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Molecular basis of chemoprevention with dietaryphytochemicals: redox-regulated transcription factorsas relevant targets
Joydeb Kumar Kundu Æ Young-Joon Surh
Received: 5 January 2009 / Accepted: 31 March 2009 / Published online: 15 May 2009
� Springer Science+Business Media B.V. 2009
Abstract A precise regulation of redox balance is
required for the cellular homeostatic control. Aber-
rant activation of redox-sensitive transcription fac-
tors, such as nuclear factor-kappaB (NF-jB),
activator protein 1 (AP-1), cyclic adenosine mono-
phosphate response element binding protein (CREB),
and hypoxia inducible factor (HIF), contributes to
carcinogenesis by promoting persistent inflamma-
tion, abnormal cell proliferation, evasion from apop-
tosis, angiogenesis, etc. A wide variety of dietary
phytochemicals have been reported to exert cancer
chemopreventive properties by suppressing the inap-
propriate activation of aforementioned transcription
factors. On the other hand, transcription of genes
involved in the activation of cellular antioxidant
arsenal and carcinogen detoxification is largely
regulated by another redox-sensitive transcription
factor, i.e. NF-E2 related factor 2 (Nrf2), which plays
a role in protecting cells/tissues from oxidative
or electrophilic damage. Some food-derived phyto-
chemicals have been shown to activate Nrf2, thereby
augmenting cellular antioxidant capacity and induc-
ing expression of phase-2 detoxification enzymes.
Therefore, the modulation of cellular signaling med-
iated by redox-sensitive transcription factors in the
right direction represents a promising approach to
achieving molecular target-based chemoprevention
with edible phytochemicals.
Keywords Chemoprevention � Nrf2 �NF-jB � AP-1 � CREB � HIF � Phytochemicals
Introduction
Despite a remarkable progress in the development of
anticancer therapies, cancer still remains as a major
global health burden. The number of cancer-related
deaths is expected to increase by two-fold in the next
50 years. Since many types of cancers are prevent-
able, the current cancer control strategy involves a
paradigm shift from chemotherapy to chemopreven-
tion. Chemoprevention refers to the use of non-toxic
chemical substances of either natural or synthetic
origin to prevent carcinogenesis by stimulating
detoxification of carcinogens and their potentially
reactive metabolites or by halting, delaying or
reversing the proliferation and subsequent malignant
transformation of damaged cells. In fact, the prom-
ising results from numerous preclinical and limited
clinical studies highlight the chemoprevention strat-
egy as a realistic approach to fight cancer (Kundu
et al. 2008; Surh 2003).
J. K. Kundu � Y.-J. Surh (&)
National Research Laboratory of Molecular
Carcinogenesis and Chemoprevention and Research
Institute of Pharmaceutical Sciences, College of
Pharmacy, Seoul National University, 599 Kwanak-ro,
Kwanak-gu, Seoul 151-742, South Korea
e-mail: [email protected]
123
Phytochem Rev (2009) 8:333–347
DOI 10.1007/s11101-009-9132-x
According to the report from the World Cancer
Research Fund (WCRF), about 30–40% of cancers
can be prevented by appropriate food and nutrition,
physical activity and avoidance of obesity.1 Meta
analysis of epidemiologic (case-control and cohort)
studies indicates that the regular consumption of non-
nutritive ingredients derived from plant-based diet,
collectively termed phytochemicals, can reduce the
risk of certain cancers.2 It is now estimated that more
than 1,000 different food-derived phytochemicals
possess chemopreventive activities. Examples of
dietary chemopreventive phytochemicals include
resveratrol and proanthocyanidins from grapes, cur-
cumin from turmeric, epigallocatechin gallate
(EGCG) from green tea, sulforaphane and isothiocy-
anates from broccoli, genistein from soybean, indole-
3-carbinol from cabbage, lycopene from tomato,
organosulfur compounds from garlic, gingerol from
ginger, caffeic acid phenethyl ester (CAPE) from
honey bee propolis, etc. (Surh 2003).
Recent progress in unraveling the process of carci-
nogenesis has identified abnormal functioning of the key
components of the intracellular signaling network,
especially a panel of redox-sensitive transcription
factors. These transcription factors regulate the tran-
scription of a wide variety of genes involved in the
maintenance of homeostatic cell growth and prolifera-
tion, and the protection of cells from oxidative and other
noxious insults. Mechanistically, chemoprevention can
be achieved by enhancing cellular antioxidant and
detoxification capacity, promoting carcinogen detoxifi-
cation, suppressing abnormally activated pro-inflam-
matory signaling pathways, down-regulating expression
of proteins involved in cell proliferation, inducing
apoptosis of precancerous or malignant cells, and
inhibiting neovascularization (Kundu et al. 2008).
Therefore, redox-sensitive transcription factors
might be potential targets for chemoprevention with
dietary phytochemicals. This chapter will focus on
how some representative edible phytochemicals can
exert chemopreventive effects on oxidative stress-
and inflammation-associated carcinogenesis by
modulating signal transduction mediated by distinct
redox-regulated transcription factors (Fig. 1).
Oxidative stress, inflammation and cancer
The generation of excessive reactive oxygen species
(ROS) as byproducts of aerobic metabolism and a
concomitant fall in the intrinsic antioxidant capacity
of cells leads to a state of oxidative stress, which
contributes to carcinogenesis. Physiologically, ROS
are often utilized as a second messenger to execute
normal cellular functions in response to growth
factors, hormones, and neurotransmitters. However,
high levels of ROS generated by external stimuli
including chemical carcinogens, ultraviolet radiation,
bacterial or viral infection, etc. elicit deleterious
effects on human health (Surh et al. 2005). ROS, such
as superoxide radical anion, hydroperoxyl radical,
hydrogen peroxide, and hydroxyl radical, contribute
to tumorigenesis either directly by damaging critical
biomolecules or indirectly by modulating cellular
signal transduction pathways (Kundu and Surh 2008).
