnica delle Marche, Ancona 60131, Italy

*Corresponding author’s:

1) Pasquapina Ciarmela, Ph.D

Department of Experimental and Clinical Medicine,

Faculty of Medicine, Università Politecnica delle Marche, via Tronto 10/a, 60020 Ancona, Italy

Phone: +390712206270, Fax: +390712206087, E-mail: p.ciarmela@univpm.it

2) Mario Castellucci, MD, PhD

Department of Experimental and Clinical Medicine,

Faculty of Medicine, Università Politecnica delle Marche, via Tronto 10/a, 60020 Ancona, Italy

Phone: +390712206086, Fax: +390712206087, E-mail: m.castellucci@univpm.it

 2

Abstract

A growing interest has emerged on dietary phytochemicals to control diverse pathological conditions.

Unfortunately, dietary phytochemical research in uterine fibroids is still under construction. Uterine

fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in premenopausal

women. They may occur in more than 70 % of women, and approximately 25 % of women show

clinically significant symptoms. These include heavy and prolonged menstrual bleeding, pelvic pressure

(urinary frequency, incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and

reproductive dysfunction. Due to lack of medical treatments surgery has been definitive choice for fibroid

management. Moreover, surgery negatively affects women’s quality of life, and its associated cost

appears to be expensive. The molecular mechanism of fibroids development and growth is not fully

elucidated. However, accumulated evidence shows that several signaling pathways, including Smad 2/3,

PI3K/AKT/mTOR, ERK 1/2 and β-catenin are involved in the leiomyoma pathogenesis, indicating that

they could serve as targets for prevention and/or treatment of this tumor. Therefore, in this review, we

discuss the involvement of signaling pathways in leiomyoma development and growth, and introduce

some potential dietary phytochemicals that could modulate those signaling pathways.

Keywords: Dietary phytochemicals, uterine fibroids, signaling pathways, growth factors, medical

treatment
 3

Introduction

Uterine fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in

premenopausal women [1, 2]. They may occur in more than 70 % of women [3], and among these, about

20-50% of women are reported to produce clinically significant symptoms [4]. Leiomyoma associated

symptoms include: heavy and prolonged menstrual bleeding, pelvic pressure (urinary frequency,

incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and reproductive

dysfunction [5]. Surgery has been a definitive treatment of uterine fibroids. Moreover, surgery negatively

affects women’s quality of life, and its associated cost appears to be expensive. For example, in United

States, surgery associated cost of uterine fibroids management is approximately $5.9-34.4 billion annually

[6].

Unfortunately, the current medical treatments are limited and no effective prevention strategies

exist [7]. Moreover, the benefits of medical treatments are tempered by lack of efficacy or serious adverse

side effects. Poor understanding of the precise molecular mechanism of uterine fibroids development and

growth is may be the reason for the limitation of medical treatments. However, in recent years, significant

advances to uncover the molecular mechanisms of uterine fibroid development and growth have been

achieved [1, 8-11]. It is thought that uterine fibroids are monoclonal tumors, and approximately 40-50 %

contain karyotypic or cytogenetic abnormalities [12]. Notably, mediator complex subunit 12 (MED12)

gene mutation has been noted in 70 % of fibroids [13].

Cell signaling is the transfer of information, by which cells perceive and respond to extracellular

stimuli including growth factors, neurotransmitters, and hormones. The signaling cascade starts with

binding of extracellular stimuli to a cell surface receptor. The receptor then activates series of downstream

signaling molecules in the cytoplasm that import signal to the nucleus for subsequent transcription of

target genes. The activation of several signaling pathways, such as Smad 2/3, phosphoinositide 3-kinase

(PI3K), extracellular-signal-regulated kinase 1/2 (ERK1/2), and β-catenin have been reported in

leiomyoma cells [8-11]. They regulate central events (such as inflammatory response, fibrosis,
 4

proliferation and angiogenesis) of leiomyoma development and growth. Therefore, signaling pathways

could serve as excellent target for prevention and treatment of uterine fibroids.

Dietary phytochemicals are plant based chemical compounds with disease-preventive properties,

found in cereals, fruits, vegetables, legumes, herbs, spices, nuts, and beverages (such as tea, wine and

beer). They are known to exert therapeutic effects on multiple pathological conditions through modulating

diverse signaling pathways [14-16]. Accumulating evidences indicate that high intake of green vegetables

and fruit seem to have a protective role and associated with reduced risk of uterine fibroids of US and

Italian populations [17, 18]. This result supports the possible use of dietary phytochemicals for the

prevention and/treatment of uterine fibroids. However, phytochemical based research in uterine fibroids is

still under construction. For example, EGCG (epigallocatechin gallate), curcumin, resveratrol,

isoliquiritigenin and genistein are only few dietary phytochemicals that have been partially studied in

uterine leiomyoma [19-26]. They are mostly known for antiproliferative effects, however, their effects on

signaling pathways have not been addressed in leiomyoma cells except curcumin [21] and genistein [27].

Hence, there is much room for future research in the area of phytochemical based studies focusing on

signaling pathways as therapeutic target. Therefore, in this review, we discussed the role of signaling

pathways in leiomyoma development and growth, and introduced 14 dietary phytochemicals (Fig. 1) that

could modulate those signaling pathways.

Health benefits of dietary phytochemicals

The father of medicine, Hippocrates, proclaimed that “Let food be thy medicine and medicine be thy

food” almost 25 centuries ago. However, the relationship between diet and health is yet to explore. The

human diet contains wide variety of plant-based foods that provide essential nutrients for the body.

Besides, plant-based foods possess huge variety of non-nutrient components that offer beneficiary effects

on health.

Accumulated epidemiologic studies indicate an inverse association between diet rich in fruits and

vegetables and the risk of cancers (such as colon, breast, and ovary) [28-30] and other diseases. The major
 5

groups of health promoting dietary phytochemicals are phenolics [phenolic acid-gallic acid, stilbene-

resveratrol, flavonoids (flavonol-quercetin, flavones-apigenin, flavanol-catechin, flavanone-naringenin,

anthocyanidin-delphinidin, and isoflavonoid-genistein), lignin-matairecinol, coumarin-warfarin, and

tannins)], alkaloids-caffeine, carotenoid-lycopene, organosulfur compound-sulforaphane, and

phytosterols-sitosterol and stigmasterol [31]. For example, strawberry, a major source of anthocyanins

(i.e. pelargonidin-3-glucoside), flavonols (quercetin and kaempferol), ellagitannin (ellagic acid), flavanols

(catechins and procyanidins), and phenolic acid (caffeic acid), is known to exert therapeutic effects in

the prevention of diabetes, obesity, cancers, cardiovascular diseases, and neurodegenerative diseases [32].

