Pharmacological Research 130 (2018) 273–291

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Review

Targeting oncogenic transcription factors by polyphenols: A novel

approach for cancer therapy
Chitra Rajagopal a , Manendra Babu Lankadasari a , Jesil Mathew Aranjani b ,
K.B. Harikumar a,∗
a
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
b
Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India

a r t i c l e i n f o a b s t r a c t

Article history: Inflammation is one of the major causative factor of cancer and chronic inflammation is involved in all
Received 31 July 2017 the major steps of cancer initiation, progression metastasis and drug resistance. The molecular mecha-
Received in revised form nism of inflammation driven cancer is the complex interplay between oncogenic and tumor suppressive
30 November 2017
transcription factors which include FOXM1, NF-kB, STAT3, Wnt/␤- Catenin, HIF-1␣, NRF2, androgen and
Accepted 31 December 2017
estrogen receptors. Several products derived from natural sources modulate the expression and activ-
Available online 4 January 2018
ity of multiple transcription factors in various tumor models as evident from studies conducted in cell
lines, pre-clinical models and clinical samples. Further combination of these natural products along with
Chemical compounds studied in this article:
4- Shogaol (PubChem CID: 9794897)
currently approved cancer therapies added an additional advantage and they considered as promising
6- Shogaol (PubChem CID: 5281794) targets for prevention and treatment of inflammation and cancer. In this review we discuss the application
Apigenin (PubChem CID: 5280443) of multi-targeting natural products by analyzing the literature and future directions for their plausible
Berberine (PubChem CID: 2353) applications in drug discovery.
Bergamottin (PubChem CID: 5471349) © 2018 Elsevier Ltd. All rights reserved.
Caffeic acid (PubChem CID:
689043)Capsaicin (PubChem CID: 1548943)
Cardamonin (PubChem CID: 641785)
Casticin(PubChem CID: 5315263)
Chrysin (PubChem CID: 5281607)
Cryptotanshinone (PubChem CID: 160254)
Cucurbitacin (PubChem CID: 5281319)
Curcumin (PubChem CID: 969516)
EGCG (PubChem CID: 65064)
Ellagic acid (PubChem CID: 5281855)
Escin (PubChem CID: 16211024)
Fistein (PubChem CID: 5281614)
Gambogic acid (PubChem CID: 16072310)
Gingerol (PubChem CID: 442793)
Gossypin (PubChem CID: 5281621)
Honokiol (PubChem CID: 72303)
Luteolin (PubChem CID: 5280445)

Abbreviations: AIF, apoptosis-inducing factor; Akt/PKA, protein kinase A; AR, androgen receptors; Bax, Bcl-2-associated X protein; Bcl2, B-cell lymphoma2; BIG3, brefeldin
A-inhibited guanine nucleotide-exchange protein3; CCL2, chemokine ligand 2; Cdc25B, cell division cycle 25B; Cdk 2, cyclin-dependent kinase 2; Cdk4, cyclin-dependent
kinase 4; c-FLIP, cellular FLICE- inhibitory protein; COX2, cyclooxygenase 2; CXCR2, C-X-C chemokine receptor type 2; DNMT1, DNA methyltransferase 1; EMT, epithelial
to mesenchymal transition; ERK1, extracellular signal-regulated kinase-1; ER␣, estrogen receptor alpha; FAK, focal adhesion kinase; FGF, fibroblast growth factors; FOXM1,
forkhead box protein M1; Foxo3a, forkhead box O3; HIF-1␣, hypoxia inducing factor-1␣; hTERT, telomerase reverse transcriptase; IAP, the inhibitors of apoptosis protein;
ICAM-1, intercellular adhesion molecule 1; IGF-1R, insulin-like growth factor 1; IKK, inhibitory kappa B kinase; iNOS, inducible nitric oxide synthase; I␬B␣, inhibitory kappa
B alpha; JAK, janus kinase; JNK, c-Jun N-terminal kinase; LRP4, LDL receptor related protein; Mcl-1, myeloid leukemia cell differentiation protein; MDM2, mouse double
minute 2 homolog; MMP, matrix metalloproteinase; mToR, mammalian target of rapamycin; NF-␬B, nuclear factor-␬B; PAIS3, protein inhibitor of activated STAT protein
3; PARP, poly (ADP-ribose) polymerase; PCNA, proliferative cell nuclear antigen; PGE2, prostaglandin E2; PHB, prohibitin; PI3K, phosphoinositide 3-kinase; PSA, prostate-
specific antigen; ROS, Reactive oxygen species; SHP1, src homology region 2 domain-containing phosphatase-1; SOCS3, suppressor of cytokine signaling 3; STAT, signal
transducer and activator of transcription; TGF␤, transforming growth factor beta; TNF-␣, tumor necrosis factor alpha; uPA, urokinase-type plasminogen activator; VEGF,
vascular endothelial growth factor; XIAP, X-linked inhibitor of apoptosis protein.
∗ Corresponding author.
E-mail address: harikumar@rgcb.res.in (K.B. Harikumar).

https://doi.org/10.1016/j.phrs.2017.12.034
1043-6618/© 2018 Elsevier Ltd. All rights reserved.
274 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291

Mangiferin (PubChem CID: 5281647)

Piperlongumine (PubChem CID:
637858)
Pterostilbene (PubChem CID: 5281727)
Quercetin (PubChem CID: 5280343)
Resveratrol (PubChem CID: 445154)
Rutin (PubChem CID: 5280805)
Sesamin (PubChem CID: 72307)
Ursolic acid (PubChem CID: 64945)
Wogonin (PubChem CID: 5281703)
Xanthohumol (PubChem CID: 639665)

Keywords:
Polyphenols
Cancer
Inflammation
Metastasis
Natural compounds
Transcription factors

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
2. Natural products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
3. Transcription factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
3.1. FOXM1 (Forkhead Box M1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
3.2. Wnt/␤-catenin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
3.3. Nrf2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.4. STAT3 (Signal transducer and activator of transcription 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
3.5. AR (androgen receptors) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
3.6. ER (estrogen receptors) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
3.7. HIF1 (hypoxia inducing factor 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
3.8. NF-␬B (nuclear factor kappaB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