Moreover, accumulation of ROS in vivo leads to a
state of persistent local inflammation. Like oxidative
stress, inflammation plays a role in multistage carci-
nogenesis by several distinct mechanisms including
damage of genomic DNA and alteration of intracel-
lular signal transduction leading to abnormal cellular
growth. Thus, both oxidative stress and inflammation
not only initiate tumorigenesis but also promote the
proliferatuion of damaged cells and create a tumor
microenvironment favorable for the neoplastic trans-
formation of premalignant cells (Kundu and Surh
2008; Surh et al. 2005).
The proximal promoter regions of many genes
encoding pro-inflammatory enzymes [e.g., cyclooxy-
genase-2 (COX-2) and inducible nitric oxide synthase
(iNOS)], cell cycle regulatory proteins (e.g., cyclins
and cyclin-dependent kinases), anti-apoptotic proteins
[e.g., survivin, B cell lymphoma (Bcl)-2, and Bcl-xL],
contain binding sequences for one or more of specific
transcription factors. It has been well-documented that
persistently elevated ROS activate redox-sensitive
transcription factors, such as nuclear factor-kappaB
(NF-jB), activator protein-1 (AP-1) and cyclic-AMP
response element binding protein (CREB). Aberrant
activation of these transcription factors leads to
inappropriate upregulation of genes encoding proteins
1 WCRF/American Institute for Cancer Research: Food,
Nutrition, Physical Activity and the Prevention of Cancer: A
Global Perspective, Washington DC, AICR 2007. pp. xxv.2 WCRF/American Institute for Cancer Research: Food,
Nutrition, Physical Activity and the Prevention of Cancer: A
Global Perspective, Washington DC, AICR 2007. pp. 75–114.
334 Phytochem Rev (2009) 8:333–347
123
involved in inflammation, cellular proliferation and
growth, and has been implicated in pathophysiology of
various malignancies (Surh et al. 2005). Hypoxia
inducible factor (HIF)-1a is another redox-sensitive
transcription factor, which plays a critical role in tumor
angiogenesis by elevating the levels of angiogenic
factors, such as vascular endothelial growth factor
(VEGF) and COX-2 (Kaidi et al. 2006; Kundu et al.
2008; Surh et al. 2005). Though this transcription
factor, as its name stands for, is upregulated under
hypoxic conditions, it is also activated by ROS-
mediated oxidative stress (Deshmane et al. 2009).
Moreover, it is noteworthy that hypoxia, despite
limited oxygen supply, can cause oxidative stress
(Emerling et al. 2009). The human umbilical vein
endothelial cells (HUVEC) were challenged with
hydrogen peroxide, and the protein levels of AP-1,
NF-jB, and HIF-1a and their DNA-binding activity
were measured. There was a strong association among
AP-1, NF-jB, and HIF-1a in the contribution to
regulation of selected genes, suggesting the coordi-
nated activation of these redox-sensitive transcription
factors under oxidative stress (Oszajca et al. 2008).
Living in an environment of various known and
unknown sources of ROS, our body has intrinsic
ability to guard against oxidative stress-induced
AP
-1
HRECRE
κB
CR
EB
ARE
TRE
p65
p50
HO-1, NQO1, GCL, GPx, GST, UGT, etc.
COX-2, iNOS, IL-8, Cyclin D1, IAP, Bcl-2, Bcl-xL, survivin,
etc.
VEGF, COX-2, etc.
Antioxidant defense and Carcinogen detoxification
Inflammation, Cell proliferation, and
Antiapoptosis
Angiogenesis
Chemopreventivephytochemicals
HIF-1α
Nrf2
Fig. 1 Redox-sensitive transcription factors as targets of
dietary chemopreventive phytochemicals. Food-derived phy-
tochemicals stimulate carcinogen detoxification and function
as antitumor initiating agents through the activation of Nrf2-
ARE signaling and induction of Nrf2-regulated gene products,
such as HO-1, NQO1, GCL, GST, GPx, etc. Dietary
phytochemicals exhibit antitumor promoting effects by block-
ing the activation of other redox-sensitive transcription factors,
such as NF-jB, AP-1 and CREB, and their target gene products
(e.g., COX-2, iNOS, cyclin D1, IAP, Bcl-2, etc.) involved in
cell proliferation, inflammation and antiapoptotic process.
Some phytochemicals also downregulate HIF-1a-dependent
expression of angiogenic factors, such as VEGF and COX-2,
thereby blocking neovascularization essential for tumor
growth. TRE, TPA-response element; HRE, Hypoxia response
element
Phytochem Rev (2009) 8:333–347 335
123
cellular damage. Naturally, cells/tissues are empow-
ered with a panel of antioxidant and detoxifying
enzymes such as, NAD(P)H:quinone oxidoreductase-1
(NQO1), superoxide dismutase (SOD), glutathione
S-transferase (GST), glutathione peroxidase (GPx),
heme oxygenase-1 (HO-1), glutamate cysteine ligase
(GCL), uridine diphosphate glucuronosyltransferase
(UGT), etc., which are responsible for inactivating/
eliminating not only ROS but also electrophilic
species, thereby protecting cellular macromolecules
from ROS-induced damage, and metabolically acti-
vated ultimate carcinogens (Surh et al. 2005).
The proximal promoter regions of aforementioned
antioxidant and detoxification genes contain a consen-
sus sequence known as antioxidant response element
(ARE) or electrophile response element (EpRE),
which is the preferred target of nuclear factor E2-
related factor-2 (Nrf2) (Surh et al. 2008). Nrf2 is
normally sequestered in the cytoplasm as an inactive
complex with its cytosolic repressor, named Kelch-like
ECH associated protein 1 (Keap1). In response to mild
oxidative or electrophilic insults, Nrf2 is dissociated
from the inhibitory protein Keap1 and translocates to
nucleus and binds to cis-acting ARE or EpRE, leading
to transcriptional activation of antioxidant and cyto-
protective genes (Surh et al. 2008).
