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Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets Joydeb Kumar Kundu Young-Joon Surh Received: 5 January 2009 / Accepted: 31 March 2009 / Published online: 15 May 2009 Ó 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 Á Nrf2 Á NF-jB Á AP-1 Á CREB Á HIF Á 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 Á 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

Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

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Page 1: Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

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

Page 2: Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

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

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Page 3: Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

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

Page 4: Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

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

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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)

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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

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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)

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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)

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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

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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

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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

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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.

References

Aggarwal S, Ichikawa H, Takada Y et al (2006) Curcumin

(diferuloylmethane) down-regulates expression of cell

proliferation and antiapoptotic and metastatic gene prod-

ucts through suppression of IjBa kinase and Akt activa-

tion. Mol Pharmacol 69:195–206

Albini A, Tosetti F, Benelli R et al (2005) Tumor inflammatory

angiogenesis and its chemoprevention. Cancer Res

65:10637–10641. doi:10.1158/0008-5472.CAN-05-3473

Bae MK, Kim SH, Jeong JW et al (2006) Curcumin inhibits

hypoxia-induced angiogenesis via down-regulation of

HIF-1. Oncol Rep 15:1557–1562

Balogun E, Hoque M, Gong P et al (2003) Curcumin activates

the haem oxygenase-1 gene via regulation of Nrf2 and the

antioxidant-responsive element. Biochem J 371:887–895.

doi:10.1042/BJ20021619

Barthelman M, Bair WB 3rd, Stickland KK et al (1998) (-)-Epi-

gallocatechin-3-gallate inhibition of ultraviolet B-induced

AP-1 activity. Carcinogenesis 19:2201–2204. doi:10.1093/

carcin/19.12.2201

Bertl E, Bartsch H, Gerhauser C (2006) Inhibition of angiogen-

esis and endothelial cell functions are novel sulforaphane-

mediated mechanisms in chemoprevention. Mol Cancer

Ther 5:575–585. doi:10.1158/1535-7163.MCT-05-0324

Bhardwaj A, Sethi G, Vadhan-Raj S et al (2007) Resveratrol

inhibits proliferation, induces apoptosis, and overcomes

chemoresistance through down-regulation of STAT3 and

nuclear factor-jB-regulated antiapoptotic and cell survival

3 http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_

Facts_and_Figures_2008.asp?from=fast. Cancer Facts and

Figures 2008.pdf; p. 57.

344 Phytochem Rev (2009) 8:333–347

123

Page 13: Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

gene products in human multiple myeloma cells. Blood

109:2293–2302. doi:10.1182/blood-2006-02-003988

Bharti AC, Aggarwal BB (2002) Nuclear factor-jB and cancer:

its role in prevention and therapy. Biochem Pharmacol

64:883–888. doi:10.1016/S0006-2952(02)01154-1

Cao Z, Fang J, Xia C et al (2004) trans-3, 4, 5’-Trihydroxy-

stibene inhibits hypoxia-inducible factor 1alpha and vas-

cular endothelial growth factor expression in human

ovarian cancer cells. Clin Cancer Res 10:5253–5263. doi:

10.1158/1078-0432.CCR-03-0588

Chen NY, Ma WY, Yang CS et al (2000) Inhibition of arsenite-

induced apoptosis and AP-1 activity by epigallocatechin-

3-gallate and theaflavins. J Environ Pathol Toxicol Oncol

19:287–295

Cho DI, Koo NY, Chung WJ et al (2002) Effects of resveratrol-

related hydroxystilbenes on the nitric oxide production in

macrophage cells: structural requirements and mechanism

of action. Life Sci 71:2071–2082. doi:10.1016/S0024-3205

(02)01971-9

Cho JW, Park K, Kweon GR et al (2005) Curcumin inhibits the

expression of COX-2 in UVB-irradiated human kerati-

nocytes (HaCaT) by inhibiting activation of AP-1: p38

MAP kinase and JNK as potential upstream targets. Exp

Mol Med 37:186–192

Choi H, Chun YS, Kim SW et al (2006) Curcumin inhibits

hypoxia-inducible factor-1 by degrading aryl hydrocarbon

receptor nuclear translocator: a mechanism of tumor

growth inhibition. Mol Pharmacol 70:1664–1671. doi:

10.1124/mol.106.025817

Choi S, Lew KL, Xiao H et al (2007) D, L-Sulforaphane-

induced cell death in human prostate cancer cells is reg-

ulated by inhibitor of apoptosis family proteins and Apaf-

1. Carcinogenesis 28:151–162. doi:10.1093/carcin/bgl144

Chun KS, Keum YS, Han SS et al (2003) Curcumin inhibits

phorbol ester-induced expression of cyclooxygenase-2 in

mouse skin through suppression of extracellular signal-

regulated kinase activity and NF-jB activation. Carcino-

genesis 24:1515–1524. doi:10.1093/carcin/bgg107

Chung JY, Huang C, Meng X et al (1999) Inhibition of acti-

vator protein 1 activity and cell growth by purified green

tea and black tea polyphenols in H-ras-transformed cells:

structure-activity relationship and mechanisms involved.

Cancer Res 59:4610–4617

Deshmane SL, Mukerjee R, Fan S et al. (2009) Activation of

the oxidative stress pathway by HIV-1 Vpr leads to

induction of hypoxia inducible factor 1a expression. J Biol

Chem 284:11364–11373. doi:10.1074/jbc.M809266200

Dickinson DA, Iles KE, Zhang H et al (2003) Curcumin alters

EpRE and AP-1 binding complexes and elevates glutamate-

cysteine ligase gene expression. FASEB J 17:473–475

Divya CS, Pillai MR (2006) Antitumor action of curcumin in

human papillomavirus associated cells involves down-

regulation of viral oncogenes, prevention of NF-jB and

AP-1 translocation, and modulation of apoptosis. Mol

Carcinog 45:320–332. doi:10.1002/mc.20170

Dong Z, Ma W, Huang C et al (1997) Inhibition of tumor

promoter-induced activator protein 1 activation and cell

transformation by tea polyphenols, (-)-epigallocatechin

gallate, and theaflavins. Cancer Res 57:4414–4419

Elson DA, Ryan HE, Snow JW et al (2000) Coordinate up-

regulation of hypoxia inducible factor (HIF)-1alpha and

HIF-1 target genes during multi-stage epidermal carci-

nogenesis and wound healing. Cancer Res 60:6189–6195

Emerling BM, Weinberg F, Snyder C et al. (2009) Hypoxic

activation of AMPK is dependent on mitochondrial ROS

but independent of an increase in AMP/ATP ratio. Free

Radic Biol Med 46:1386–1391. doi:10.1016/j.freerad

biomed.2009.02.019

Farombi EO, Shrotriya S, Na HK et al (2008) Curcumin attenuates

dimethylnitrosamine-induced liver injury in rats through

Nrf2-mediated induction of heme oxygenase-1. Food Chem

Toxicol 46:1279–1287. doi:10.1016/j.fct.2007.09.095

Garg R, Gupta S, Maru GB (2008) Dietary curcumin modulates

transcriptional regulators of phase I and phase II enzymes

in benzo[a]pyrene-treated mice: mechanism of its anti-

initiating action. Carcinogenesis 29:1022–1032. doi:

10.1093/carcin/bgn064

Garvin S, Ollinger K, Dabrosin C (2006) Resveratrol induces

apoptosis and inhibits angiogenesis in human breast can-

cer xenografts in vivo. Cancer Lett 231:113–122. doi:

10.1016/j.canlet.2005.01.031

Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as

‘‘Curecumin’’: from kitchen to clinic. Biochem Pharmacol

75:787–809. doi:10.1016/j.bcp.2007.08.016

Gupta S, Hastak K, Afaq F et al (2004) Essential role of

caspases in epigallocatechin-3-gallate-mediated inhibition

of nuclear factor-jB and induction of apoptosis. Onco-

gene 23:2507–2522. doi:10.1038/sj.onc.1207353

Han SS, Keum YS, Chun KS et al (2002a) Suppression of

phorbol ester-induced NF-jB activation by capsaicin in

cultured human promyelocytic leukemia cells. Arch

Pharm Res 25:475–479. doi:10.1007/BF02976605

Han SS, Keum YS, Seo HJ et al (2002b) Curcumin suppresses

activation of NF-jB and AP-1 induced by phorbol ester in

cultured human promyelocytic leukemia cells. J Biochem

Mol Biol 35:337–342

Heiss E, Herhaus C, Klimo K et al (2001) Nuclear factor-jB is

a molecular target for sulforaphane-mediated anti-

inflammatory mechanisms. J Biol Chem 276:32008–

32015. doi:10.1074/jbc.M104794200

Hickey MM, Simon MC (2006) Regulation of angiogenesis by

hypoxia and hypoxia-inducible factors. Curr Top Dev

Biol 76:217–257. doi:10.1016/S0070-2153(06)76007-0

Hsieh TC, Lu X, Wang Z et al (2006) Induction of quinone

reductase NQO1 by resveratrol in human K562 cells

involves the antioxidant response element ARE and is

accompanied by nuclear translocation of transcription fac-

tor Nrf2. Med Chem 2:275–285. doi:10.2174/1573

40606776930709

Jang M, Pezzuto JM (1998) Effects of resveratrol on 12-O-

tetradecanoylphorbol-13-acetate-induced oxidative events

and gene expression in mouse skin. Cancer Lett 134:81–

89. doi:10.1016/S0304-3835(98)00250-X

Jeong WS, Kim IW, Hu R et al (2004) Modulation of AP-1 by

natural chemopreventive compounds in human colon HT-

29 cancer cell line. Pharm Res 21:649–660. doi:

10.1023/B:PHAM.0000022412.69380.d7

Joung EJ, Li MH, Lee HG et al (2007) Capsaicin induces heme

oxygenase-1 expression in HepG2 cells via activation of

PI3 K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase

as a potential target. Antioxid Redox Signal 9:2087–2098.

doi:10.1089/ars.2007.1827

Phytochem Rev (2009) 8:333–347 345

123

Page 14: Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

Juge N, Mithen RF, Traka M (2007) Molecular basis for chemo-

prevention by sulforaphane: a comprehensive review. Cell

Mol Life Sci 64:1105–1127. doi:10.1007/s00018-007-6484-5

Kaidi A, Qualtrough D, Williams AC et al (2006) Direct

transcriptional up-regulation of cyclooxygenase-2 by

hypoxia-inducible factor (HIF)-1 promotes colorectal

tumor cell survival and enhances HIF-1 transcriptional

activity during hypoxia. Cancer Res 66:6683–6691. doi:

10.1158/0008-5472.CAN-06-0425

Kang G, Kong PJ, Yuh YJ et al (2004) Curcumin suppresses

lipopolysaccharide-induced cyclooxygenase-2 expression

by inhibiting activator protein 1 and nuclear factor kappab

bindings in BV2 microglial cells. J Pharmacol Sci

94:325–328. doi:10.1254/jphs.94.325

Keum YS, Yu S, Chang PP et al (2006) Mechanism of action of

sulforaphane: inhibition of p38 mitogen-activated protein

kinase isoforms contributing to the induction of antioxi-

dant response element-mediated heme oxygenase-1 in

human hepatoma HepG2 cells. Cancer Res 66:8804–8813.

doi:10.1158/0008-5472.CAN-05-3513

Kim SO, Kundu JK, Shin YK et al (2005) [6]-Gingerol inhibits

COX-2 expression by blocking the activation of p38 MAP

kinase and NF-jB in phorbol ester-stimulated mouse skin.

Oncogene 24:2558–2567. doi:10.1038/sj.onc.1208446

Kim AL, Zhu Y, Zhu H et al (2006) Resveratrol inhibits prolifer-

ation of human epidermoid carcinoma A431 cells by modu-

lating MEK1 and AP-1 signalling pathways. Exp Dermatol

15:538–546. doi:10.1111/j.1600-0625.2006.00445.x

Kode A, Rajendrasozhan S, Caito S et al (2008) Resveratrol

induces glutathione synthesis by activation of Nrf2 and

protects against cigarette smoke-mediated oxidative stress

in human lung epithelial cells. Am J Physiol Lung Cell Mol

Physiol 294:L478–L488. doi:10.1152/ajplung.00361.2007

Kundu JK, Surh Y-J (2004) Molecular basis of chemoprevention

by resveratrol: NF-jB and AP-1 as potential targets. Mutat

Res 555:65–80. doi:10.1016/j.mrfmmm.2004.05.019

Kundu JK, Surh Y-J (2007) Epigallocatechin gallate inhibits

phorbol ester-induced activation of NF-jB and CREB in

mouse skin: role of p38 MAPK. Ann N Y Acad Sci

1095:504–512. doi:10.1196/annals.1397.054

Kundu JK, Surh Y-J (2008) Inflammation: gearing the journey to

cancer. Mutat Res 659:15–30. doi:10.1016/j.mrrev.2008.