1. Introduction prises of three main subclasses namely flavonoids, phenolic acids,

and stilbenoids which include hydroxybenzoic acids, hydroxycin-
Cancer is a multifactorial disease caused by dysregulation of namic acids, anthocyanins, proanthocyanidins, flavonols, flavones,
numerous gene products and alteration of multiple cell signal- flavanols, flavanones, isoflavones, stilbenes, lignansetc [5]. Its his-
ing pathways. The key reasons for more than 90% of cancer tory of evolution as major class of phytochemicals in the field
are attributed to somatic mutations and environmental factors. of therapeutics started from leather industry. Before 20th cen-
Another major factor is epigenetic changes and research in recent tury, polyphenols were named as vegetable tannins used in
years clearly demonstrated that DNA methylation and other type of the conversion of animal skin to leather. Later, its co-evolution
histone modifications can lead to alterations in chromatin conden- along with molecular chemistry leads to its establishment as an
sation status, thereby regulating the expression of specific genes. important category of biomolecules in the field of therapeutics.
Any kind of perturbation in the expression of these genes can lead Structural elucidation of polyphenols shows them as the polymers
to cellular transformation eventually leading to cancer [1]. Several of phenol groups, poly-hydroxylated phytochemicals. Mode of
epidemiological, pre-clinical and clinical studies over the last sev- extraction varies according to its physicochemical properties. Dif-
eral decades established the relationship between the process of ferent extraction methods include solvent extraction, microwave
inflammation and cancer. The acute inflammatory response has assisted extraction, ultrasound assisted extractions etc which is
therapeutic advantages however chronic inflammation is associ- followed by its colorimetric quantification [3,9]. Polyphenols are
ated with a myriad of diseases [2]. dominated for their antioxidant property but the recent research
showed their ability to bind to certain proteins directly leading
2. Natural products to physiological changes. Their antioxidant properties make them
usable against different diseases like cancer, diabetes, cardiovas-
Natural products can be defined as structurally diverse func- cular diseases etc. [10]. They directly interacts with key enzymes,
tional entities with multiple biological functions derived from receptors, transcription factors and even with protein aggregates
natural sources such as plants [3]. Many of the currently using which changes different biochemical reactions and signaling path-
chemotherapeutics are derived from natural sources [4]. Polyphe- ways. These molecular level control mechanisms give their potency
nols are a class of natural products present in various plant as promising agents against different diseases including cancer
products like vegetables, fruits, seeds, legumes etc. Apart from [3,9]. The Table 1 describes the various details of polyphenols dis-
yielding colour, aroma and taste to plants, they can also act as cussed in the review which include their sources, scientifically
the major component of plant immune system [5–8]. It com- documented major biological functions and structure.
 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291 275

Table 1
Summary of different polyphenols with its plant sources, chemical structures and established biological functions.

SL No. Name of the compound Plant source Known activities Structure Reference

1 4- shogaol Ginger Anticancer [140,141]

2 6- Shogaol Ginger Anticancer, antiproliferative, [140,141]

anti-inflammatory and for hypertension

3 Apigenin Parsley, celery, chamomile tea Antioxidant, antistress, anti-inflammatory and [142–144]
anticancer

4 Berberine Berries, turmeric, orange grape, Anti-inflammatory, antidiabetic, anticancer, [145,146]

yellow root, cork tree antiviral, neuroprotective and antidepressant

5 Bergamottin Grapes, citrus Anticancer [147]

6 Caffeic acid Coffee Anticancer [148,149]

7 Capsaicin Chilli peppers Anticancer and antioxidant [150]

8 Cardamonin Cardamom Antioxidant, anticancer and anti-inflammatory [139,151]

9 Casticin Sweet worm wood Anticancer, inhibition of angiogenesis and [152]

chemosensitization

10 Chrysin Passion fruit Neuroprotective and anticancer [153]

11 Cryptotanshinone Salvia Anticancer [154]

12 Cucurbitacin Pumpkins, guards Anticancer [155]

13 Curcumin Turmeric, mango, ginger Anticancer, antidepressant, anti-inflammatory [121,122,156]

and anti- allergic

14 EGCG Tea leaves Antiviral, antidiabetic, anticancer and [157–159]

anti-inflammatory

15 Ellagic acid Berries, walnuts, pecans Anticancer and antioxidant [160,161]

16 Escin Horse chestnut Anticancer [162]

17 Fisetin Strawberries, apple, cucumber, Antioxidant, anticancer and antiproliferative [163] [164]
acacia, onion, persimmons