Redox-regulated transcription factors as targets
of chemopreventive phytochemicals
A wide variety of dietary phytochemicals have been
shown to exert chemopreventive effects by potenti-
ating cellular antioxidative or detoxification capacity
through activation of Nrf2 signaling (Surh et al. 2008,
2005) and/or by suppressing inflammation, tumor cell
proliferation and growth signaling mediated by
NF-jB, AP-1 or CREB (Surh and Kundu 2007; Surh
et al. 2005). Some chemopreventive phytochemicals
are capable of blocking HIF-1a-mediated tumor
angiogenesis (Kundu et al. 2008). Dietary phyto-
chemicals that can activate Nrf2 protect against DNA
damage caused by oxidative stress and electrophilic
carcinogens, thereby inhibiting the tumor initiation
process, and hence are known as ‘blocking agents’.
On the other hand, phytochemicals that act as
negative regulators of signaling mediated by NF-jB,
AP-1, CREB or HIF-1a, and thereby prevent tumor
promotion and progression, can be better classified as
‘suppressing agents’ (Surh et al. 2005). The following
section will introduce readers some representative
phytochemicals that target aforementioned redox-
sensitive transcription factors in exerting their che-
mopreventive effects (summarized in Table 1).
Nrf2
The ultimate risk of chemically induced carcinogen-
esis depends on the relative rate of carcinogen
activation and inactivation. The induction of detox-
ification enzymes, predominantly regulated by Nrf2,
facilitates inactivation and subsequent elimination of
metabolically activated carcinogenic species that are
electrophilic in general. Nrf2 also regulates expres-
sion of a wide array of antioxidant enzymes, confer-
ring cytoprotection against oxidative DNA damage.
Dietary chemopreventive phytochemicals have been
shown to induce the expression of different antiox-
idant and detoxification enzymes through activation
of Nrf2-ARE signaling (Surh et al. 2008).
Resveratrol has been reported to elevate the
expression and/or the activity of GST, GPx, UGT-1A,
NQO1, HO-1, and GCL (Surh et al. 2008, 2005). The
compound restored cigarette smoke extract (CSE)-
induced depletion of cellular glutathione (GSH) by
inducing Nrf2-driven upregulation of GCL expres-
sion in human primary small airway epithelial cells
(SAEC) and human alveolar epithelial (A549) cells,
thereby protecting these cells from CSE-induced
oxidative damage (Kode et al. 2008). Moreover,
resveratrol increased the phosphorylation and nuclear
translocation of Nrf2, and induced the activity as well
as the expression of NQO1 at both protein and
mRNA levels in human leukemia K562 cells (Hsieh
et al. 2006).
The induction of antioxidant or detoxifying
enzymes by curcumin is also mediated via the
Nrf2-ARE signaling. Dietary administration of cur-
cumin elevated the protein expression, enhanced
nuclear translocation and increased DNA binding of
Nrf2 in the liver and the lung of Swiss albino mice as
compared with controls (Garg et al. 2008). According
to this study, elevated protein and mRNA levels, and
the activities of hepatic GST and NQO1 resulted in
increased detoxification of benzo[a]pyrene in mice
fed curcumin (Garg et al. 2008). Oral administration
of curcumin also enhanced the nuclear translocation
and the ARE-binding of Nrf2 and induced the
336 Phytochem Rev (2009) 8:333–347
123
Table 1 Redox-regulated transcription factors as targets of selected chemopreventive phytochemicals
Target Phytochemicals Effects Cells/tissues (References)
Nrf2
Resveratrol
;Post-translational modification of Nrf2, :Nrf2 nuclear
localization; :GCL mRNA level; :GSH synthesis
Disruption of the Nrf2-Keap1 complex, :Nrf2 nuclear
translocation, :Nrf2 phosphorylation, :mRNA expression
and activity of NQO1
CSE-stimulated human lung epithelial
cells (Kode et al. 2008)
K562 cells (Hsieh et al. 2006)
Curcumin
:Nuclear translocation and DNA binding of Nrf2; :GCL
mRNA and protein level
:Phosphorylation of p38 MAP kinase; :Dissociation
of Nrf2-Keap1; :Nrf2 binding to ho-1-ARE, :expression
and activity of HO-1
:GSTP1 mRNA; :Nrf2-ARE-regulated GSTP1 promoter
activity
HBE1 cells (Dickinson et al. 2003)
Porcine renal epithelial cells and rat
kidney epithelial cells (Balogun
et al. 2003)
HepG2 cells (Nishinaka et al. 2007)
EGCG
:Expression of GCL, MnSOD, and HO-1; :nuclear
translocation of Nrf2; :Nrf2-ARE binding; :Nrf2