It is thought that the health benefits of fruits and vegetables are the result of additive and synergistic

interactions of the phytochemicals present in whole foods [33].

Chemoprevention is characterized by the use of natural or synthetic agents to block, reverse or

restrict tumorigenic steps: initiation, promotion, and progression [16]. In recent years, dietary

phytochemicals are being considered as a cost effective, acceptable and accessible approach for cancer

prevention and treatment. Therefore, dietary phytochemicals have been extensively investigated for their

multiple therapeutic effects as well as their safety, and low toxicity [34].

Signaling pathways in uterine leiomyoma

Accumulated evidence suggests that several signaling pathways, including Smad 2/3 (Fig.2A), PI3K

(Fig.2B), ERK 1/2 (Fig.3A), and β-catenin (Fig.3B) activated by growth factors, other peptide or

proteins, and hormones have been found in leiomyoma cells [8-11]. They regulate inflammatory response,

fibrosis, proliferation and angiogenesis that are important phenomenon for leiomyoma pathogenesis.

Since dietary phytochemicals may exert multiple therapeutic effects against diverse pathological

conditions, they could regulate leiomyoma development and growth through targeting signaling

pathways.

Smad 2/3 signaling

 6

Smads are group of intracellular proteins that deliver extracellular signal to the nucleus induced by

transforming growth factor (TGF)-β superfamily members. Smads are classified into three different

groups, including receptor-regulated Smads (R-Smad), common-mediator Smad (Co-Smad), and

inhibitory Smads (I-Smad). Smad1, Smad2, Smad3, Smad5 and Smad8 are known as R-Smad. R-Smads

interact with Co-Smad (Smad4) to promote downstream signaling [35]. In contrast, I-Smads (Smad6 and

Smad7) act as blocker of activation of R-Smads and Co-Smads [36].

In myometrial and leiomyoma cells, activin-A and TGF-β1 has been reported to induce Smad 2/3

signaling [9, 37]. They initiate signaling by binding to a type II receptor (ActRIIA or ActRIIB for activin-

A, and TGF-βRII for TGF-β), which recruits and phosphorylates a type I receptor [activin receptor-like

kinase (ALK)-4/ActRIB for activin-A, and ALK5/TGF-βRI for TGF-β). Next, activated type-I receptor

phosphorylates Smad2 and Smad3 that interact with Smad4 in the cytoplasm. This smad complex then

travels to the nucleus where interacts with other transcription factors and regulates transcription of target

genes [38, 39].

Uterine leiomyoma demonstrated an elevated level of Smad3, Smad4 and phosphorylated Smad3

(p-Smad3) as well as TGF-βRI and TGF-βRII expression compared to normal counterpart [40]. TGF-β1

was reported to increase p-Smad3 induction in both myometrial and leiomyoma smooth muscle cells [37].

A number of studies reported that TGF-β1 can modulate inflammatory response, fibrosis, cell growth, and

apoptosis in myometrial and leiomyoma cells [41-45], which may be acquired , at least in part, through

activation of Smad 2/3 signaling [37]. The involvement of Smad 2/3 signaling in leiomyoma growth was

further documented by the observation that TGF-βRI kinase inhibitor, SB-525334 can block TGF-β

signaling in uterine leiomyoma cells, and significantly decreased tumor (leiomyoma) size, incidence and

multiplicity in Eker rat model [46]. Recently, we found that activin-A can induce phosphorylation of

Smad 2/3 in both primary myometrial and leiomyoma cells [9]. The ability of activin-A to increase

mRNA expression of fibronectin, collagen1A1, versican and vascular endothelial growth factor (VEGF)-

A in primary myometrial and/or leiomyoma cells [9, 47], demonstrating its profibrotic and angiogenic

role in this cell types. Ulipristal acetate is one of the most promising therapeutic options for leiomyoma
 7

was found to decrease activin-A, follistatin, ActRIIB, and ALK4 mRNA expression in leiomyoma

cultured cells [47]. We also found that ulipristal acetate can block activin-A-induced mRNA expression

of fibronectin and VEGF-A in myometrial and leiomyoma cultured cells [47].

PI3K signaling

PI3Ks are a large family of intracellular signal transducers. Activation of PI3K signaling can occur

through G protein-coupled receptors and tyrosine kinase receptors [48]. Induction of PI3K signaling by

prolactin-releasing peptide (PrRP) and epidermal growth factor (EGF) has been reported in uterine

leiomyoma cells [8, 49]. Upon ligand binding, receptor complex becomes activated, and phosphorylates

PI3K at the cell membrane [48]. Phosphorylated PI3K converts PIP2 (phosphatidylinositol-4,5-

diphosphate) to PIP3 (phosphatidylinositol-3,4,5-triphosphate) [48, 50], which subsequently mediates the

phosphorylation of protein kinase B (PKB/AKT) through phosphoinositide dependent protein kinase 1

(PDK1) [51]. Next, phosphorylated AKT activates/inactivates series of downstream proteins to facilitate

translation of target proteins. mTOR (mammalian target of rapamycin) is a best studied downstream

substrate of AKT. There are two complexes of mTOR: TORC1-Raptor complex and TORC2-Rictor

complex. AKT activates mTOR through phosphorylating and inactivating TSC 1/2, which inhibits mTOR

through GTP-binding protein, Rheb (Ras homolog enriched in brain). Thus, Rheb accumulates and

activates the mTOR-raptor kinase complex. The activated TORC1-Raptor complex mediates

phosphorylation of downstream substrates, eukaryotic translation initiation factor 4E-binding protein 1

(4E-BP1) and p70S6Kinase, which subsequently promote synthesis of target proteins [52].