03.002

Kundu JK, Na HK, Chun KS et al (2003) Inhibition of phorbol

ester-induced COX-2 expression by epigallocatechin

gallate in mouse skin and cultured human mammary

epithelial cells. J Nutr 133:3805S–3810S

Kundu JK, Shin YK, Kim SH et al (2006a) Resveratrol inhibits

phorbol ester-induced expression of COX-2 and activation of

NF-jB in mouse skin by blocking IkappaB kinase activity.

Carcinogenesis 27:1465–1474. doi:10.1093/carcin/bgi349

Kundu JK, Shin YK, Surh Y-J (2006b) Resveratrol modulates

phorbol ester-induced pro-inflammatory signal transduc-

tion pathways in mouse skin in vivo: NF-jB and AP-1 as

prime targets. Biochem Pharmacol 72:1506–1515. doi:

10.1016/j.bcp.2006.08.005

Kundu JK, Na H-K, Surh Y-J (2008) Intracellular signaling

molecules as targets of selected dietary chemopreventive

agents. In: Surh Y-J, Packer L, Cadenas E, Dong Z (eds)

Dietary modulation of cell signaling pathways. CRC

Press, Taylor & Francis Group, USA, pp 1–44

Lando D, Peet DJ, Gorman JJ et al (2002) FIH-1 is an aspa-

raginyl hydroxylase enzyme that regulates the transcrip-

tional activity of hypoxia-inducible factor. Genes Dev

16:1466–1471. doi:10.1101/gad.991402

Li L, Aggarwal BB, Shishodia S et al (2004) Nuclear factor-jB

and IjB kinase are constitutively active in human pan-

creatic cells, and their down-regulation by curcumin

(diferuloylmethane) is associated with the suppression of

proliferation and the induction of apoptosis. Cancer

101:2351–2362. doi:10.1002/cncr.20605

Liao D, Johnson RS (2007) Hypoxia: a key regulator of

angiogenesis in cancer. Cancer Metastasis Rev 26:281–

290. doi:10.1007/s10555-007-9066-y

Lin W, Wu RT, Wu T et al (2008) Sulforaphane suppressed

LPS-induced inflammation in mouse peritoneal macro-

phages through Nrf2 dependent pathway. Biochem Phar-

macol 76:967–973. doi:10.1016/j.bcp.2008.07.036

Lopez-Lazaro M (2006) Hypoxia-inducible factor 1 as a pos-

sible target for cancer chemoprevention. Cancer Epi-

demiol Biomarkers Prev 15:2332–2335. doi:10.1158/

1055-9965.EPI-06-0369

Lu YP, Chang RL, Lou YR et al (1994) Effect of curcumin on

12-O-tetradecanoylphorbol-13-acetate- and ultraviolet B

light-induced expression of c-Jun and c-Fos in JB6 cells

and in mouse epidermis. Carcinogenesis 15:2363–2370.

doi:10.1093/carcin/15.10.2363

Mayr B, Montminy M (2001) Transcriptional regulation by the

phosphorylation-dependent factor CREB. Nat Rev Mol

Cell Biol 2:599–609. doi:10.1038/35085068

Na HK, Kim EH, Jung JH et al (2008) (-)-Epigallocatechin

gallate induces Nrf2-mediated antioxidant enzyme

expression via activation of PI3 K and ERK in human

mammary epithelial cells. Arch Biochem Biophys

476:171–177. doi:10.1016/j.abb.2008.04.003

Nishinaka T, Ichijo Y, Ito M et al (2007) Curcumin activates

human glutathione S-transferase P1 expression through

antioxidant response element. Toxicol Lett 170:238–247.

doi:10.1016/j.toxlet.2007.03.011

Okabe S, Ochiai Y, Aida M et al (1999) Mechanistic aspects of

green tea as a cancer preventive: effect of components on

human stomach cancer cell lines. Jpn J Cancer Res

90:733–739

Oszajca K, Bieniasz M, Brown G et al (2008) Effect of oxi-

dative stress on the expression of t-PA, u-PA, u-PAR, and

PAI-1 in endothelial cells. Biochem Cell Biol 86:477–

486. doi:10.1139/O08-137

Pollard JW (2004) Tumour-educated macrophages promote

tumour progression and metastasis. Nat Rev Cancer 4:71–

78. doi:10.1038/nrc1256

Richard DE, Berra E, Gothie E et al (1999) p42/p44 mitogen-

activated protein kinases phosphorylate hypoxia-inducible

factor 1alpha (HIF-1alpha) and enhance the transcrip-

tional activity of HIF-1. J Biol Chem 274:32631–32637.