transcriptional activity
:Nrf2 mRNA and protein expression; :mRNA levels of
UGT1A10; ;atypical hyperplasia; ;number of aberrant
crypt foci and adenocarcinomas
MCF-10A cells (Na et al. 2008)
IQ-treated mouse colon
(Yuan et al. 2008)
Sulforaphane
;Phosphorylation of p38 MAP kinase; :Nrf2-ARE activity;
:HO-1 expression
:mRNA levels of NQO1, GCL, and GST in small intestine
HepG2 cells (Keum et al. 2006)
Nrf2-wild type mice (Thimmulappa
et al. 2002)
Capsaicin
:ROS generation; :Akt activation; ;NQO1 expression
and activity; :activation of Nrf2
HepG2 cells (Joung et al. 2007)
NF-jB
Resveratrol
;NF-jB DNA binding; ;IKK activity;;MAP kinase
activation; ;IjBa phosphorylation and degradation;
;p65 phosphorylation and nuclear translocation;
;expression of COX-2
;NF-jB nuclear translocation; ;NO production
;NF-jB DNA binding; ;IKK activity;
;IjBa phosphorylation; ;expression of cyclin D1,
survivin, cIAP2, xIAP, Bcl-2, and Bcl-xL; :expression
of Bax and caspase-3
Mouse skin treated with TPA (Kundu
et al. 2006a)
LPS-stimulated macrophages (Cho
et al. 2002)
Human multiple myeloma cells
(Bhardwaj et al. 2007)
Phytochem Rev (2009) 8:333–347 337
123
Table 1 continued
Target Phytochemicals Effects Cells/tissues (References)
Curcumin
;NF-jB DNA binding; ;IjBa phosphorylation ;p65
nuclear translocation; ;ERK phosphorylation;
;expression of COX-2
;NF-jB activity; ;IKK activity; ;cell proliferation;
;expression of Bcl-2, Bcl-xL, COX-2 and IL-6;
cell cycle arrest at G1/S phase; :apoptosis
;NF-jB DNA binding; ;IjBa degradation;
;p65 nuclear translocation
Mouse skin treated with TPA (Chun
et al. 2003)
Human mantle cell lymphoma
(Shishodia et al. 2005)
HL-60 cells (Han et al. 2002b)
EGCG
;CSE-induced cell proliferation; ;p65 nuclear
translocation; ;IjBa phosphorylation; ;NF-jB
transcriptional activity; ;expression of cyclin D1,
MMP-9, IL-8 and iNOS
;NF-jB DNA binding; ;IjBa phosphorylation and
degradation; ;nuclear translocation of p65 and p50
;NF-jB activation; ;expression of iNOS;
;production of NO
;NF-jB activation; ;expression of MMP-2,-9;
;phosphorylation of ERK and p38 MAP kinase
Bronchial epithelial cells (Syed et al.
2007)
TPA-treated mouse skin (Kundu and
Surh 2007)
UVB-stimulated HaCaT cells (Song
et al. 2006)
Human prostate cancer DU-145 cells
(Vayalil and Katiyar 2004)
Sulforaphane
Induction of apoptosis; ;NF-jB transcriptional activity;
;p65 nuclear translocation; ;expression of cIAP1,
cIAP2, xIAP; :expression of Bax and Apaf1
;NF-jB transcriptional activity; ;p65 nuclear
translocation; ;IKK phosphorylation; ;expression
of VEGF, cyclin D1 and Bcl-xL
;NF-jB DNA binding; ;expression of iNOS and
COX-2; ;production of PGE2 and NO
Human prostate cancer cells (Choi
et al. 2007)
PC3 cells (Xu et al. 2005)
LPS-stimulated Raw 264.7 cells
(Heiss et al. 2001)
Thymoquinone
;TNF-a-induced activation of NF-jB; ;IKK activity
and IjBa phosphorylation; ;expression of IAP1,
IAP2, xIAP, Bcl-2, Bcl-xL and survivin;
;expression of COX-2, cyclin D1, c-Myc,
;expression of MMP-9 and VEGF
Human myeloid KBM-5 cells (Sethi
et al. 2008)
AP-1
Resveratrol
;c-Jun expression, ;AP-1 DNA binding, cell cycle
arrest at G1 phase, ;expression of cyclin A, D1,
and cdk-6
;AP-1 activity; ;IL-8 production
;TPA-induced AP-1 activity; ;COX-2 expression,
;PGE2 production
;AP-1 DNA binding; ;expression of c-Jun and c-Fos,
;COX-2 expression
Human epidermoid A431 cells (Kim
et al. 2006)
TPA-treated U937 cells (Shen et al.
2003)
Human mammary and oral epithelial
cells (Subbaramaiah et al. 1998)
TPA-treated mouse skin (Kundu et al.
2006b)
338 Phytochem Rev (2009) 8:333–347
123
Table 1 continued
Target Phytochemicals Effects Cells/tissues (References)
Curcumin
;AP-1 DNA binding; ;expression of COX-2
;TPA-induced AP-1 DNA binding
;AP-1 DNA binding; ;expression of COX-2
;AP-1 DNA binding; ;expression of COX-2;
;phosphorylation of p38 MAP kinase and
c-Jun-N-terminal kinase (JNK)
TPA-treated gastrointestinal cells
(Zhang et al. 1999)
TPA-treated ICR mouse skin and
HL-60 cells (Surh et al. 2000)
LPS-stimulated BV2 microglial cells
(Kang et al. 2004)
UVB-irradiated HaCaT cells (Cho
et al. 2005)
EGCG
;AP-1 DNA binding and transcriptional activity
;AP-1 activity; ;phosphorylation of c-Jun and ERK
;AP-1 activity; ;TNF-a release; ;TNF-a mRNA levels
;UVB-induced AP-1 activity
Arsenite-treated JB6 cells (Chen et al.