18 Gambogic acid Garcinia Anticancer [165,166]

19 Gingerol Ginger Anticancer and anti-inflammatory [167,168]

20 Gossypin Hibiscus Anticancer [169]

21 Honokiol Magnolia Anticancer, neuroprotective and cardiac [170,171]

hypertrophy

22 Icarisidell Horny goat weed Anticancer and for erectile dysfunctions [172]

23 Luteolin Orange, grape, lemon Anticancer [173,174]

24 Mangiferin Mango Antioxidant, anti infectious, antidiabetic, [175,176]

antiatherosclerotic and anticancer

25 Piperlongumine Long pepper Neuroprotective and anticancer [168,177]

26 Pterostilbene Almond, berries, grapes Antioxidant, anticancer and anti-inflammatory [5,178,179]

27 Quercetin Cherries, berries, tomato, Antioxidant, anticancer and anti-inflammatory [180–182]

spinach, pepper

28 Resveratrol Grapes, berries Anticancer, antiviral, neurodegenerative [62,183,184]

diseases and vascular diseases
276 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291
Table 1 (Continued)
SL No. Name of the compound Plant source
29 Sesamin Sesame, long pepper, magnolia,
camellia, Pyrethrum
30 Ursolic acid Apple, berries, peppermint,
rosemary
31 Wogonin Baikal skullcap
32 Xanthohumol Hops
3. Transcription factors
Transcription factors are gene expression regulators whose
activity resides inside nucleus. Differential expression of genes
according to the demands of a cell is achieved with the action of
specific transcription factors which have direct binding accessi-
bility on the DNA [11]. Different categories of proteins are there
according to its mode of action and role in transcriptional regu-
lation. Alteration in the level of these proteins will result in the
abnormal variations in its downstream effectors which affects the
entire homeostatic balance of the system [12]. Transcription factors
which include both oncogenes as well as tumor suppressor genes
act as major link between the inflammation and tumorigenesis. The
expressions of several transcription factors are deregulated in most
of the cancers [13,14].
Transcription factors have emerged as the coupling link
between inflammation and tumorigenesis. The process of tumori-
genesis is multistep which can be activated by various environ-
mental carcinogens and inflammatory agents, obesity, stress etc
[15]. Most importantly all the above mentioned risk factors are pro-
inflammatory in nature. These agents are known to activate various
types of transcription factors to modulate different signal transduc-
tion cascades [16,17]. Chronic inflammatory conditions often lead
to the process of initiation of tumorigenesis. The expression or acti-
vation status of many of these factors is highly altered in tumor cells
providing survival advantages to them [18]. The functional ingre-
dients derived from natural sources are mostly anti-inflammatory
in nature thereby it was postulated and later on proved by sev-
eral scientific groups across the globe that these agents possess
significant anticancer activity as well [14,19]. A critical analysis
of drug discovery studies in the last few decades established the
fact that natural product and/or lead molecule derived/synthesized
from natural products continue to play a vital role in the drug dis-
covery and development process [4]. In this review, we discuss the
major transcription factors targeted by natural products in diverse
models of cancer and their potential mechanism of action.
3.1. FOXM1 (Forkhead Box M1)
Forkhead Box M1 (FOXM1), an oncofetal transcription factor,
is one of the members of the forkhead family of proteins and is
required for normal cell division and its deletion is embryoni-
cally lethal. Upregulation of FOXM1 is reported in a broad range
of cancers. In vitro studies showed that its increased expression
can lead to invasion and angiogenesis of cancer cells [20]. Silencing
FOXM1 expression resulted in reduced tumor formation in immun-
odeficient animals [21]. Genistein, a major active component of
soybean and synthetic derivatives (7-Difluoromethoxyl-5, 4 -di-
n-octylgenistein, DFOG) attenuates the expression of FOXM1 and
its downstream targets such as survivin, cdc25 B and cyclin B in
ovarian, gastric and small-cell lung cancer cells. In SKOV-3 ovar-
ian cancer stem cells, DFOG inhibited proliferation, self-renewal
Known activities Structure Reference
Anticancer and antioxidant [185–187]
Anticancer [188,189]
Anticancer. neuroprotective, antiviral and [190]
antioxidant
Antioxidant, anticancer, antiviral and [191]
anti-inflammatory
capacity and expression of stem cell markers along with FOXM1
and rescued the stem cells [22]. In addition, DFOG repressed
the stemness, EMT phenotype in SGC-7901 cells derived gastric
cancer stem-like cells (GCSLCs), with an associated inhibition of
FOXM1 [23]. Casticin, a polymethoxyflavone, inhibited FOXM1 and
its downstream molecular targets (survivin and PLK1) in human
hepatocellular and ovarian cancer cell lines [24,25]. The FOXM1
inhibition is associated with activation of FOXO3a and p27 which
leads to growth arrest and cell cycle inhibition. Curcumin, an active
principle of turmeric also inhibited the FOXM1 expression in malig-
nant glioma and acute myeloid leukemia cells (AML). The siRNA
mediated silencing of FOXM1 in AML made them more susceptible
to doxorubicin mediated cell death. Combinatorial administration
of curcumin and doxorubicin has shown more evident inhibitory
effects in AML cells through the repression of FOXM1 expression
at both mRNA and protein levels. These studies clearly support the
therapeutic potential in targeting FOXM1 with natural products in
chemosensitization, apoptosis, cell proliferation and angiogenesis
in different carcinoma [26,27].
3.2. Wnt/ˇ-catenin
Wnt/␤-catenin signaling is an evolutionarily conserved and
versatile pathway involved in normal tissue homeostasis but
its aberrant activation leads to wide variety of human diseases
[28–30]. Wnt binds to its cell surface receptors, frizzled (Fz) and
LDL-receptor related proteins (LRP5/6), trigger a signaling cascade
through ␤-catenin, a fascinating molecule in the field of cancer
research [31]. ␤-catenin is a multifunctional protein which is well
studied for its structural and signaling roles and also acts as a tran-
scription factor [32]. Targeting wnt signaling cascade proteins is
becoming a dynamic research zone in tumor therapy. In medul-
loblastoma cells, curcumin attenuated wnt/␤-catenin signaling and
inhibited the cell proliferation [33]. Curcumin was found to silence
the TGF-␤ dependent ␤-catenin activation in human cervical cancer
cells [34], attenuated wnt/␤-catenin signaling and cell proliferation
in medulloblastoma cells. Decreased population of CD133+ cells
inhibited cancer stem cells and tumorsphere formation through
suppression of wnt and hedgehog signaling in lung cancer cells.
The expression of various members of wnt family proteins such as,
LRP6, survivin and ␤-catenin in gastric carcinoma cells were also
down regulated [35].
Resveratrol, a phytoalexin has decreased ␤-catenin/TCF-
mediated transcriptional activity. Resveratrol did not alter the
levels of ␤- catenin in either cytoplasm or nucleus but disrupted the
complex formation between TCF and ␤- catenin which terminates
the signal cascade [36]. In colorectal cancer cells, decreased ␤-
catenin nuclear translocation and its downstream cascade showed
positive correlation with the MALAT-1 (a long non-coding RNA)
expression linked with inhibition of cell invasion and metasta-
sis [37]. However Liu et al. proposed yet another mechanism for
the action of resveratrol in CRC cells which is elucidated through
 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291 277

Fig. 1. Schematic representation of wnt/EGF-␤-catenin signaling and the effects of different polyphenols in its downstream pathway. Curcumin and resveratrol exhibits
direct inhibition of wnt-receptor interaction. Resveratrol disrupts ␤-catenin-TCF complex which prevents the gene expression along with the promotion of autophagy and
inhibition of CSC proliferation. EGCG promotes apoptosis in cancer cells.

increased level of PTEN and inhibition of PI3/Akt and wnt/␤-catenin
signaling with concomitant decrease in the proliferation of CRC
cells [38]. Resveratrol is also known for its ability to decrease the
survival of cancer stem cells (CSCs). In breast cancer, the effects
were mediated through the induction of autophagy in wnt/catenin
pathway dependent manner [39]. Similarly EGCG also induced
apoptosis in colon [40] and lung cancer stem cells and inhibited
spheroid formation by suppressing ␤-catenin signaling [41]. These
studies are highly promising since non-toxic natural products dis-
cussed here have the ability to suppress the proliferation of CSCs in
metastasis, drug resistance and tumor recurrence (Fig. 1).
3.3. Nrf2
The redox sensitive transcription factor, Nrf2 is a member of
basic leucine-zipper family. Its expression is stimulated by the pres-
ence of electrophilic chemicals and ROS and leads to translocation
into the nucleus where it binds to antioxidant-responsive element
(ARE) and activate a subset of cytoprotective genes. A cytoskeleton
binding protein keap-1 binds with Nrf2 and prevents the nuclear
translocation under normal physiological condition. Aberrant Nrf2
activation and mutations on keap-1 is reported in various types of
malignancies. Currently there are two approaches (either induc-
tion or inhibition) to target Nrf2 for cancer therapy [42,43]. Nrf2
inducer class of compounds will help in the detoxification of car-
cinogens and environmental mutagens. They can decrease the level
of this transcription factor in tumor cells and make them sus-
ceptible for cancer therapy [44]. Tamoxifen resistant MCF7 breast
cancer cells have shown evident response to a combination of EGCG
(Epigallocatechin- 3 gallate) and siRNA against Nrf2. It reverses
chemoresistance and Nrf2 dependent gene expression [45]. EGCG
chemosensitizes triple negative breast cancer cells to cisplatin
through activation of Nrf2 signaling [46]. Similar mechanism was
observed in cervical cancer where EGCG enhanced cisplatin activity
and induced apoptosis [47]. A combination of copper and curcumin
was found to have better activity as compared with the agent alone
in decreasing the proliferation of oral squamous cell carcinoma
(OSCC) where the combination increased ROS levels and activation
of Nrf2 and suppress the EMT associated changes [48]. In prostate
cancer cells a curcumin analogue, FN1 reactivated Nrf2 and its
downstream effectors, detoxification enzymes which inhibited the
colony formation of cells [49]. Pterostilbene, a derivative of grape
polyphenol resveratrol, decreased the proliferation of melanoma
cells where it downregulated Nrf2 expression [50]. In an ultraviolet
B driven skin carcinogens model, Pterostilbene was found to pro-
tect the mice through the upregulationofNrf2 and Nrf2 dependent
gene expression [51]. Resveratrol also induced its expression in rat
breast cancer model along with the upregulation of Nrf2 depen-
278 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291

Table 2
Possible mechanism of action of polyphenols on various tumor models through STAT3.