doi:10.1074/jbc.274.46.32631

Saha P, Das S (2002) Elimination of deleterious effects of free

radicals in murine skin carcinogenesis by black tea infu-

sion, theaflavins & epigallocatechin gallate. Asian Pac J

Cancer Prev 3:225–230

Sarkar FH, Li Y (2008) NF-jB: a potential target for cancer

chemoprevention and therapy. Front Biosci 13:2950–

2959. doi:10.2741/2900

346 Phytochem Rev (2009) 8:333–347

123

Page 15: Molecular basis of chemoprevention with dietary phytochemicals: redox-regulated transcription factors as relevant targets

Semenza GL (2004) Hydroxylation of HIF-1: oxygen sensing

at the molecular level. Physiology (Bethesda) 19:176–

182. doi:10.1152/physiol.00001.2004

Sethi G, Ahn KS, Aggarwal BB (2008) Targeting nuclear

factor-kappa B activation pathway by thymoquinone: role

in suppression of antiapoptotic gene products and

enhancement of apoptosis. Mol Cancer Res 6:1059–1070.

doi:10.1158/1541-7786.MCR-07-2088

Shen F, Chen SJ, Dong XJ et al (2003) Suppression of IL-8

gene transcription by resveratrol in phorbol ester treated

human monocytic cells. J Asian Nat Prod Res 5:151–157.

doi:10.1080/1028602031000066852

Shishodia S, Amin HM, Lai R et al (2005) Curcumin (difer-

uloylmethane) inhibits constitutive NF-jB activation,

induces G1/S arrest, suppresses proliferation, and induces

apoptosis in mantle cell lymphoma. Biochem Pharmacol

70:700–713. doi:10.1016/j.bcp.2005.04.043

Song XZ, Bi ZG, Xu AE (2006) Green tea polyphenol epigallo-

catechin-3-gallate inhibits the expression of nitric oxide

synthase and generation of nitric oxide induced by ultraviolet

B in HaCaT cells. Chin Med J (Engl) 119:282–287

Subbaramaiah K, Chung WJ, Michaluart P et al (1998) Res-

veratrol inhibits cyclooxygenase-2 transcription and

activity in phorbol ester-treated human mammary epi-

thelial cells. J Biol Chem 273:21875–21882. doi:

10.1074/jbc.273.34.21875

Surh Y-J (2003) Cancer chemoprevention with dietary phyto-

chemicals. Nat Rev Cancer 3:768–780. doi:10.1038/nrc1189

Surh Y-J, Kundu JK (2007) Cancer preventive phytochemicals

as speed breakers in inflammatory signaling involved in

aberrant COX-2 expression. Curr Cancer Drug Targets

7:447–458. doi:10.2174/156800907781386551

Surh Y-J, Han SS, Keum YS et al (2000) Inhibitory effects of

curcumin and capsaicin on phorbol ester-induced activa-

tion of eukaryotic transcription factors, NF-jB and AP-1.

Biofactors 12:107–112. doi:10.1002/biof.5520120117

Surh Y-J, Kundu JK, Na HK et al (2005) Redox-sensitive

transcription factors as prime targets for chemoprevention

with anti-inflammatory and antioxidative phytochemicals.

J Nutr 135:2993S–3001S

Surh Y-J, Kundu JK, Na HK (2008) Nrf2 as a master redox

switch in turning on the cellular signaling involved in the

induction of cytoprotective genes by some chemopre-

ventive phytochemicals. Planta Med 74:1526–1539. doi:

10.1055/s-0028-1088302

Syed DN, Afaq F, Kweon MH et al (2007) Green tea polyphenol

EGCG suppresses cigarette smoke condensate-induced NF-

jB activation in normal human bronchial epithelial cells.