2000)
Ras-transformed JB6 cells (Chung
et al. 1999)
KATO III cells (Okabe et al. 1999)
Human keratinocytes and AP-1
transgenic mouse skin (Barthelman
et al. 1998)
Sulforaphane
;DNA binding of several transcription factors including
AP-1; ;expression of COX-2 protein and mRNA
Direct inhibition of UVB-induced AP-1 DNA binding
Induction of apoptosis; :AP-1 activity;
:phosphorylation of ERK and JNK
LPS-stimulated Raw 264.7 cells (Woo
and Kwon 2007)
Human keratinocytes (Zhu et al. 2004)
PC-3 cells (Xu et al. 2006b)
CREB
Sulforaphane
;DNA binding of several transcription factors including
CREB; ;expression of COX-2 protein and mRNA
LPS-stimulated Raw 264.7 cells (Woo
and Kwon 2007)
EGCG
;CREB DNA binding; ;phosphorylation of p38 MAP
kinase
TPA-treated mouse skin (Kundu and
Surh 2007)
6-MITC
;DNA binding of CREB, AP-1 and C/EBP;
;COX-2 protein and mRNA expression;
;phosphorylation of MAP kinases
LPS-stimulated Raw 264.7 cells (Uto
et al. 2005)
HIF-1a
Resveratrol
;Expression of HIF-1a and VEGF; :proteasomal
degradation of HIF-1a
;Hypoxia-induced expression of HIF-1a and VEGF;
:proteasomal degradation of HIF-1a
OVCAR-3 cells (Cao et al. 2004)
SCC-9 cells, HepG2 cells (Zhang
et al. 2005)
Phytochem Rev (2009) 8:333–347 339
123
expression of HO-1 in the liver of male ICR mice,
protecting the animals against dimethylnitrosamine-
induced hepatotoxicity (Farombi et al. 2008).
Intraperitoneal administration of EGCG, at a dose
equivalent to four cups of 2% tea for 15 days,
elevated the levels of GST, GPx, SOD and catalase in
mouse liver, and reduced lipid peroxidation and cell
proliferation during the dimethylbenz[a]anthracene
(DMBA)-initiated and 12-O-tetradecanoylphorbol-
13-acetate (TPA)-promoted mouse skin carcinogen-
esis (Saha and Das 2002). EGCG, given by gavage,
significantly decreased 2-amino-3-methylimi-
dazo[4,5-f]quinoline-induced atypical hyperplasia,
the number of aberrant crypt foci and adenocarci-
noma formation by activating Nrf2 and upregulating
UGT1A10 in mouse colon (Yuan et al. 2008). The
compound also enhanced the mRNA expression of
GCL and GSTp, and the nuclear translocation and the
ARE binding of Nrf2 in human mammary epithelial
cells (Na et al. 2008).
Another extensively investigated chemopreven-
tive phytochemical, sulforaphane, derived from
broccoli sprouts and mature broccoli, has been
reported to induce antioxidant as well as phase-2
detoxifying enzymes predominantly by activating
Nrf2 (Juge et al. 2007). The compound induced
marked expression of NQO1, GST and GCL in the
small intestine of Nrf2-wild-type mice, while the
Nrf2-null mice displayed lower levels of these
enzymes upon sulforaphane treatment (Thimmulap-
pa et al. 2002). While topical application of
sulforaphane reduced the incidence of DMBA-
initiated and TPA-promoted skin papillomas in
Nrf2?/? mice, no such chemopreventive effect was
achieved in Nrf2-/- mice (Xu et al. 2006a).
Pretreatment of Nrf2?/? primary peritoneal macro-
phages with sulforaphane induced HO-1 expression
whilst the compound also inhibited lipopolysachaa-
ride (LPS)-induced expression or production of
tumor necrosis factor (TNF)-a, interleukin (IL)-1b,
COX-2 and iNOS (Lin et al. 2008). The anti-
inflammatory effects of sulforaphane were attenu-
ated in Nrf2-/- primary peritoneal macrophages
(Lin et al. 2008). Mechanistically, sulforaphane
activated Nrf2 through enhanced phosphorylation
of upstream Akt kinase and extracellular signal-
regulated protein kinase (ERK), blockade of p38
mitogen-activated protein (MAP) kinase, and direct
modification of specific cysteine residues on Keap1
(Surh et al. 2008).
Capsaicin, the major pungent ingredient of hot
chili pepper, induced the expression of HO-1 in
HepG2 cells by activating Nrf2 signaling in a ROS-
dependent manner (Joung et al. 2007). Chemopre-
ventive phytochemicals, such as carnosol (from
rosemary), diallyl trisulfide (from garlic), zerumbone
(from subtropical ginger), and xanthohumol (from
hops) are also known to activate Nrf2 and induce
various antioxidant or detoxification enzymes (Surh
et al. 2008).
NF-jB
The redox-sensitive transcription factor NF-jB func-
tions as a link between inflammation and cancer. In
resting cells, NF-jB remains sequestered in the
Table 1 continued
Target Phytochemicals Effects Cells/tissues (References)
Curcumin
;Expression and activity of HIF-1a; ;expression of
erythropoetin and VEGF
;Hypoxia-induced expression and activity of HIF-1a;
;expression of VEGF
Hepatoma xenografted tumor in mice
(Choi et al. 2006)
Vascular endothelial cells and HepG2
cells (Bae et al. 2006)
EGCG
;Expression of HIF-1a and VEGF; :proteasomal
degradation of HIF-1aHypoxia- and serum-stimulated HeLa
and HepG2 cells (Zhang et al. 2006)
Sulforaphane
;mRNA levels of HIF-1a, VEGF and c-Myc Hypoxia-stimulated human
microvascular endothelial cells
(Bertl et al. 2006)
340 Phytochem Rev (2009) 8:333–347
123
cytoplasm, predominantly as a heterodimer of p65
and p50 proteins, by forming an inactive complex
with its inhibitory counterpart IjBa. Exposure to
oxidative and inflammatory stimuli, such as H2O2,
TNF-a, IL-1, phorbol ester, ultraviolet (UV) irradi-
ation or microbial infection, leads to the phosphor-
ylation and subsequent proteasomal degradation of
IjBa, allowing NF-jB to migrate to nucleus. The
induction of a wide array of proinflammatory genes
such as TNF-a, IL-8, IL-1, iNOS, COX-2, etc. is
transcriptionally regulated by NF-jB. This ubiquitous
transcription factor plays a pivotal role in carcino-
genesis by stimulating the expression/production of
proinflammatory enzymes and cytokines, antagoniz-
ing the function of tumor suppressor protein p53,
up-regulating genes involved in cell cycle progres-
sion, and inducing expression of anti-apoptotic gene
products, including inhibitor of apoptosis (IAP)-1,
IAP2, xIAP, Bcl-2 and Bcl-xL (Surh and Kundu
2007; Surh et al. 2005). Numerous dietary phyto-
chemicals have been reported to block inappropriate
activation of NF-jB, thus reducing the degree of
inflammation, blocking cell cycle progression and
inducing apoptosis in various premalignant and
malignant cells (Bharti and Aggarwal 2002; Sarkar
and Li 2008).