Polyphenols Type of cancer Mode of action Reference

In vitro

6-Shogaol Lung cancer (NCI-H1650, NCI-H520 and ⊥STAT3 activation, ↓CCl2, ⊥JAK2, caspase- 3, 8, [192–195]
NCI-H1975), Breast cancer(MDA-MB-231), 9 kinase, ⊥Bcl-2,⊥Bcl-XL, ⊥ Survivin, ⊥ c-Src
Prostate cancer (DU145, LNCaP, PC-3, HMVP2)
Acteoside Liver cancer (HepG2, HUH-7, Hep3b) ↓BCL2 [196]
Berberine Gastric cancer (AGS), Colorectal cancer ↓COX2/PGE2, ↓Survivin,↑Apoptosis, ↓MMP-2, [197–201]
(SW620, LoVo, AGS, SW620)0, Nasopharyngeal 9.
cancer (C666-1), Lung cancer (NCI-H460,
NCI-H1975), Skin cancer (A431)
Bergamottin Myeloma (U266), Prostate cancer (DU145), ⊥JAK activation, ↓COX-2, ↓Survivin, ↓VEGF, [202]
Breast cancer (MDA-MB-231) ↓Cyclin D1,↓IAP-1,↓Bcl-2,↓Bcl-XL,↓MMPs and
↑Caspase3
Capsaicin Liver cancer (HepG2) ↑Autophagy [203]
Cardamonin Prostate cancer (LNCaP), Glioblastoma (GSC) ↓STAT3, ⊥DNA binding [71,73]
Chrysin Lung cancer (A549), cervical cancer (HeLa) ↓MCL1, ⊥STAT3 [204]
Cryptotanshinone Liver cancer (BEL-S404, HepG2), pancreatic ↓STAT3, ↓BCL2, ↑Bax, ↑Cas3/9,↑ADP Ribose [205–208]
cancer (BxPC-3), Colorectal cancer (HCT116, polymerase,↓Cyclin-D1, ↓Survivin, ↓EGFR
SW480, LoVo), Glioblastoma (T98G, U8)
Cucurbitacin Lymphoma (Ramos, Raji, jeko), Breast cancer ⊥STAT3 activation, JAK inactivation, [209–213]
(MCF7, T47D, SKBR3, MDA-MB-468), Lung ↓Cyclin-B1, ↑ Apoptosis, ↑Cytochrome C, ↑p53,
cancer (A549),Neuroblastoma (SH-SY5Y), ↑p21
Pancreatic cancer(PC3), Umbilical vein
endothelial cancer (HUVEC)
Curcumin Lung cancer (NCI- H460), Squamous cell ⊥JAK2, ↓MMP2, ↓VEGF, ↓ERK, ↓MMP2, 9, [60,214–218]
carcinoma (Hep-2), Prostate cancer (LNCaP), ↓uPAR, ↓uPA, ↑ROS, Reactivation of RANK
Breast cancer (MCF-7), Bladder cancer
(253J-Bv, P24), Pancreatic cancer (Panc1,
BxPC-3), Tongue cancer (SCC-25), Glioblastoma
(U251, U87, GSC)
Epigallocatechin3- Gallate Leukemia (K562, KBM5), Breast cancer SHP1 activation, ⊥ BCR-ABL, ↓Pro-PARP [45,128]
(MDA-MB-231, MCF-7)
Ellagic acid Prostate cancer (PC3) ↓STAT3, ↑IL6, ↓ Mcl-1. [219]
Honokiol Lung cancer (BrM3, H2030-BrM3), Leukemia ↓p-STAT3, ↑SHP phosphatase, BAX/BCL2 ratio [220,221]
(HEL, THP1) disruption
Icariside II Lymphoma (U937) ⊥JAK, ↓Survivin, ↓Cox2, ↓Bcl2, ↓Bcl-xL [222]
Piperlongumine Gastric cancer (MKN45, AGS) ↓JAK phosphorylation, ↓MMP-9, ↓Twist [223]
Resveratrol Lung cancer (A549, SCC4, FaDu), Ovarian ↓STAT3, ⊥NF-kB, ↑SOCS3, ⊥JAK, ↓IL-6, ↑Beclin, [65–67,224–227]
cancer (OVCAR3, Caov-3), Cervical cancer ↑Autophagy, ↑PAIS3, ⊥Wnt, ⊥Notch
(SiHa,C33a),Leukemia (THP-1, HEL), Bone
marrow cancer (K562), Prostate cancer (LNCaP)
Sesamin Gall bladder cancer (SGC-996, GBC-SD),Liver ⊥NF-kB/AKT, ↓IL-6, ↑p53 [228,229]
cancer (HepG2)
Ursolic acid Colorectal cancer (HT29, HCT116, Sw480, ⊥STAT3 activation [70,230,231]
DLD1), Pancreatic cancer (MiaPaCa-2, AsPC-1)
Wogonin Lung cancer (A549) ⊥JAK activation, ↓Snail, ↓Twist,↓p-STAT3, [232]
↑E-Cadherin, ↓N-Cadherin.
Xanthohumol Bile duct cancer (CCA, M214, M139) ↓NF-kB/AKT, ↓STAT3 [233]

In vivo

Polyphenols Type of cancer Dose Mode of action Reference

6-Shogaol NCI-H1650,4T1, HMVP2Xenograft 10–40 mg/kg, 30 mg/kg, 50–100 mg/kg ↓Metastasis, ↑Caspase, ↑ PARP, [192,194,195]
↓Survivin, ↓p-STAT3
Acteoside DEN induced HCC model 0.1–0.3% of diet/animal ↑ Apoptosis [196]
Berberine C666 Xenograft 5 and 10 mg/kg ↓p-STAT3 [199]
Cryptotanshinone Bel-7404 Xenograft 100 mg/kg ↑Caspase3, 9 [205]
Cucurbitacin Ramos, PC3 cell Xenograft 250 ␮g/kg, 3 mg/kg ↓PCNA, ↓p-STAT3, ↓VEGF [209,213]
Curcumin NCI-H460 Xenograft model 40 mg/kg ↓p-JAK2, ↓p-STAT3, ↑Cleaved [60]
caspase 3, 9
Epigallocatechin3-Gallate K563 Xenograft mice model 15 mg/kg ↑SHP1, ↑Caspase-3, ↓Pro-PARP [234]
Honokiol H2030-BrM3 Orthotopic model 2 and 3 mg/kg ↓p-TrkA, ↓p-TrkB, ↓p-STAT3, [220]
↓p-VEGFR
Resveratrol RG2 Orthotopic model 50 ␮M per animal ↓Cyclin- D1, ↑Beclin, ↓p-STAT3 [64]
Sesamin GBC Xenograft 100 ␮M per animal ↓Drug resistance [228]
Ursolic acid TRAMP mice model, HCT116 1% of diet, 250 mg/kg, 250 mg/kg ↓CyclinD1, ↓Cox2, ↓VEGF, [68–70]
Xenograft, Panc-28 Orthotopic ↓Metastasis, ↓ Angiogenesis,
model ↓Gli-1, ↓VEGF, ↓FGF
Wogonin A549 cell Xenograft 30 and 60 mg/kg ↓p-STAT3, ↑E-Cadherin, [232]
↓N-Cadherin, ↓Vimentin
Xanthohumol KKU-M214 Xenograft 50 mg/animal ↓Ki-67 [233]
 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291 279