Accumulated evidences suggest a central role of PI3K/AKT/mTOR pathway in the pathogenesis

of uterine leiomyomas [8, 53-55]. Using in vivo and in vitro studies, Crabtree and co-workers confirmed

the upregulation of mTOR signaling pathway in both human and rat leiomyomas/tumors [53]. They found

that rapamycin analogue WAY-129327 decreased tumor size, incidence and multiplicity in Eker rats, and

inhibited mTOR signaling [53]. MK-2206, an AKT Inhibitor, was reported to reduce mTOR and p70S6K

phosphorylation and promote leiomyoma cell death [56]. Varghese’s group showed that PrRP promoted
 8

PI3K/AKT/mTOR pathway through activation of GPR10, and increased primary leiomyoma cell

proliferation [8]. EGF has been reported to increase cell proliferation, and induce phosphorylation and

activation of EGFR and AKT in leiomyomal smooth muscle cells [49]. Involvement of PI3K/AKT

pathway in leiomyoma growth was further evidenced by the observation that inhibition of AKT using

API-59 (AKT inhibitor) decreased leiomyoma cell proliferation and cell viability, and promoted apoptosis

[57]. PTEN (phosphatase and tensin homolog) is a negative regulator of PI3K pathway. Uterine

leiomyoma and myometrium demonstrated an unchanged expression level of PTEN [55].

ERK 1/2 signaling

ERK 1/2 is a cytoplasmic protein [58] that mediates signaling by EGF, platelet-derived growth factor

(PDGF), insulin-like growth factor (IGF)-I and TGF-β in myometrial and/or leiomyoma cells [10, 44,

59]. The signaling is initiated by binding of ligands to their corresponding receptors. Upon lingand

binding, receptor complex (homo- or heterodimers) become auto-and transphosphorylates and activates

that leads to the association of the receptor to cytoplasmic target proteins. Grb2 (growth factor receptor-

bound protein 2 adapter protein), a docking protein, that binds to the activated receptors either directly or

through Shc (src homology and collagen domain protein) [60]. Shc and Grb2 then recruit SOS (son of

sevenless), a guanine nucleotide exchange factor, which in turn activates Ras by exchanging GDP for

GTP. Ras is a small GTP-binding protein that recruits Raf and activates it. Activated Raf then

phosphorylates and activates MEK 1/2, which in turn phosphorylates and activates ERK 1/2 [61].

Activated ERK 1/2 moves to the nucleus where it regulates transcription of target genes [62, 63].

EGF has been reported to stimulate proliferation of leiomyomal smooth muscle cells through

activation of the EGFR-ERK1/2 pathway [49]. Stimulation of primary leiomyoma cells with EGF

markedly increased intracellular reactive oxygen species (ROS) production that mediates mitogen-

activated protein kinase (MAPK)3/MAPK1 (ERK 1/2) activation leading to cell proliferation [10]. The

role of EGF in leiomyoma growth was also supported by the observation that AG1478 and TKS050

(selective EGFR blockers) can block leiomyoma cell proliferation by inducing cell cycle arrest and
 9

apoptosis [64, 65]. PDGF has been reported to activate ERK 1/2 signaling through intracellular ROS

production, and increase primary leiomyoma cell proliferation [10]. PDGF also increased collagen α1 (I)

mRNA expression in both myometrial and leiomyoma cells [66]. IGF-I was reported to increase uterine

leiomyoma cell proliferation by upregulating proliferating cell nuclear antigen (PCNA) expression and

downregulating apoptosis by upregulation of B-cell lymphoma-2 (Bcl-2) protein expression [59, 67]. The

stimulatory effect of IGF-I on leiomyoma growth was mediated, at least in part, by increasing

phosphorylation of IGF-IRβ, Shc and MAPKp44/42 (ERK1/2) [59]. TGF-β1 has been shown to regulate

inflammatory response, fibrosis, cell growth, and apoptosis in myometrial and leiomyoma cells [41-45], at

least in part, by ERK 1/2 signaling activation [44].

β-catenin signaling

β-catenin is the central component of wingless-type (WNT) signaling cascade. In the absence of WNT

ligands, β-catenin is degraded by a multiprotein ‘destruction complex’ in the cytoplasm. This

‘destruction complex’ contains APC (adenomatous polyposis coli) and AXIN, which facilitate the

phosphorylation of β-catenin by CK1 (casein kinase 1) and GSK3 (glycogen synthase kinase 3) [68]. In

the presence of WNT ligands, WNT binds to the Frizzled receptors and several co-receptors such as LRP-

5/6 (lipoprotein receptor-related protein-5/6), RYK (receptor-like tyrosine kinase) or ROR2 (receptor

tyrosine kinase-like orphan receptor 2) [69] resulting in the inhibition of ‘destruction complex’ that

stabilize β-catenin in the cytoplasm. Next, stabilized β-catenin moves to the nucleus and interacts with

LEF (lymphoid enhancer factor)/TCF (T-cell factor) transcription factors to regulate transcription of

target genes [70].

A considerable amount of evidence has suggested that WNT/β-catenin signaling is involved in

the pathogenesis of uterine fibroids [11, 71-73]. Tanwar and co-investigators developed a mouse model

that expresses constitutively activated β-catenin in uterine mesenchyme which gives rise to mesenchymal

tumors/leiomyoma-like tumors in the uterus [71]. The constitutive activation of β-catenin induced the

expression of TGF-β3 [71], which was shown to induce proliferation and extracellular matrix (ECM)
 10

formation in human uterine leiomyoma cells [74]. The tumor suppressor gene, MED12, is mutated in ~

70% of uterine leiomyomas [13], which directly binds to β-catenin and regulates WNT signaling [75].

The expression of WNT4 was found to be elevated in leiomyoma with MED12 mutations versus those

without mutations [73]. An elegant experiment by Ono and co-workers uncovered a central role of the

WNT/β-catenin pathway induced by estrogen and progesterone in leiomyoma growth, which was

confirmed by the observation that blocking of WNT activity through inhibitor of β-Catenin and TCF4

inhibits the growth of leiomyoma-like tumors in immunodeficient mice [11]. They found that WNT11

and WNT16 were increased at mRNA levels in myometrial cells, which were remained constitutively

increased (not significant) in leiomyoma cells in response to estrogen and progesterone treatment [11]. In

addition, frizzled receptors, FZD1 and FZD7 were found to be significantly higher at mRNA levels in

leiomyoma side-population cells than in total leiomyoma cells or leiomyoma mature population cells [11].

This group also found that LRP5 and LRP6 (co-receptors for WNT) were expressed in leiomyoma side-

population cells and leiomyoma mature population cells. Furthermore, estrogen and progesterone were

found to selectively induce nuclear translocation of β-catenin and transcriptional activity of TCF and

AXIN2 in leiomyoma side-population cells cocultured with mature myometrial cells [11].

Dietary phytochemicals that might target signaling pathways in uterine leiomyoma

Here, we discuss 14 dietary phytochemicals that might target signaling pathways, including Smad 2/3

(Fig.2A), PI3K (Fig.2B), ERK 1/2 (Fig.3A), and β-catenin (Fig.3B) involved in cell proliferation,

angiogenesis, inflammation and fibrosis that are linked to uterine leiomyoma development and growth.