The inhibitory effects of resveratrol on the
expression of various pro-inflammatory gene prod-
ucts (e.g., COX-2 and iNOS), cell cycle regulatory
proteins (e.g., cyclin D1), and anti-apoptotic proteins
(e.g., Bcl-2 and Bcl-xL) are mediated through
suppression of induced as well as constitutively
active NF-jB (Bharti and Aggarwal 2002). Resvera-
trol inhibits multi-organ carcinogenesis in various
experimental models (Kundu and Surh 2004). Top-
ical application of resveratrol attenuated TPA-
induced COX-2 expression by blocking NF-jB
activation, which may account for its inhibitory
effects on mouse skin tumor promotion (Kundu et al.
2006a). Resveratrol induced apoptosis through down-
regulation of NF-jB-mediated expression of prolif-
erative and antiapoptotic genes, such as cyclin D1,
cIAP-2, xIAP, survivin, Bcl-2, Bcl-xL, and TNF-areceptor-associated factor (TRAF)-2, in human multi-
ple myeloma cells (Bhardwaj et al. 2007).
Molecular mechanisms underlying the anti-tumor
promoting effect of curcumin have partly been
attributed to its suppression of tumor promoter-
induced or constitutive activation of NF-jB (Kundu
et al. 2008; Surh and Kundu 2007; Surh et al. 2005).
Curcumin inhibited expression of COX-2 and the
generation of prostaglandin (PG) E2 in TPA-stimu-
lated mouse skin (Chun et al. 2003) and human
pancreatic cancer cells (Li et al. 2004). Treatment of
human leukemia cells with curcumin inhibited TNFa-
induced inhibitory jB kinase (IKK) phosphorylation,
IjBa degradation, p65 nuclear translocation and
NF-jB-dependent reporter gene expression. Curcu-
min inhibition of NF-jB in these cells resulted in the
down-regulation of NF-jB-regulated gene products
involved in cellular proliferation (e.g., COX-2, cyclin
D1, and c-Myc), cell survival (e.g., IAP1, IAP2,
Bcl-2, Bcl-xL, etc.), and metastasis (e.g., VEGF)
(Aggarwal et al. 2006). The inhibition of constitutive
activation of NF-jB has been associated with anti-
proliferative and proapoptotic effects of curcumin in
many other cancer cells (Goel et al. 2008).
The inhibition of NF-jB and its target genes
accounts for the anti-inflammatory and antitumor
promoting effects of green tea polyphenol EGCG.
The mechanisms of NF-jB inhibition by EGCG
include suppression of the IKK activity, the blockade
of phosphorylation-dependent degradation of IjBa,
and subsequent decrease in nuclear localization of
p65 protein. Besides interference with the IKK-IjB
signaling, suppression of signal transduction medi-
ated by MAP kinases and phosphatidylionositol-3-
kinase (PI3K)-Akt by EGCG also leads to the
inactivation of NF-jB (Surh and Kundu 2007). Thus,
EGCG diminished TPA-induced activation of ERK
and p38 MAP kinase, and attenuated the nuclear
translocation and the DNA binding of NF-jB,
thereby suppressing COX-2 expression in mouse
skin (Gupta et al. 2004). The compound exhibited
anti-inflammatory and anti-proliferative effects on
CSE-stimulated human bronchial epithelial cells by
down-regulating NF-jB activation and suppressing
the expression of NF-jB-regulated pro-inflammatory
and proliferative gene products, such as cyclin D1,
matrix metalloproteinase (MMP)-9, IL-8 and iNOS
(Syed et al. 2007).
Sulforaphane exerts an inhibitory effect on the
growth and proliferation of human prostate cancer
(PC-3) cells by inhibiting NF-jB transcriptional
activity, nuclear translocation of p65, and suppressing
NF-jB-regulated expression of VEGF, cyclin D1,
and Bcl-xL (Xu et al. 2005). Choi et al. demonstrated
that sulforaphane attenuated NF-jB activation and
Phytochem Rev (2009) 8:333–347 341
123
induced apoptosis in human prostate cancer PC3 and
LNCaP cells via a mechanism involving the induc-
tion of Bax and Apaf1 and inhibition of anti-
apoptotic proteins (e.g., IAP1, IAP2 and xIAP),
which are NF-jB regulated gene products (Choi et al.
2007). In LPS-treated Raw 264.7 murine macro-
phages, sulforaphane inhibited COX-2 expression by
suppressing the NF-jB DNA binding possibly
through direct thiol modification of NF-jB proteins
(Heiss et al. 2001).
Many other dietary phytochemicals have been
reported to diminish NF-jB activation in various
tumor cells as well as in cells or tissues stimulated with
tumor promoters and other noxious stimuli. Examples
are thymoquinone from black cumin (Sethi et al. 2008),
capsaicin from chili pepper (Han et al. 2002a),
[6]-gingerol from ginger (Kim et al. 2005), CAPE
from honey bee propolis (Watabe et al. 2004), etc.