Fig. 2. Schematic representation of various polyphenols acting on STAT3 signaling and associated gene expression. Curcumin inhibits STAT3 activation by inhibiting JNK2
leading to blockage of AKT activation and increased PIAS3 levels. EGCG, cardamonin, resveratrol and ursolic acid directly blocks the STAT3 activation through its inhibition
of phosphorylation and in some cases along with inhibition of acetylation as well.

dent antioxidant genes, thereby reducing the oxidative stress and
inflammation in mammary tissues [52].
3.4. STAT3 (Signal transducer and activator of transcription 3)
STAT3 is a transcriptional activator of genes involved in cell
proliferation, differentiation, inflammation etc. In response to the
binding of various cytokines to tyrosine kinase receptors the active
dimerization and activation of STAT3 occurs which promotes its
translocation in to the nucleus [53,54]. Being a candidate in cell
proliferation, it acts as an acute phase response factor which is asso-
ciated with various processes of inflammation and tumorigenesis
and it is activated by several cytokines, growth factors and onco-
genic proteins. A number of naturally derived agents have been
shown to inhibit the activation of STAT3 and STAT3 dependent gene
expression [55]. Curcumin inhibited dextran sodium sulphate (DSS)
induced colitis (a chronic inflammation model of colon) murine
model through the inhibition of STAT3 pathway [56]. A novel cur-
cumin analogue, H-4073 enhanced the sensitivity of cisplatin in
head and neck squamous cell carcinoma (HNSCC) through the inhi-
bition of STAT3 activation and increased expression of p21 and
cleaved caspase 3 [57]. Low expression of protein inhibitor of acti-
vated STAT3 (PIAS3) is associated with increased STAT3 activity
and poor patient survival in mesothelioma. Curcumin have shown
effects in increasing the expression of PIAS3 in these cells with a
parallel reduction in p-STAT3 levels [58]. It also inhibited the prolif-
eration of OSCC through decreasing the activation of Akt and STAT3
[59]. Wu et al. also reported that in lung cancer stem cells, curcumin
inhibited the growth and reduced tumor spheres through downreg-
ulation of JAK2/STAT3 signaling pathway [60]. Gersey et al. reported
the effect of curcumin on patient derived glioblastoma stem cell
lines and found that this polyphenol was effective in decreasing
cell proliferation through increased ROS production and down reg-
ulated STAT3 activation [61].
Resveratrol, have shown effects on STAT3 proteins in both its
transcriptional and translational levels which ensure its regulatory
mechanisms on cancer [62]. Loss of endogenous STAT3 acetylation
resulted in the reactivation of tumor-suppressor genes associ-
ated with the demethylation at their promoters. Treatment with
Resveratrol inhibited the tumor growth in mice and mechanism of
action is through the inhibition of STAT3 acetylation and demethy-
lation of several tumor-suppressor gene promoters [63]. Studies
conducted in orthotopic rat glioblastoma models established the
relevance of resveratrol as a potent antitumor agent. Capability to
cross blood brain barrier facilitates its greater bio availability in
brain which helps to overcome a major problem in cancer thera-
peutics against brain tumors [64]. CAOV-3 and OVCAR-3, ovarian
cancer cell lines exhibit increased autophagy with decreased cell
proliferation through the regulation of STAT3 signaling. Resver-
atrol have shown prominent inhibitory effects on JAK2 protein
280 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291

Fig. 3. Schematic representation of androgen receptor signaling and the effects of different polyphenols in its pathway. Resveratrol inhibits androgen receptor activation
with the down regulation of HIF1 and SIRT1 along with increased AR proteasomal degradation. EGCG and quercetin in combination with curcumin shows epigenetic level
regulation of ARs with the inhibition of DNMT and HAT. Curcumin alone prevents wnt dependent expression of androgen receptors.

phosphorylation and thereby indirectly suppress STAT3 activation.
Resveratrol mediated indirect inhibition of STAT3 is also char-
acterised by the increased expression of SOCS1 which is a well
explained regulatory protein involved in STAT3 signal desensitisa-
tion [65]. In prostate cancer cells elevated transcriptional activity
of both androgen receptors (ARs) and STAT3 was decreased by
resveratrol leading to the inhibition of cellular proliferation [66].
Prominent reduction in ovarian cancer progression and cell survival
with the effective down regulation or inhibition of STAT3 empha-
sises the potential of resveratrol as an effective polyphenol in the
field of cancer therapeutics [67].
Studies performed using TRAMP mice revealed the protective
role of ursolic acid (UA) in prostate cancer. UA inhibited the acti-
vation of NF-kB, STAT3 and Akt in tumor as well as reduced the
levels of tumor necrosis factor (TNF) and interlukin-6 (IL-6) in
serum. Further, UA downregulated the elevated cyclin D1 and COX-
2 and increased caspase 3 expression [68]. Similar effects had been
observed in orthotopic human colorectal cancer and pancreatic
cancer mice models, where UA inhibited the tumor volume and
metastasis and enhanced the effects of capecitabine/gemcitabine
through downregulation of NF-kB and STAT3 [69,70].
Cardamonin, a chalcone inhibited growth of prostate cancer
cells through the prevention of STAT3 activation. Further, compu-
tational analysis revealed that cardamonin binds directly to the src
homology 2 domain of STAT3 and thereby inhibits its dimerization
[71]. Chemotherapeutic drugs induced STAT3 and NF-kB expres-
sion and IL-6 both at mRNA and protein level was downregulated
by cardamonin in breast cancer cells [72]. Wu et al. reported that
cardamonin induces apoptosis in glioblastoma stem cells through
suppression of STAT3 activation [73].
EGCG enhanced therapeutic potential of gemcitabine and JAK3
inhibitor CP- 690550 (tasocitinib) in pancreatic cancer through
the suppression of STAT3 activation and STAT3 dependent gene
expression [74]. In cholangiocarcinoma, a combination of EGCG and
quercetin inhibited the growth and migration of cancer cells and
abolished JAK/STAT cascade and it’s downstream signaling [75]. In
nasopharyngeal carcinoma, EGCG treatment eradicated stem cells
like tumor cells and increased chemosensitivity through attenu-
ating STAT3 activation [76]. We summarized the observations in
Table 2 and Fig. 2. All these reports provided the evidences that
STAT3 is involved in the process of inflammation and tumorigene-
sis and there for considered as a common molecular hub for drug
targeting in the field of cancer therapeutics.
3.5. AR (androgen receptors)
AR is a member of nuclear receptor super family which mediates
the biological effects of androgens. It binds to an androgen-
response element (ARE) and regulate gene expression [77]. Several
lines of evidence indicate that AR and associated signaling are
implicated in the progression of different type of tumors especially
prostate and urothelial cancer. Several polyphenols are shown to
 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291
Fig. 4. Schematic representation of estrogen receptor signaling and polyphenol regulation in its pathway. Curcumin and EGCG show direct inhibition of estrogen receptors.
Xanthohumol disrupts BIG3- prohibitin complex leading to the arrest of activated ER in the cytoplasm. Resveratrol inhibits lGFR- ER signaling and prevents the transcription
of ER response genes. Resveratrol mediated AKT inhibition prevents cell cycle.
modulate AR function and AR dependent gene expression EGCG
has effects in prostate cancer cell lines with the inhibition of AR
acetylation along with successful blocking of histone acetyl trans-
ferase (HAT) activity [78]. A combination of curcumin and quercetin
inhibited the proliferation of androgen refractory prostate cancer
cells through decreasing DNA methyl transferase (DNMT) expres-
sion and methylation marks in AR promoter [79]. PLGA based
curcumin nanoparticle was effective in suppressing prostate can-
cer xenografts as compared to curcumin alone. The mechanism of
action was by decreasing AR, Akt and STAT3 signaling [80]. Cur-
cumin downregulated AR signaling through modulation of wnt
pathway in human endometrial carcinoma leading to apoptosis of
tumor cells [81].
Resveratrol inhibited HIF-1 driven AR signaling and suppress
the tumor formation in castration-resistant prostate cancer. The
elevated AR expression on breast cancer is associated with shorter
overall survival and over expression of BRCA1 in breast cancer cells
abrogates AR signaling through activation of SIRT1. Resveratrol is a
known SIRT1 agonist, which inhibited AR dependent proliferation
of breast cancer cells [82]. It can mediate proteasomal degradation
of ARV7, a splice variant of ARs with its increased ubiquitination;
can keep its cellular level as very low in castration resistant prostate
cancer cell lines[83]. Parallel to the AR suppression, resveratrol
induces increased expression of caspase 3 and 7 which programs
cells to get in to its apoptotic fate [84] (Fig. 3).
281
3.6. ER (estrogen receptors)
Estrogen receptors are members of nuclear receptor family pro-
teins. ER-␣ and ER-␤ are the two types which are well known for
its nuclear translocation in response to 17␤-estradiol (estrogen)
binding [85]. ER-␣ is one of the major culprits in the develop-
ment of cancer. Many naturally occurring compounds found in diet
which can inhibit the process of inflammation and breast carcino-
genesis through suppression of ER signaling pathway [86,87]. ER-␣
has the capacity to shuttle between both nucleus and cytoplasm
and E2 binding can happen in any of the compartments. Xan-
thohumol destabilizes the BIG3-prohibitn 2 complex and released
prohibitin 2 binds with ER-␣ and inhibited the estrogen depen-
dent gene expression in breast cancer cells [88]. Resveratrol can
cause p53 dependent apoptosis in a dose dependent manner along
with ER␣ down regulation in T-47D breast cancer cell lines [89].
Resveratrol inhibited the proliferative effects of estrogen and BPA
(an endocrine disrupting chemical) in ovarian cancer cell line BG1
by down regulating the expressions of ER-␣, IGF-1R, p-Akt1/2/3
and cyclinD1 both at mRNA and protein levels [90]. Recently a
crystal structure of the ER␣ ligand-binding domain (LBD) as a com-
plex with resveratrol was reported. This study identified resveratrol
as a pathway-selective ER␣ ligand which modulate the inflam-
matory response surprisingly without affecting cell proliferation
[91]. The study by Saluzzo et al. demonstrated the regulation of
p53 and ER-␣ by resveratrol at the molecular level [89]. Sev-
282 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291