These dietary phytochemicals were chosen based on their ability to modulate signaling pathways in

different pathological cell types.

Betulinic acid

Betulinic acid is a pentacyclic triterpene found in leaves of rosemary, and fruits of elephant apple.

Recently, Jin and co-workers reported that betulinic acid can inhibit 3-isobutyl-1-methylxanthine induced
 11

melanogenesis via the downregulation of p-MEK, p-ERK and p-AKT in B16F10 cells [76]. Betulinic

acid may exert antiangiogenic activity in cultured endometrial adenocarcinoma cells through decreasing

expression of hypoxia-inducible factor (HIF)-1α, and VEGF [77]. In addition, betulinic acid was reported

to suppress lipopolysaccharide (LPS)-induced interleukin (IL)-6 production through preventing nuclear

translocation of nuclear factor-κB (NF-κB) in peripheral blood mononuclear cells [78]. The antifibrotic

effect of betulinic acid was documented by the observation that betulinic acid can attenuate liver hepatic

stellate cell (HSC) activation by downregulating ethanol-induced p-Smad3 expression [79].

Butein

Butein is a type of chalcone derivative found in cashews. Khan and co-workers reported that butein can

inhibit prostate tumor growth in vivo through inhibition of PI3K/AKT pathway [80]. Butein also

suppressed breast cancer cell growth through downregulation of AKT phosphorylation [81]. Furthermore,

butein was reported to inhibit cell proliferation and clonogenecity of bladder cancer cells, through

reducing phosphorylation of ERK 1/2 [82].

Butein has been reported to inhibit VEGF-induced angiogenesis by downregulating the

phosphorylation of AKT, mTOR, and the major downstream effectors, p70S6K, 4E-BP1, and eIF4E in

endothelial progenitor cells [83]. Matrix metallopeptidase (MMP)-9 and VEGF are prominently involved

in the processes of tumor cell invasion and metastasis. It was shown that butein repressed tumor necrosis

factor (TNF)-α and phorbol-12-myristate-13-acetate induced expression of VEGF and MMP-9 via the

suppression of NF-κB activity in human prostate cancer cells [84].

The anti-inflammatory effect of butein has been reported by several investigators [85-87]. Wang

and co-workers reported that butein suppressed adipocyte inflammation in 3T3-L1 cells by

downregulation of TNF-α+LPS+interferon (IFN)-γ-induced secretion and/or expression of inflammatory

mediators, such as IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase

(iNOS), nitric oxide (NO), NOS2 (nitric oxide synthase 2), CXCL (C-X-C motif chemokines)-1, and

CXCL-10) through partly suppression of NF-κB activation and MAPKs [ERK 1/2, c-Jun N-terminal
 12

protein kinase (JNK), and p38 MAPK] signaling pathways [87]. Butein also decreased TNF-α-induced

monocyte cell adhesion to lung epithelial cells through inhibiting ROS generation and NF-κB activation

as well as the phosphorylation of MAPKs and AKT [85]. Furthermore, butein was reported to ameliorate

colitis in IL-10(-/-) mice, at least in part, by downregulation of IL-6, IL-1β, IFN-γ and MMP-9 as well as

IL-6-induced activation of signal transducer and activator of transcription (STAT)3 [86].

The antifibrotic effect of butein has been documented by the observation that butein can inhibit

ethanol-induced activation of liver stellate cells through inhibition of TGF-β, p38 MAPK, and JNK

signaling pathways [88].

Capsaicin

Capsaicin, active component of chili peppers, is known to have tumor suppressive effects. Recently, Park

and co-workers reported that capsaicin can potentially inhibit the proliferation of human gastric cancer

cells and induce apoptosis, through decreasing the expression of p-ERK 1/2 [89]. Capsaicin was also

reported to exert anticancer effect on human colorectal cancer cells through modulating β-catenin

signaling pathway [90]. This compound promoted proteosomal- degradation of β-catenin, and suppressed

TCF-4 expression and disrupted the interaction between TCF-4 and β-catenin [90].

Capsaicin can induce antiangiogenic activity both in vitro and in vivo [91]. Treatment of human

multiple myeloma cells with capsaicin inhibited IL-6-induced STAT3 activation, and STAT3-regulated

gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and VEGF [92], suggesting its regulatory

function in proliferation, survival and angiogenesis, and apoptosis. In addition, capsaicin was reported to

increase degradation of HIF-1α, which is a key transcription factor in increasing VEGF transcription in

non-small cell lung carcinoma [93]

Bitencourt and co-investigators reported that capsaicin induced down-regulation of HSC

activation by decreasing cyclooxygenase (COX)-2, TGF-β1 and collagen expression [94], suggesting its

antifibrotic and antiinflammatory actions. Accordingly, capsaicin has been reported to suppress the
 13

production of TNF-α [95], as well as prostaglandin E2 (PGE2) and NO production in macrophages via

NF-κB inactivation [96].

Delphinidin

Delphinidin is a polyphenolic compound found in many pigmented fruits, including cranberries, Concord

grapes, and pomegranates. A recent study reported that delphinidin suppressed proliferation and migration

of human ovarian clear cell carcinoma cells through blocking phosphorylation of downstream targets of

PI3K (AKT and p70S6K) and MAPKs (ERK1/2 and JNK) [97]. Pal’s group demonstrated that

delphinidin can inhibit growth of non-small-cell lung cancer cells through inhibition of EGFR, VEGFR2

as well as PI3K/AKT and MAPKs pathways [98]. Delphinidin also inhibited in vivo tumor growth

induced by B16-F10 melanoma cell xenograft in mice, through suppression of VEGFR2-mediated

endothelial cell proliferation as well as VEGFR2 signaling pathways, MAPKs (ERK1/2 and p38 MAPK)

and PI3K [99].

Angiogenesis is an energetic process and VEGF-induced angiogenesis is associated with

mitochondrial biogenesis. Delphinidin was reported to inhibit VEGF induced-mitochondrial biogenesis

and AKT activation in endothelial cells [100]. Lamy and co-workers reported that delphinidin can inhibit

smooth muscle cell migration as well as the differentiation and stabilization of endothelial cells, at least in

part, by inhibiting activation of PDGFR, and PDGF-BB-induced activation of ERK-1/2 signaling

pathway [101].