AP-1
Another important redox-sensitive transcription fac-
tor implicated in the tumorigenesis is AP-1, which
exists as 18 different dimeric combinations of basic
leucine zipper proteins from the Jun (c-Jun, JunB and
JunD) and/or Fos (c-Fos, Fos B, Fra-1 and Fra-2)
family, Jun dimerization partners and the closely
related activating transcription factor (ATF) subfam-
ilies. In response to oxidative and proinflammatory
stimuli, the activation of AP-1 is triggered predom-
inantly via the upstream MAP kinase signaling
pathways. Since transactivation of AP-1 promotes
induction of proinflammatory and proliferative gene
products, targeted inhibition of this transcription
factor also constitutes the molecular basis of chemo-
prevention with dietary phytochemicals (Surh 2003;
Surh and Kundu 2007).
Resveratrol suppressed chemically induced mouse
skin tumor promotion, partly by blocking AP-1
activation (Kundu et al. 2006b). Jang and colleagues
reported that resveratrol inhibited c-fos mRNA expres-
sion in CD-1 mouse skin treated with TPA (Jang and
Pezzuto 1998). The compound also inhibited TPA-
stimulated DNA binding of AP-1 and the expression of
AP-1 component proteins, c-Jun and c-Fos, in mouse
skin in vivo (Kundu et al. 2006b). Moreover, resvera-
trol diminished TPA-induced transcriptional activity
of AP-1 in human mammary epithelial cells (Subbar-
amaiah et al. 1998) and attenuated IL-8 expression by
blocking the AP-1 DNA binding in human leukemia
(U937) cells (Shen et al. 2003).
Curcumin inhibited TPA-induced expression of
c-Jun and c-Fos in mouse skin and mouse epidermal
JB6 cells, thereby suppressing the anchorage-indepen-
dent growth of these cells (Lu et al. 1994). Likewise,
curcumin abolished AP-1 activation in TPA-stimulated
human promyelocytic leukemia (HL-60) cells (Surh
et al. 2000). The inhibition of AP-1 activity by curcumin
accounts for the induction of apoptosis in human
papilloma virus-infected cervical cancer cells treated
with this phytochemical (Divya and Pillai 2006).
EGCG suppressed TPA-induced malignant trans-
formation of mouse epidermal JB6 cells through
inactivation of AP-1 (Dong et al. 1997). EGCG
inhibited the AP-1 activity in H-ras-transformed JB6
cells (Chung et al. 1999), and in the epidermis of
transgenic mice bearing an AP-1-driven luciferase
reporter gene (Barthelman et al. 1998). In contrast,
oral administration of EGCG failed to affect TPA-
induced AP-1 DNA binding in mouse skin in vivo
(Kundu et al. 2003).
Sulforaphane diminished UVB-induced DNA bind-
ing and transcriptional activity of AP-1 in human
epidermal keratinocyte (HaCaT) cells transfected with
an AP-1 luciferase reporter gene (Zhu et al. 2004).
Dietary phytochemicals have also been shown to
induce AP-1 activity in various cancer cells, result-
ing in apoptosis. Resveratrol induced apoptosis in
human breast cancer MCF-7 and MDA-MB-231
cells via a novel mechanism that involved AP-1-
dependent induction and nuclear translocation of
COX-2, and subsequent interaction among COX-2,
serine-phosphorylated p53 and p300 (Tang et al.
2006). Sulforaphane induced apoptosis in human
prostate cancer PC3 cells through activation of ERK
and JNK, and subsequent induction of the AP-1
activity (Xu et al. 2006b). Jeong et al. demonstrated
that resveratrol, curcumin, EGCG and sulforaphane
increased AP-1-luciferase activity and induced
apoptosis in human colon cancer (HT-29) cells
(Jeong et al. 2004).
CREB
CREB mediates cAMP-, growth factor-, and calcium-
dependent gene expression through the cAMP
response element (CRE) located in the promoter
regions of many proliferative and proinflammatory
342 Phytochem Rev (2009) 8:333–347
123
genes. In resting cells, unphosphorylated CREB can
bind to DNA, but remains transcriptionally inactive.
In response to oxidative and pro-inflammatory stim-
uli, CREB is phosphorylated at serine residue 133,
and becomes active to upregulate the transcription of
various cell cycle regulatory as well as proinflamma-
tory genes (Mayr and Montminy 2001). CREB has
been shown to be responsible for the induction of
COX-2 expression in activated mast cells and UVB-
stimulated human keratinocytes, and also shear
stress-induced COX-2 promoter activity in osteoblast
cells (Surh and Kundu 2007).
Although CREB regulates various pro-inflamma-
tory and growth promoting genes, only a few dietary
phytochemicals have been investigated for their
effect on the modulation of CREB function as a
mechanism of chemoprevention. EGCG, given by
gavage, attenuated TPA-induced CREB DNA bind-
ing in mouse skin by blocking the activation of p38
MAP kinase (Kundu and Surh 2007). Sulforaphane
suppressed LPS-induced COX-2 protein and mRNA
expression in Raw 264.7 murine macrophages
through modulation of multiple transcription factors
including NF-jB, CCAAT/enhancer binding protein
(C/EBP), AP-1 as well as CREB (Woo and Kwon
2007). 6-(Methylsulfinyl)hexyl isothiocyanate
(6-MITC), a major component of wasabi, abolished
LPS-induced COX-2 expression in Raw 264.7 murine
macrophages by blocking the activation of C/EBP,
CREB and AP-1, but not NF-jB (Uto et al. 2007).