Table 3
Possible mechanism of action of polyphenols on various tumor models through NF-kB.

Polyphenols Type of cancer Mode of action Reference

In vitro
4- Shogaol Breast cancer (MDA-MB-231) ↓Snail, ↓ NF-kB [194]
6-Shogaol Prostate cancer (DU145), Breast cancer ↓ NF-kB, ↓ IkB, ↓ cyclin- D1, ↓ survivin, ↓ c- [195,235]
(MDA-MB-231) Myc, ↓MMP
Apigenin Prostate cancer (PC3, 22Rv1),Pancreatic cancer ↓CSC, ↓p50/p105, ↓p65, ↓IKK, ↓CXCR4, [236–240]
(BxPC-3, Panc1), Lung cancer (A549), Breast ↓Bcl2,↓Cox2, ↑Caspase 3, 8, ↓TNF-␣, ↓IL6,
cancer (MCF-7) ↓miR-16, ↓MMP-9, ↓Cyclin-D
Berberine Liver cancer (HepG2), Lung cancer(NSCLC), ↓P65, ↓P50, ↓IKK, ⊥cox2,↓HIF-1␣, [241,242]
Lymphoma (PEL) ↓VEGF,↓MMPs, ↓PARP and Caspase cleavage
Caffeic acid Skin cancer (HaCaT), Breast cancer(MCF-7) ↑Apoptosis, ↓ NF-kB, ↓ Snail, ↑P38, ↑FAS, ↑BAX, [243,244]
↑JNK
Capsaicin Bile duct carcinoma (HuCCT1) ↓ NF-kB, ⊥ MMP-9 [245]
Cardamonin Breast cancer(MDA-MB-231, 4T1), Liver cancer ↓ NOX-1, ⊥ TSP50 activation, ↓ IKB↓ IL6 and 8, [246]
(HepG2, H7402), Gastric cancer (SGC7901), ↓ MCP1, ↓ NF-kB,
Lung cancer (A549)
Curcumin Colorectal cancer (SW480, LoVo, HT-29, MC38, ↓ p65, ↓Cyclin-D1, ⊥IkB interaction, ↑ IkB, ↓ [127,197,218,247–268]
HCT116), Pancreatic cancer uPA, ↓ MMP2, 9, ROS, ↓ ␤-catenin, ⊥ Cox2, ↓
(BxPC-3,Panc-1,MIAPaCa-2), Breast cancer IKK, ↓MAPK, ↓c-jun, ↓Vimentin, ↓COX2, ↓
(MCF7, MDA-MB 231), Leukemia (Kasumi-1, CXCL1,↑ E-cadherin, ↓ c-PARP, ↓Survivin,
SHL-1), Liver cancer (Hep3B, ↑miR-146A, ↓ DNMT1, ↓ CSC, ⊥ERK, ↑ P38,
HepG2),Glioblastoma (U-87), Prostate cancer ↑JNK, ⊥BCL2,↑ Bax, ↓ Mcl-1, ↓ PI3 K, ↓ mTOR
(PC3, LNCaP,Melanoma (MV3, M14), kinase phosphorylation
Non-Hodgkin’s lymphoma (Namalwa,Ramos,
Raji),Osteoclastoma(GCT), Gastric cancer(AGS),
Oral squamous carcinoma(SAS), Non-Small
Celllung cancer (A549)
Delphinidin Breast cancer (MCF-7) ↓MAPK signaling,↓MMP-9 [269]
Escin Pancreatic cancer (Panc1) ↓ NF-kB [270]
Fisetin Cervical cancer (SiHa, CaSki,), Bladder cancer ↓ p50/p65, ↑Apoptosis, ↑ p21↓ IKKB, ↑ p53, ↓ [271–273]
(T24, J82) BAX, ↓uPA, ↓ Cyclin-D1, ↓ Cyclin-A, ↑ BAK,
↓CDK2, ↓CDK4, ↓Bcl-2
Gambogic acid Prostate cancer (PC3), Lukemia (K562), ↓CXCR4, ↓ NF-kB, ↓ c-Myc, ↓ IL-6, ⊥TNF-␣, ↓ [274–276]
Myeloma (MM.1S, RPMI 8226, UT66NCIH929) Bcl2, ↓ p-AKT
Genistein Bladder cancer (J82, SCaBER, ↓ERK, ↓Notch signaling, ↑miR-29b, ↓XIAP, [134–136,277–279]
TCCSUP),Leukemia(HUT102), Breast cancer ↓cIAP, ↓survivin, ↓PI3 K, ↓cyclin-B1, ↓Bcl-2,
(MDA-MB-231),Colorectal cancer (HT29,LoVo), ↓Bcl-xL
Myeloma (U266)
Gingerol Pancreatic cancer (Panc1) ↓ NF-kB, ⊥ ERK [280]
Gossypin Chronic myelogenous leukemia (KBM-5), ⊥IkB␣ kinase, ↓ Survivin, ↓ COX2, ↓ Cyclin-D1, [281]
Myeloma (U266), Lung cancer (H1299), ↓MMP-9, ↓c-Myc, ↓VEGF
Pancreatic cancer (BxPC-3), Urinary bladder
cancer (253J-BV)
Honokiol HTLV-1 infected Cell lines ↓NFkB,⊥I␬B␣, ⊥IKK␣, ⊥IKK␤, ⊥STAT3,↓Jun D, [282]
⊥ STAT5, ⊥ p-Akt, ↓ Jun B
Luteolin Ovarian cancer (X10, X22), ↓FAK, ↓ERK,↓ BACE1 [283–285]
Neuroblastoma(SH-SY5Y), Lung cancer (A549)
Mangiferin Lung cancer (A549), Prostate cancer (LNCaP) ↓NF-kB, ↓IKK, ↓Protein Kinase C, ↑PARP-1, [286,287]
↓Survivin, ↑Caspase, ↓MMP-9
Quercetin Glioma (C6), Tongue cancer(SAS) ↓ IKK, ↑ Caspase3, ↑Apoptosis, ↓ PI3 K, ↓MMP- [288,289]
2, 7, 9, 10, ↓ VEGF, ↓ IKB- ␣, ↓ COX2, ↓iNOS, ↓
uPA
Sesamin Prostate cancer (PC3), Gall bladder cancer ↓ NF-kB, ↓MMP-9,↓VEGF, ↓iCAM-1, ↓IL-6, ↓ [228,290]
(SGC-996, GBC-SD) Vimentin,↓Twist
Ursolic acid Skin melanoma (CRL-11147), Bladder cancer ↑Apoptosis, ↓p65, ↓ IkB␣,⊥AKT, ↓Bcl2 [291–293]
(T24), Pancreatic cancer (Panc1, Capan-1)
Xanthohumol Liver cancer (HepG2) ⊥IkB, ↑ P53, ↑ Cleaved PARP,↑ AIF, ↑ [294]
Cytochrome C