In athymic nude mice implanted with human prostate cancer PC3 cells, delphinidin treatment

induced a significant inhibition of tumor growth, through downregulation of NF-κB expression [93].

Delphinidin also inhibited UVB-induced MMP-1 expression as well as ROS production and NOX activity

in primary cultured human dermal fibroblasts partly through suppression of MAPKs phosphorylation

[102].

Delphinidin has been reported to inhibit TGF-β1-induced expression of α-smooth muscle actin

(α-SMA), fibronectin, and collagen as well as activation of MAPKs and NF-κB in nasal polyp-derived
 14

fibroblasts [103], suggesting its role in the regulation of myofibroblast differentiation and ECM

production through the MAPK/NF-κB signaling pathway.

3,3′-Diindolylmethane

3,3′-Diindolylmethane (DIM) is a polymeric compound produced after digestion of indole-3-carbinol in a

low pH environment. Several cruciferous vegetables, such as Brussels sprouts, cauliflower, cabbage,

broccoli, kale and turnips are known to be major sources of DIM. It has been shown that DIM can induce

antiproliferative and proapoptotic effects in oral squamous cell carcinoma cells and breast cancer cells,

through inactivation of NF-κB, AKT and MAPKs pathways [104, 105]. DIM also induced anti-

proliferative and pro-apoptotic effects in human cervical cancer cells through downregulating the

expression of p-AKT, PI3K, GSK-3β, p-PDK1 as well as p-c-Raf, p-ERK1/2 and p-p38 MAPK [106]. A

recent genome-wide transcriptome analysis showed that DIM can inhibit proliferation of colon cancer

cells through inactivation of Wnt/β-catenin signaling pathway [107]. DIM also suppressed the growth of

ovarian tumors in vitro and in vivo, at least in part, through reduction of EGFR, MEK, and ERK

phosphorylation [108].

Chang and co-workers found that DIM can inhibit VEGF-induced cell proliferation in human

umbilical vascular endothelial cells (HUVECs), at least in part, via downregulation of ERK1/2 and AKT

[109, 110]. DIM also inhibited invasion and angiogenesis in PDGF-D-overexpressing PC3 cells through

inactivation of mTOR and AKT [111].

The anti-inflammatory effect of DIM was documented by the observation that DIM can inhibit

LPS-induced microglial hyperactivation and brain inflammation through attenuating DNA-binding

activity of NF-κB and phosphorylation of inhibitor of κB [112].

Zhang and co-investigators reported that DIM can attenuate hepatic fibrosis by inhibiting miR-21

expression, and TGF-β induced α-SMA and COL1A1 as well as p-Smad2/3 and total Smad2/3 expression

[113]. A recent study reported that DIM can attenuate TGF-β1-induced myofibroblastic transformation of
 15

cardiac fibroblast through suppression of α-SMA, collagen I, collagen III, and connective tissue growth

factor (CTGF) expression via downregulation of AKT/GSK-3β signaling pathways [114].

Emodin

Emodin is an anthraquinone compound found in the root and rhizomes of Rhubarb. It has been shown that

emodin can inhibit tumor growth in orthotopic hepatocellular carcinoma mice model, at least in part, by

blocking of STAT3, JAK1/2 and AKT phosphorylation [115]. Emodin also downregulated the expression

of STAT3 regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, Mcl-1, survivin and VEGF in

HepG2 cells [115]. In human colorectal cancer cells, emodin downregulated the expression of β-catenin

and TCF7L2, as well as several downstream proteins, including cyclin D1, c-Myc, snail, vimentin, MMP-

2 and MMP-9 [116]. Emodin was also reported to repress TWIST1 (Twist-related protein 1)-induced

epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinoma FaDu cells through

inactivation of β-catenin and AKT signaling pathways [117]. A recent study reported that emodin can

inhibit the TGF-β-induced migration and invasion of human cervical cancer cells, partly through

decreasing the expression of TGF-βRII, p-Smad3, Smad4, and β-catenin [118].

Kaneshiro and co-investigators reported that emodin can inhibit endothelial cell proliferation,

migration, and tube formation through blocking ERK 1/2 phosphorylation [119], suggesting its

antiangiogenic properties.

Emodin has been reported to inhibit homocysteine-induced C-reactive protein generation in

vascular smooth muscle cells, through downregulating ROS generation, and phosphorylation of ERK1/2

and p38 MAPK [120], suggesting its antiinflammatory and antiatherosclerotic effects. Yin and co-

investigators reported that emodin can protect against LPS/D-galactosamine-induced liver injury in mice

through attenuating TNF-α production as well as p38 MAPK and NF-κB activation [121]. In addition,

emodin was reported to ameliorate LPS-induced mastitis in mice through reducing secretion and

expression of TNF-α, IL-1β and IL-6 via inactivating NF-κB and MAPKs pathways [122].
 16

Emodin can exhibit antifibrotic effect on pancreatic fibrosis, at least in part, by reducing collagen

and TGF-β1 expression (Wang et al., 2007a). Lee and co-workers reported that emodin suppressed TNF-

α-induced MMP-1 expression in human dermal fibroblast cells through inhibition of the activator protein

1 (AP-1) and MAPKs (ERK 1/2 and JNK) pathways [123]. Emodin was also reported to suppress

glucose/IL-1β induced mesangial cell proliferation and ECM (fibronectin and/or collagen) production by

blocking p38 MAPK pathway [124, 125].

Ferulic acid

Ferulic acid is a ubiquitous polyphenolic compound in plant kingdom, found especially in artichokes,

eggplants and maize bran. Ambothi and co-investigators reported that ferulic acid can inhibit UVB-

radiation induced photocarcinogenesis through downregulation of VEGF, iNOS, mutant p53, Bcl-2

expressions and upregulation of the Bax expression [126], suggesting its antiinflammatory,

antiangiogenic and apoptosis inducing capability.

A recent report indicated that ferulic acid can inhibit fibroblast growth factor (FGF)1-induced

endothelial cell proliferation, migration and tube formation as well as microvessel sprouting of rat aortic

rings and angiogenesis [127]. The antiangiogenic effect of ferulic acid was mediated by inactivation of

FGFR1 and PI3K/PKB signaling [127]. Hou’s group reported that ferulic acid suppressed proliferation of

ECV304 endothelial cells and blocked the cell cycle in G0/G1 phase, and inhibited phosphorylation of

ERK 1/2 [128].