HIF-1a
One of the key transcription factors that regulate
expression of hypoxia-responsive genes in premalig-
nant and malignant tissues is HIF-1a, which acts as a
master regulator of cellular oxygen homeostasis
(Semenza 2004). The HIF-1a expression is induced
at early stages of tumorigenesis and often correlated
with increased angiogenesis in developing as well as
progressing tumors (Lopez-Lazaro 2006). In a hyp-
oxic environment of benign tumors, the induction of
HIF-1a-regulated genes encoding angiogenic factors
requires the protein stability and enhanced activity of
HIF-1a. In response to hypoxia, HIF-1a protein
escapes prolylhydroxylase-von Hippel-Lindau
(VHL)-mediated proteasomal degradation and forms
a heterodimer with HIF-1b and subsequently binds to
the hypoxia response elements (HRE) located in the
promoter region of target genes (Semenza 2004;
Hickey and Simon 2006; Lopez-Lazaro 2006). The
transcriptional activity of HIF-1a is regulated by
Factor Inhibiting HIF-1a (FIH) under normoxic
conditions. FIH inhibits the binding of HIF-1a with
transcriptional coactivator p300/CREB-binding pro-
tein (CBP) by hydroxylating an asparagene residue
located in the C-terminal domain of HIF-1a (Lando
et al. 2002). Several mechanisms that lead to
accumulation and increased activity of HIF-1ainclude ERK-mediated phosphorylation and subse-
quent nuclear localization of HIF-1a, inactivation of
tumor suppressor genes such as VHL, p53 and PTEN,
and activation of oncogene products, such as Ras,
vSrc, epidermal growth factor receptor (EGFR), etc.
and subsequent amplification of signaling via PI3
K/Akt and MAP kinase pathways (Richard et al. 1999;
Hickey and Simon 2006; Liao and Johnson 2007).
An increase in HIF-1a protein expression has been
observed in cancers of breast, prostate, lungs and
pancreas (Hickey and Simon 2006). The induction of
HIF-1a has also been investigated in a transgenic
mouse model of epidermal carcinogenesis (Elson
et al. 2000). A number of HIF-regulated angiogenic
factors, such as VEGF, basic fibroblast growth factor
(bFGF), VEGF receptor (VEGFR), IL-8, iNOS,
angiopoietins, etc., are released by tumor-associated
macrophages (Hickey and Simon 2006; Pollard
2004). Many of these factors further accelerate the
inflammatory angiogenic process, thereby triggering
tumor growth (Albini et al. 2005). Thus, HIF-1arepresents another potential target for dietary
chemoprevention.
Resveratrol reduced tumor growth and angiogen-
esis in estrogen receptor (ER)a- and ERb-positive
human breast tumor (MDA-MB-231) xenografts in
nude mice, and reduced extracellular levels of VEGF
in cultured MDA-MB-231 cells (Garvin et al. 2006).
The compound also suppressed the expression
of HIF-1a and VEGF in human ovarian cancer
(OVCAR-3) cells (Cao et al. 2004). Moreover,
resveratrol significantly reduced hypoxia-induced
HIF-1a protein accumulation and VEGF expression
in human tongue squamous cell carcinomas and
HepG2 cells, without affecting HIF-1a mRNA levels,
by blocking the activation of ERK and Akt and
promoting proteasomal degradation of HIF-1a(Zhang et al. 2005). Curcumin reduced the growth
of Hep3B hepatoma-xenografted tumors in mice by
Phytochem Rev (2009) 8:333–347 343
123
down-regulating HIF-1a activity and the expression
of HIF-1a-regulated angiogenic factors, such as
erythropoetin and VEGF (Choi et al. 2006). Under
hypoxic conditions, curcumin inhibited the expres-
sion and the activity of HIF-1a, and decreased the
expression of VEGF in vascular endothelial cells and
HepG2 cells (Bae et al. 2006).
The inhibition of signaling mediated via HIF-1a and
VEGF also contributes to the antiangiogenic effects of
EGCG and sulforaphane. Thus, EGCG significantly
inhibited hypoxia- and serum-induced HIF-1a protein
expression in HeLa and HepG2 cells by blocking PI3K/
Akt and ERK1/2, and enhancing proteasomal degra-
dation of HIF-1a, thereby decreasing the mRNA and
protein expression of VEGF (Zhang et al. 2006).
Sulforaphane also elicited a time- and concentration-
dependent inhibitory effect on hypoxia-induced
expression of HIF-1a, VEGF and c-Myc mRNA in
human microvascular endothelial cells (Bertl et al.
2006).
Conclusion
The magnitude of cancer as a global threat has been
reflected in a recent report published by the American
Cancer Society. According to this report, cancer has
caused about 7.6 million deaths globally in the year
2007, and this figure is expected to be 17.5 million by
the year 2050.3 While the cancer statistics is so
frightening, there are glimpses of hope flared through
the chemoprevention research conducted over the last
several decades. Promising results from studies
including epidemiological, preclinical and clinical
trials suggest that dietary chemoprevention would be
the ultimate choice for reducing the global cancer
burden. In fact, numerous food-derived phytochemi-
cals have been shown to be effective in preventing
malignant transformation of cells in culture and
experimentally induced tumorigenesis in various
animal models in vivo.
Mechanistically, chemoprevention with dietary
phytochemicals could be achieved by stimulating
metabolic inactivation or detoxification of potential
carcinogens, inhibition of abnormal cell proliferation,
suppression of persistent inflammation, induction of
programmed cell death and halting/delaying the
angiogenic process. At the molecular level, cancer-
related pathophysiological events, such as oxidative
damage of cellular macromolecules, activation of
oncogenes, inactivation of tumor suppressor genes,
rapid proliferation of tumor cells, increased rate of
neovascularization and the escape of tumor cells from
program cell death. Many of these events are associ-
ated with improper intracellular signaling mediated via
a panel of redox-sensitive transcription factors such as
Nrf2, NF-jB, AP-1, CREB and HIF-1a. In the current
era of molecular target-based chemoprevention, many
food factors, especially phytochemicals present in our
regular diet, have been explored as promising cancer
chemopreventive agents, which modulate the function
of one or more of redox-regulated transcription factors
highlighted in this review.
Acknowledgments This study was supported by the research
grant from the Korea Science and Engineering Foundation
(KOSEF) for Biofoods Research Program, Ministry of
Education, Science and Technology, Republic of Korea.
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