In vivo

Polyphenols Type of cancer Dose Mode of action Reference

6-Shogaol PC3 Allograft mice model 50 mg/kg ↓ NF-␬B, ↓ I␬B [195]

Apigenin Buccal Pouch carcinoma hamster 2.5 mg/kg ↓ PCNA, ↓ Cyclin-D, ↓ COX2 [295]
Berberine B16F-10 Melanoma mice model 10 mg/kg ↓ NF-␬B [296]
Cardamonin 4T1 Xenograft 25 mg/kg ⊥TSP50 activation, ↓ CSC [246]
Curcumin B[a] PDE induced lung cancer, SAS 2%of the diet, 70 mg/kg, ⊥NF-␬B/MAPK, ↓ Cox-2, ↓ Cyclin- [126,218,257,258,297–299]
Xenograft, GL261, leukemia cells mice 2 mg/animal,100–200 mg/kg, D1, ↓ p65, ↓ NF-␬B, ↓TNF- ␣, ↓ IL6,
model, H1975 ectopic tumor model, 0.6% of the diet, 0.6% of the ↓ CXCL1
MiaPaCa-2 orthotopic model, diet, 0.6% of the diet
MDA-MB-231 xenograft
Fisetin MNU induced bladder cancer model 200 mg/kg ↓ IKKB, ↓ NF-␬B [273]
Mangiferin A549 Xenograft mice model, Mouse 10, 50 and 100 mg/kg ↓NF-␬B, ↓ IKK, ↓ Protein Kinase C [286,300]
metastatic Melanomamodel (B16BL6) 50, 100 and 200 mg/kg
Rutin BaP induced lung cancer 40 and 80 mg/kg ↓ LDH activity, ↓ p65 [301]
Ursolic acid MiaPaCa-2 Xenograft 100 and 200 mg/kg ⊥p-I␬B [293]
 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291
Fig. 5. Schematic representation of various polyphenols and it derivatives acting on HIF-1␣ leading to decrease tumor growth, proliferation, metastasis etc. Curcumin and
EF24, a curcumin analogue inhibits EMT and chemosensitizes the cells to drugs. Tetrahydrocurcumin and EGCG inhibit VEGF and prevent angiogenesis. Resveratrol prevents
metastasis. Quercetin promotes autophagy of cancer cells.
eral studies conclusively established that ER- ␣ negative breast
cancer is more aggressive and less responsive to hormonal ther-
apies. A combination of resveratrol and pterostilbene was found
to restore the ER-␣ expression and thereby sensitizes the cancer
cells to hormonal therapies [92]. These studies clearly demon-
strated the epigenetic regulatory activity of resveratrol. Curcumin
is yet another natural product which regulates ER-␣ expression
and downstream signaling. This polyphenol inhibited the growth of
several ER positive cancer cells in culture [93]. A curcumin analogue
PAC (4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone)
was found to be more stable than curcumin in blood which sup-
pressed the ER-␣expression and induced apoptosis in different
breast cancer cells [94]. ER-␣36 is a variant of ER-␣ expressed
in both hormonal positive and negative cancer cells. EGCG was
found to abrogate to AR-␣36-EGFR loop and suppress the growth
and proliferation of breast cancer stem cells. EGCG regulates ER-␣
expression at promoter, mRNA and protein levels [95]. EGCG and
a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) syner-
gistically re-activate ER-␣ expression in ER-␣ negative cancer cells
by altering the histone acetylation status in its promoter. This will
be an ideal chemotherapeutic strategy in hormone resistant breast
cancer [96] (Fig. 4).
3.7. HIF1 (hypoxia inducing factor 1)
HIF-1 is a transcription factor that mediates cellular response
to reduced availability of oxygen through modulating the expres-
283
sion of genes involved in oxygen delivery to tissues and energy
metabolism. Increased expression of HIF1 is often associated with
poor prognosis which is observed in several types of human can-
cers. Several natural products have shown promising results in
regulating HIF-1 synthesis and transcriptional activity thereby
bringing the potential role of HIF-1 inhibitors in cancer therapy
[97,98]. Curcumin in combination with cisplatin reversed drug
resistance in lung cancer cells through HIF-1 degradation and cas-
pase 3 activation and enhanced cisplatin mediated cell death [99].
A similar mechanism was executed by EF24, a novel curcumin
analogue with improved pharmacokinetic activity as compared
to parent curcumin. In hepatic cancer combinations EF24 with
sorafenib overcome the sorafenib resistance [100] and EMT reg-
ulated HIF-1 expression [101]. Tetrahydrocurcumin, a metabolite
of curcumin was also found to suppress the expression of HIF-
1 and VEGF, thereby suppressing the process of angiogenesis
[102]. Resveratrol inhibited hypoxia driven invasion and migra-
tion of pancreatic cells with decreased expression of HIF-1 [103]
and hypoxia lead to EMT changes which reduced proliferation of
osteosarcoma cells [104]. Mitani et al. reported that in prostate
cancer, resveratrol was effective in suppressing hypoxia driven
accumulation of ␤ −catenin in nucleus and activation of AR thereby
contribute to regression of tumors [105]. EGCG abrogates lung
cancer angiogenesis through the inhibition of HIF-1 and VEGF
expression [106]. Honokiol a lignin class of compound was found to
have radio sensitizing activity in murine colorectal cancer models
by modulating hypoxia driven signaling pathways [107].
284 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291