Recently, Xu and co-workers reported that ferulic acid can exhibit antifibrotic effects on hepatic

stellate cells through inhibiting ERK 1/2 and Smad 2/3 signaling pathways [129]. Particularly, this

compound reduced TGF-βRII, TGF-βRI and Smad4 mRNA and protein expression as well as Smad

transcriptional activity, and blocked ERK 1/2 phosphorylation in HSC-T6 cells [129]. Ferulic acid also

attenuated TGF-β1-induced renal cellular fibrosis in NRK-52E cells via inactivation of Smad 2/3

signaling pathway [130]. Furthermore, ferulic acid was reported to attenuate ischemia/reperfusion-

induced hepatocyte apoptosis via inhibition of JNK activation [131].

 17

Fisetin

Fisetin is a flavonoid commonly present in apples, kiwis, strawberries, grapes, persimmons, onions and

cucumbers. Khan and co-workers reported that fisetin can inhibit growth of human non-small cell lung

cancer cells via suppression of PI3K/AKT/mTOR signaling [132]. In PC3 prostate cancer cells, fisetin

induced autophagic cell death through inhibition of mTOR signaling pathway [133].}. Particularly, fisetin

inhibited phosphorylation of mTOR kinase and downregulated the expression of Raptor, Rictor, PRAS40

and GβL as well as activated the mTOR repressor, TSC2 in this cell type [133]. Furthermore, fisetin was

reported to inhibit human laryngeal carcinoma cells of TU212 cell proliferation and induce apoptosis via

downregulating Raf, Ras, p-ERK1/2, PI3K, p-AKT, NF-κB and mTOR expression [134].

Fisetin has been reported to exert antiangiogenic effect by inhibiting VEGF-induced growth and

survival of HUVEC as well as capillary-like tube formation on Matrigel [135]. It also inhibited the

expression of eNOS (endothelial nitric oxide synthase), VEGF, iNOS, MMP-2 and MMP-9 in A549 and

DU145 human cancer cells [135].

Fisetin exerts antiinflammatory effects in human mast cells by suppressing phorbol-12-myristate

13-acetate plus calcium ionophore A23187-stimulated gene expression and production of TNF-α, IL-1β,

IL-4, IL-6, and IL-8 via downregulation of MAPKs and NF-κB pathways [136]. Fisetin also reduced

secretion of IL-6 and TNF-α via inactivation of JNK and NF-κB in LPS-stimulated macrophage cells

[137]. Furthermore, fisetin was reported to inhibit IL-1β-induced cytokines (TNF-α, IL-6) and

chemokines (IL-8, MCP-1) in rheumatoid arthritic fibroblast-like synovial cells and in vivo models [138].

Kaempferol

Kaempferol is a flavonoid present in green tea, broccoli, apples, strawberries and green beans. A recent

study reported that kaempferol can suppress estrogen and triclosan stimulated breast cancer cell growth in

cellular and xenograft breast cancer models via downregulation of p-AKT and p-MEK1/2 expression

[139]. Kaempferol also inhibited proliferation of esophageal squamous cell carcinoma cells and induced
 18

G0/G1 cell cycle arrest, and suppressed tumor growth in KYSE150 xenograft model via suppression of

EGFR and its downstream signaling pathways, ERK 1/2 and AKT [140]. Furthermore, kaempferol was

reported to suppress bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis

via downregulation of the p38 MAPK phosphorylation and c-Fos expression [141]. Kim and co-workers

reported that kaempferol inhibited PDGF-BB-induced rat aortic vascular smooth muscle cell proliferation,

at least in part, by downregulation of PDGFR-β phosphorylation and its downstream signal transduction

pathways, ERK1/2, AKT and PLC-γ1 phosphorylation and c-fos expression [142]. The ability of

kaempferol to downregulate IGF-I-induced phosphorylation of the IGF-IR and ERK 1/2 pathways in HT-

29 human colon cancer cells was reported by Lee and co-investigators [143].

In chorioallantoic membranes of chicken embryos, kaempferol inhibited OVCAR-3-induced

angiogenesis and tumor growth, at least in part, by reducing VEGF and HIF-1α expression via

downregulation of AKT phosphorylation [144]. Kaempferol also suppressed hepatocarcinoma cell

survival through downregulation of HIF-1 activity and p44/42 MAPK activation [145]. Furthermore,

kaempferol was reported to inhibit VEGF secretion, and in vitro angiogenesis, via downregulation of

ERK phosphorylation as well as NF-κB and cMyc expression [146].

Kaempferol exhibited a protective effect on LPS-induced acute lung injury in mice via

suppression of TNF-α, IL-1β and IL-6 production and MAPKs and NF-κB phosphorylation [147].

Kaempferol also attenuated myocardial ischemic injury via downregulation of TNF-α and IL-6

production as well as inhibition of MAPKs phosphorylation and NF-κB expression [148]. Yoon and co-

investigators reported that kaempferol can inhibit IL-1β-induced proliferation of rheumatoid arthritis

synovial fibroblasts and the expression of COX-2, PGE2 as well as MMP-1 and MMP-3, partly through

downregulation of NF-κB activation as well as MAPKs phosphorylation [149].

The antifibrotic effect of kaempferol was documented by the observation that kaempferol can

suppress collagen deposition, epithelial excrescency and goblet hyperplasia in the lung of ovalbumin-

challenged mice, at least in part, by inhibition of TGF-β-induced EMT by reversing E-cadherin

expression and retarding the induction of N-cadherin and α-SMA [150].

 19

Morin

Morin is a member of flavonols found in almonds that suppressed growth and invasion of the metastatic

breast cancer cell line MDA-MB 231 as well as cancer cell progression in xenograft mouse model, partly

through suppression of AKT pathway [151].

Morin has been reported to attenuate ovalbumin-induced airway inflammation in mice by

suppression of goblet cell hyperplasia and collagen deposition and ovalbumin-induced TNF-α, IL-4, IL-

13, and MMP-9 via inactivating MAPKs pathway [152]. In human bronchial epithelial cells, morin also

inhibited TNF-α induced ROS generation and expression of eotaxin-1, MCP-1, and IL-8 [152].

Furthermore, morin was reported to suppress monosodium urate crystal-induced inflammation in RAW

264.7 macrophages through inhibition of expression and/or secretion of inflammatory mediators (TNF-α,

IL-1β, IL-6, MCP-1, NO, PEG2, iNOS and COX-2), VEGF expression, ROS generation, and NF-κB

activation [153].

Morin has been reported to ameliorate in vivo diethylnitrosamine-induced liver fibrosis in male

albino Wistar rat as well as inhibit proliferation of LX-2 cells (culture-activated human HSCs), partly

through inhibition of β-catenin and GSK-3β expression [154].