Oncogene 26:673–682. doi:10.1038/sj.onc.1209829

Tang HY, Shih A, Cao HJ et al (2006) Resveratrol-induced

cyclooxygenase-2 facilitates p53-dependent apoptosis in

human breast cancer cells. Mol Cancer Ther 5:2034–2042.

doi:10.1158/1535-7163.MCT-06-0216

Thimmulappa RK, Mai KH, Srisuma S et al (2002) Identifi-

cation of Nrf2-regulated genes induced by the chemo-

preventive agent sulforaphane by oligonucleotide

microarray. Cancer Res 62:5196–5203

Uto T, Fujii M, Hou DX (2005) Inhibition of lipopoly-

saccharide-induced cyclooxygenase-2 transcription by

6-(methylsulfinyl) hexyl isothiocyanate a chemopreventive

compound from Wasabia japonica (Miq.) Matsumura, in

mouse macrophages. Biochem Pharmacol 70:1772–1784.

doi:10.1016/j.bcp.2005.07.011

Uto T, Fujii M, Hou DX (2007) Effects of 6-(methylsulfinyl)hexyl

isothiocyanate on cyclooxygenase-2 expression induced by

lipopolysaccharide, interferon-gamma and 12-O-tetra-

decanoylphorbol-13-acetate. Oncol Rep 17:233–238

Vayalil PK, Katiyar SK (2004) Treatment of epigallocatechin-

3-gallate inhibits matrix metalloproteinases-2 and -9 via

inhibition of activation of mitogen-activated protein

kinases, c-jun and NF-jB in human prostate carcinoma

DU-145 cells. Prostate 59:33–42. doi:10.1002/pros.10352

Watabe M, Hishikawa K, Takayanagi A et al (2004) Caffeic

acid phenethyl ester induces apoptosis by inhibition of

NF-jB and activation of Fas in human breast cancer

MCF-7 cells. J Biol Chem 279:6017–6026. doi:

10.1074/jbc.M306040200

Woo KJ, Kwon TK (2007) Sulforaphane suppresses lipopoly-

saccharide-induced cyclooxygenase-2 (COX-2) expression

through the modulation of multiple targets in COX-2 gene

promoter. Int Immunopharmacol 7:1776–1783. doi:

10.1016/j.intimp.2007.09.018

Xu C, Shen G, Chen C et al (2005) Suppression of NF-jB and

NF-jB-regulated gene expression by sulforaphane and

PEITC through IjBa, IKK pathway in human prostate

cancer PC-3 cells. Oncogene 24:4486–4495. doi:

10.1038/sj.onc.1208656

Xu C, Huang MT, Shen G et al (2006a) Inhibition of 7, 12-

dimethylbenz(a)anthracene-induced skin tumorigenesis in

C57BL/6 mice by sulforaphane is mediated by nuclear

factor E2-related factor 2. Cancer Res 66:8293–8296. doi:

10.1158/0008-5472.CAN-06-0300

Xu C, Shen G, Yuan X et al (2006b) ERK and JNK signaling

pathways are involved in the regulation of activator pro-

tein 1 and cell death elicited by three isothiocyanates in

human prostate cancer PC-3 cells. Carcinogenesis

27:437–445. doi:10.1093/carcin/bgi251

Yuan JH, Li YQ, Yang XY (2008) Protective effects of epigal-

locatechin gallate on colon preneoplastic lesions induced by

2-amino-3-methylimidazo[4, 5-f] quinoline in mice. Mol

Med 14:590–598. doi:10.2119/2007-00050.Yuan

Zhang F, Altorki NK, Mestre JR et al (1999) Curcumin inhibits

cyclooxygenase-2 transcription in bile acid- and phorbol

ester-treated human gastrointestinal epithelial cells. Car-

cinogenesis 20:445–451. doi:10.1093/carcin/20.3.445

Zhang Q, Tang X, Lu QY et al (2005) Resveratrol inhibits

hypoxia-induced accumulation of hypoxia-inducible fac-

tor-1alpha and VEGF expression in human tongue squa-

mous cell carcinoma and hepatoma cells. Mol Cancer

Ther 4:1465–1474. doi:10.1158/1535-7163.MCT-05-0198

Zhang Q, Tang X, Lu Q et al (2006) Green tea extract and (-)-

epigallocatechin-3-gallate inhibit hypoxia- and serum-

induced HIF-1a protein accumulation and VEGF expres-

sion in human cervical carcinoma and hepatoma cells. Mol

Cancer Ther 5:1227–1238. doi:10.1158/1535-7163.MCT-

05-0490

Zhu M, Zhang Y, Cooper S et al (2004) Phase II enzyme

inducer, sulforaphane, inhibits UVB-induced AP-1 acti-

vation in human keratinocytes by a novel mechanism. Mol

Carcinog 41:179–186. doi:10.1002/mc.20052

Phytochem Rev (2009) 8:333–347 347

123