Fig. 6. Schematic representations of various polyphenols and it derivatives acting on NF-kB signaling and associated gene expression. Resveratrol through downregulation
of PI3 K and AKT pathways block the nuclear translocation of NF-kB. Curcumin modulates MAPK, NF-kB and chemokine signaling and inhibited cell and cancer stem cell
proliferation. EGCG inhibits both MAPK and NF-kB signaling and expression of NF-kB dependent genes VEGF, MMP 2 and 8. Both Cardamonin and Genistein reduce NF-kB
activation and increases apoptosis in cancer cells.

In gastric cancer cells the anti-proliferative effect of quercetin is
mediated through the induction of protective autophagy through
modulation of Akt/mTOR/HIF-1 pathway [108]. Interestingly,
Isorhamnetin, a metabolite of quercetin was found to be a better
inhibitor of HIF-1 than quercetin [109]. Currently, there is a search
for agents that can effectively inhibit HIF-1 and VEGF1/2 which are
responsible for increased survivability for tumor cells in hypoxic
condition. Polyphenolic class of compounds can be potential source
for such inhibitors (Fig. 5).
3.8. NF-B (nuclear factor kappaB)
Nuclear factor-kB is a pro-inflammatory transcription factor
which regulates numerous pathways that has direct implications
in inflammation and cancer [110]. Several in vitro, pre-clinical and
clinical studies showed that NF-kB and NF-kB dependent gene
expressions play a major role in inflammation, cancer progression,
metastasis and drug resistance [111]. Over the last few decades
several phytochemicals and their analogues were identified and
demonstrated to have significant inhibitory effects on NF-signaling
by targeting members of this cascade [112–114]. In colorectal can-
cer cells, resveratrol attenuated the phosphorylation, acetylation
and nuclear translocation of NF-kB [115]. This phytoalexin inhib-
ited adhesion, invasion and migration of glioblastoma-initiating
cells (GICs) both in vitro and in vivo through suppression of
PI3 K/Akt/NF-␬B cascade signifying the therapeutic potential of
resveratrol in glioblastoma cases [116]. The pre-treatment of either
resveratrol or EF24, was effective in promoting ionizing radiation
(IR) induced apoptosis in hypoxic cancer cells through the suppres-
sion of IR induced NF-kB activation in breast cancer cells [117].
Others have also shown that resveratrol inhibited the growth of dif-
ferent tumor types through attenuating NF-kB signaling [118–120].
Curcumin, its natural and synthetic analogues and different formu-
lations were studied extensively in the regulation of NF-kB and
its dependent gene expression in multiple systems [121,122]. A
liposomal formulation of EF24 was effectively down regulated NF-
kB cascade in pancreatic cancer cells and inhibited the growth
both in vitro and in vivo [123]. A combination of curcumin and
tolfenamic acid was found have synergistic activity in suppress-
ing the growth of pancreatic cancer cells [124]. This polyphenol
also reversed the oxaliplatin resistance in colorectal cancer through
modulation of CXC-Chemokine/NF-␬B signaling pathway [125]. A
diet containing curcumin was able to prevent benzopyrene induced
lung cancer in mice by reducing NF-kB activity and MAPK signal-
ing [126]. In liver cancer, curcumin depleted the cells having cancer
stem cell like properties through NF-kB dependent histone deacety-
lase (HDAC) inhibition [127]. A combination of EGCG and curcumin
was suppressive in nature against breast cancer derived CSCs where
both NF-kB and STAT3 pathways were downregulated [128] (Fig. 6).
EGCG, the tea polyphenol was also found to modulate NF-kB
pathway in a variety of tumor cells. It blocked the proliferation and
invasion of colorectal cancer cells [129]. A combination of EGCG
and radiotherapy in breast cancer patients showed lower levels of
NF-kB dependent genes such as VEGF, MMP-2 and 9 in serum [130].
 C. Rajagopal et al. / Pharmacological Research 130 (2018) 273–291
In human bladder cancer, EGCG inhibited the invasion and migra-
tion of cells through suppression of PI3 K/Akt/NF-kB axis [131]. In
nasopharyngeal cancer, this tea polyphenol reversed the process
of EMT and inhibited the self-renewal of CSCs [132]. In lung can-
cer models EGCG modulate the expression of microRNAs that can
regulate NF-kB and MAP kinase pathways [133].
Genistein is also explored for its potential pharmacological
effects. It induced cell death in human multiple myeloma with the
possible mechanism of modulation of NF-kB and miR-29 expres-
sion [134]. GEN-27, a derivative of genistein was found to have
therapeutic benefits in colitis associated cancer models and human
colorectal cancer and effects were mediated through suppression of
p65-CDX2-␤-catenin axis [135]. Genistein was reported to induce
apoptosis in T-cell leukemia [136], breast cancer [137] and gas-
tric cancer [138] with the suppression of NF-kB signaling. We
have recently shown that cardamonin inhibited the azoxymethane
induced colorectal cancer in mice and one of the mechanisms was
found to be the inhibition of NF-kB signaling[139].We have sum-
marized both in vitro and in vivo studies in Table 3 and Fig. 6.
4. Conclusion
The process of tumorigenesis is a complex phenomenon where
several perturbations of various signaling pathways elicited by sev-
eral transcription factors get altered leading to aberrant signaling
that cause cellular transformation. Currently, we are focusing more
on multi-targeted therapies which have several advantages over
conventional therapies with less side effects and toxicity. Natu-
ral products based drug discovery has significant potential against
various types of cancers as seen from various in vitro, ex vivo, pre-
clinical and clinical studies. In most of the cases, the target of natural
products is transcription factors. These agents derived from Mother
Nature acts at different phases of signal transduction cascades initi-
ated by transcription factors there by regulating three major steps
in carcinogenesis viz. initiation, promotion and progression. The
current need of the situation is to start appropriate randomized
clinical trials of natural products either alone or in combination
with existing standard of care for the benefit of cancer patients.
Conflict of interest
The authors showed no conflict of interest.
Acknowledgements
This work was supported by the Ramalingaswami Re-entry fel-
lowship of Department of Biotechnology, Government of India
(BT/RLF/Re-entry/38/2011) to KBH. CR and MBL acknowledge
research fellowship from Council of Scientific & Industrial Research
(CSIR) and University Grant Commission (UGC) respectively. We
also acknowledge the members of KBH lab for critical reading of
the manuscript.
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