Naringin

Naringin is a flavanone glycoside found in grapefruit and related citrus species. Li and co-workers

reported that naringin can inhibit proliferation of triple-negative (ER-/PR-/HER2-) breast cancer cells

(MDA-MB-231, MDA-MB-468 and BT-549), through induction of apoptosis and G1 cycle arrest [155].

They also noticed that inactivation of β-catenin signaling pathway was responsible for this anticancer

effect [155]. Naringin also induced autophagy-mediated growth inhibition in AGS cancer cells by

downregulating the phosphorylation of PI3K and its activated downstream targets p-AKT and p-mTOR

via activation of MAPKs pathways [156].

 20

Recently, Zhang and co-workers reported that naringin can prevent intestinal tumorigenesis in

Apc (Min/+) mouse model through suppression of cell proliferation, induction of apoptosis and inhibition

of expression and/or secretion of inflammatory mediators (Cox-2, NF-κB, TNF-α, PGE2 and IL-6) as

well as β-catenin expression and GSK-3β phosphorylation [157]. Naringin also inhibited growth of HeLa

cervical cancer cells and induces apoptosis, at least in part, by suppression of NF κB phosphorylation

and COX 2 expression [158]. Furthermore, naringin was reported to inhibit TNF-α-induced invasion and

migration of vascular smooth muscle cells as well as expression and/or secretion of MMP-9, IL-6 and IL-

8, at least in part, through blocking of PI3K/AKT/mTOR/p70S6K pathway via suppression of

transcriptional activity of AP-1 and NF κB [159].

The protective effects of naringin against paraquat-induced acute lung injury and pulmonary

fibrosis in mice have been reported, which was mediated primarily through downregulation of expression

of TGF-β1 and TNF-α as well as modulation of expression and ratios of MMP-9 and TIMP-1 [160].

Naringin also inhibited renal interstitial fibrosis and collagen formation partly through inhibiting

oxidative stress and NF-κB activation [161].

Pterostilbene

Pterostilbene is a stilbene, biologically classified as a phytoalexin, chemically related to resveratrol.

Several types of grapes and blueberries are major sources of pterostilbene. Pterostilbene has been reported

to inhibit 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate-induced mouse skin

tumor formation possibly via inactivation of NF-κB and AP-1, and their upstream signaling pathways,

MAPKs, PI3K and AKT [162]. Paul’s group reported that pterostilbene can inhibit the growth of cultured

colon cancer HT-29 cells and induce apoptosis through downregulating TNF-α+IFN-γ+LPS-induced

iNOS and COX-2 expression via suppression of p38 MAPK signaling pathway [163]. Later study

reported that pterostilbene can reduce colon tumor multiplicity of non-invasive adenocarcinomas in rats

by inhibiting TNF-α, IL-1β and IL-4 expression via suppression of β-catenin and NF-κB signaling

pathways [164]. Chiou and co-workers reported that pterostilbene inhibited azoxymethane-induced
 21

colorectal aberrant crypt foci and adenomas through upregulation of apoptosis and downregulation of

iNOS, COX-2, VEGF, cyclin D1, MMP-7, MMP-26, MMP-2, and MMP-9 expression and/or activity, at

least in part, via suppression of multiple signaling molecules, including p-GSK-3β, β-catenin, p-PI3K, p-

AKT, EGF, and EGFR [165].

Pterostilbene has been reported to suppress 12-O-tetradecanoylphorbol 13-acetate-induced

invasion, migration and metastasis of HepG2 cells by downregulation of angiogenic factors, such as

VEGF, EGF and EGFR expression, and their downstream signal transduction pathways, MAPKs,

PI3K/AKT and PKC as well as NF-κB and AP-1 [166].

Pterostilbene has been reported to inhibit high fat-induced atherosclerosis inflammation in mice

through inhibition of TNF-α, TGF-β1, IL-18, IL-6, IFN-γ, MCP-1 and IL-17 expression and/or secretion

via inactivation of NF-κB [167]. Pterostilbene also reduced the expression of TNF-α, IL-1 β, IL-6, COX-

2, MMP-2 and MMP-9, and ROS overproduction in hyperosmotic medium exposed human corneal

epithelial cells [168], suggesting its ability to protect corneal epithelial cells through antiinflammatory and

antioxidative effects.

It has been shown that pterostilbene inhibited dimethylnitrosamine-induced liver fibrosis in rats

[169]. The antifibrotic effect of pterostilbene in the dimethylnitrosamine-treated rats was mediated by

downregulation of α-SMA and MMP-2 expression as well as TGF-β1, and its signaling molecules, p-

Smad2 and p-Smad3 expression [169].

Silibinin

Silibinin (also known as silybin) is a flavonolignan compound found artichokes. This compound can

induce antiproliferative, antiinflammatory, proapoptotic and antiangiogenic effects in colorectal cancer as

evidenced by decreased cell proliferation [170, 171], and TNF-α-induced NF-κB activation, and thereby

NF-κB-regulated molecules, including Bcl-2, COX-2, iNOS, VEGF, HIF-1α and MMP9 [170-172]. This

effect was mediated, at least in part, by downregulation of β-catenin, IGF-1Rβ, p-GSK-3β, p-ERK 1/2

and p-AKT [170, 171]. Kim’s group reported that silibinin can suppress EGF-induced phosphorylation of
 22

EGFR and ERK 1/2 in SKBR3 and BT474 breast cancer cells [173]. In nude mice model, silibinin also

attenuated the growth of melanoma xenograft tumors through inhibiting phosphorylation of MEK 1/2 and

ERK 1/2 [174].

Antiangiogenic effect of silibinin was documented by the observation that silibinin can inhibit

VEGF secretion and HIF-1α subunit accumulation in retinal pigmented epithelia cells through

downregulation of p-PI3K, p-AKT, p-mTOR and p70S6K [175]. In the rat model of age-related macular

degeneration, silibinin also prevented VEGF- and VEGF plus hypoxia-induced retinal oedema and

neovascularization [175]. Furthermore, silibinin was reported to inhibit human cervical and hepatoma

cancer cell growth by inhibiting HIF-1α protein synthesis and hypoxia-induced VEGF secretion via

suppression of the p-mTOR and its effectors, p70S6K and 4E-BP1 [176].

Silibinin has been reported to suppress LPS-induced neutrophilic airway inflammation, at least in

part, by downregulation of ERK phosphorylation [177]. Silibinin also inhibited ovalbumin-induced

airway inflammation, and reduced the production of various cytokines (TNF-α, IL-1β, IL-4, IL-5, and IL-

13), partly via downregulation of NF-κB activity [178]. Furthermore, silibinin showed inhibitory effect on

skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate by down-regulating IL-1β, IL-6,

TNF-α and COX-2 expression via inhibiting the PI3K/AKT signaling pathway, and NF-κB activation

[179].

Silibinin has been reported to attenuate cardiac hypertrophy and fibrosis by downregulating

EGFR-dependent ERK1/2 and PI3K/AKT, as well as activation of NF-κB and Smad 2/3 signaling

pathways [180]. Chen and colleagues reported that silibinin can inhibit myofibroblast transdifferentiation

in human tenon fibroblasts and reduce fibrosis in a rabbit trabeculectomy model [181]. Particularly,

silibinin inhibited TGF-β1-induced expression of α-SMA, vimentin, collagen contraction, CTGF,

collagen type I in human tenon fibroblasts through downregulation of p-Smad3 [181]. A study by Cho

and co-workers indicated that silibinin has the potential to prevent fibrotic skin changes by inducing the

downregulation of type I collagen expression in human skin fibroblasts, partly by the inhibition of TGF-

β1-induced p-Smad2 and p-Smad3 expression [182]. Silibinin exerts antiinflammatory and antifibrogenic
 23

effects on human hepatic stellate cells by downregulation of human HSC cell proliferation, cell migration,

and de novo synthesis of collagen type I as well as IL-1β-induced synthesis of MCP-1 and IL-8 via

directly inhibiting ERK, MEK, and Raf phosphorylation [183].

Thymoquinone

Thymoquinone is a bioactive component of black seed oil. It has been shown that thymoquinone can

induce cell cycle arrest and apoptosis in breast cancer cells through inhibition of PI3K/AKT pathway

[184, 185]. Particularly, thymoquinone reduced the phosphorylation of PTEN (inactivated form of

PTEN), PDK1 and AKT that resulted in the inhibition of 4E-BP1 and p70S6K [184]. In human

cholangiocarcinoma cells, thymoquinone induced inhibition of cell growth by inducing cell cycle arrest

and apoptosis through downregulation of PI3K/AKT and NF-κB pathways, and their regulated gene

products, including Bcl-2, COX-2, and VEGF [186]. Furthermore, thymoquinone was reported to inhibit

proliferation and invasion of human nonsmall-cell lung cancer cells via downregulation of ERK pathway

as confirmed by the reduced expression level of PCNA, cyclin D1, MMP-2 and MMP-9, and p-

ERK1/2[187].

Thymoquinone has been reported to prevent tumor angiogenesis in a mouse xenograft human

prostate cancer (PC3) model, and inhibited human prostate tumor growth through suppressing AKT and

ERK signaling pathways [188]. Thymoquinone also exhibited antiangiogenic effects on osteosarcoma in

vitro and in vivo through inactivating the NF-κB pathway as evidenced by downregulation of NF-κB

DNA-binding activity, survivin and VEGF in SaOS-2 cells [189].

A recent study by Su and co-investigators reported that thymoquinone can inhibit inflammation

and neoangiogenesis induced by Ovalbumin in asthma mice by reducing IL-4 and IL-5 production, as

well as VEGF, p-VEGFR2, p-PI3K and p-AKT expression and tube information in HUVECs [190].

Thymoquinone also inhibited IL-1β-induced inflammation in human osteoarthritis chondrocytes as

evidenced by decreased production of COX-2, iNOS, NO, and PGE2 as well as MMP-1, MMP-3, and

MMP-13 expression via inhibiting NF-κB activation and IκBα degradation as well as MAPKs pathway
 24

activation [191]. Furthermore, thymoquinone was reported to inhibit TNF-α-induced IL-6 and IL-8

production in rheumatoid arthritis synovial fibroblasts by inhibiting JNK and p38 MAPK signaling

pathways [192].

Thymoquinone has been reported to attenuate liver fibrosis by reducing α-SMA, collagen1A1,

collagen3A1, TIMP-1, L-1α, IL-1β and IL-18 levels, at least in part, via inactivating PI3K and TLR4

signaling pathways [193-195]. Thymoquinone can also block lung injury and fibrosis in rats induced by

bleomycin/paraquat herbicide through downregulation of TGF-β1, α-SMA, collagen 1A1 and collagen

4A1, and inhibition of oxidative stress and NF-κB activation [196, 197].

Conclusions and future perspectives

The precise molecular mechanisms of leiomyoma pathogenesis are not well understood. However,

accumulating evidences suggest that several signaling pathways, such as Smad 2/3, PI3K, ERK1/2 and β-

catenin are involved in regulating central events (such as inflammatory response, fibrosis, proliferation

and angiogenesis) of leiomyoma development and growth. Thus, they may act as excellent target for

possible prevention and treatment of uterine fibroids. Here, we introduced 14 dietary phytochemicals

(betulinic acid, butein, capsaicin, delphinidin, 3,3'-diindolylmethane, emodin, ferulic acid, fisetin,

kaempferol, morin, naringin, pterostilbene, silibinin and thymoquinone) that could potentially be used as

therapeutic and/or preventive compounds for uterine leiomyoma (Fig. 1). These dietary phytochemicals

have shown their ability to regulate major tumor initiating and promoting events such as, inflammation,

fibrosis, proliferation and angiogenesis in different experimental conditions through regulating several

signaling pathways, including Smad 2/3, PI3K, ERK 1/2 and β-catenin. Future research may include these

dietary phytochemicals to check their ability to modulate signaling pathways in uterine fibroids. Dietary

phytochemicals are not limited to these 14 compounds. Other potential dietary phytochemicals that have

not yet been tested could be included for future research in uterine fibroids.
 25

Funding body

This work was supported by a grant from the “Fondazione Cassa di Risparmio di Fabriano e

Cupramontana” (to MC and PC).

Conflict of interest

None

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Figure legends

Fig. 1. Dietary phytochemicals and their chemical structure and dietary sources.

Fig. 2A-B. Smad 2/3 (A) and PI3K (B) signaling pathways in uterine leiomyoma targeted by dietary

phytochemicals.

Fig. 3A-B. ERK 2/3 (A) and β-catenin (B) signaling pathways in uterine leiomyoma targeted by dietary

phytochemicals.
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Figure 1
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Figure 2
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Figure 3