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Introduction
Chemoprevention is an active cancer preventive
strategy to inhibit, delay or reverse human carcinogenesis, using
naturally occurring or synthetic chemical agents. The term
"chemoprevention" was first introduced by Dr Michael B.
Sporn, when he referred to the prevention of cancer
development by natural forms of vitamin A and by its synthetic
analogs[1]. Thereafter, a variety of naturally-occurring
dietary compounds have been shown to possess significant
chemopreventive effects and many experimental attempts
have been made to address their underlying mechanisms of
actions[2]. Numerous cancer cell lines and animal cancer
models have been used to evaluate the chemopreventive effects
of phytochemicals as well as to elucidate their mechanisms
of cancer prevention. These studies have resulted in the
discovery of several new phytochemicals that possess
cancer preventive effects, such as isothiocyanates from
cruciferous vegetables, polyphenols from green and black tea,
and flavonoids from soybeans[2]. Several cellular
mechanisms contribute to the overall cancer preventive effects of
these dietary phytochemicals. These include oxidative or
electrophilic stresses that can trigger a wide variety of
cellular events such as increasing expression of detoxifying
enzymes and/or antioxidant enzymes, inhibiting cell cycle
progression and cell proliferation, inducing differentiation
and apoptosis, inhibiting expression and functional
activation of oncogenes, increasing expression of
tumor-suppressor genes, and inhibiting angiogenesis and metastasis by
modulating cellular signaling
pathways[2,3]. These signal transduction pathways are now recognized as potential
molecular targets for chemoprevention by dietary phytochemicals[4]. The scope of the present review will focus on
the molecular basis of chemopreventive potential of dietary
phyto-chemicals, with special emphasis on their effects on
cellular signaling cascades mediated by nuclear factor
E2-related factor 2 (Nrf2), nuclear factor-kappaB
(NF-κB), cyclooxy-genases-2 (COX-2), activator protein-1 (AP-1),
mitogen-activated protein kinases (MAPKs), and inflammatory
mediator-related pathways, as well as several animal cancer
models for cancer chemoprevention research.
Natural dietary phytochemicals
Over millions of years, plants have developed the
capacity to synthesize a diverse array of chemicals. In general,
these phytochemicals function to attract beneficial
organisms, repel harmful organisms, serve as photoprotectants and
respond to environmental cues for the plants' survival. For
example, numerous classes of phytochemicals, including
flavonoids, polyphenols and anthocyanins function as
phytoalexins, substances that assist a plant to resist
patho-gens. Humans and animals have been ingesting plants since
the inception of evolution. Needless to say both humans
and animals have developed a robust digestive system that
helps them reap the benefits of such ingestion. The primary
research in our laboratory is focused towards
understanding the beneficial effects of some of these dietary
phyto-chemicals.
Studies from our laboratory, as well as others, have
shown that these phytochemicals can act as blocking agents
obstructing the initiation phase of carcinogenesis or
suppressing agents retarding the promotion and progression
phases of carcinogenesis. Recently, we showed that
sulforaphane (SFN) a component of cruciferous vegetables
inhibited adenoma formation in the gastro-intestinal tract of
ApcMin/+mice[5,6]. Profiling the gene expression modulated
by SFN in the small intestinal polyps of these mice revealed
that several pro-apoptotic genes such as MBD4, TNF-7 and
TNF (ligand)-11 were upregulated while pro-survival genes
such as cyclin-D2, integrin-b1, Wnt-9A were found to be
downregulated[7]. In MCF-7, a breast cancer cell line and
MCF-10F, a non-cancerous human breast cell-line, SFN has
been shown to inhibit DNA adduct formation by polycyclic
aromatic hydrocarbon-benzo[a]pyrene (BaP) and 1,6
dinitro-pyrene[8]. Curcumin the diketone obtained from the Indian
spice turmeric has been long known as an anti-inflammatory
and anti-cancer agent. Curcumin has been shown to inhibit
tumor initiation by BaP and 7,12-dimethyl-benz[a]anthracene
(DMBA) and also to inhibit tumor promotion induced by
12-O-tetradecanoylphorbol-13-acetate
(TPA)[9]. Phenylethyliso-thiocyanate (PEITC), another component of cruciferous
vegetables has been shown to induce apoptosis in the human
colon cancer cell line HT-29 by activating the mitochondrial
caspase cascade[10,11]. It has been shown to potently inhibit
NF-κB activity in human prostate cancer (PC3) cells by
inhibiting IKKα/β signaling pathway[12]. Interestingly a
combination of curcumin and PEITC demonstrated an additive
effect in inducing apoptosis in PC3 cells by significantly
inhibiting EGFR and its downstream signaling molecules PI3K
and Akt[13]. A similar combination significantly inhibited
tumor formation in athymic nude mice implanted with PC3
xenografts[14]. Transgenic adenocarcinoma of the mouse
prostate (TRAMP) is a transgenic mouse model that
recapitulates all of the salient features of human prostate cancer.
Both curcumin and PEITC individually as well as in
combination inhibited tumor development in these mice
(unpubli-shed data). (-) epigallocatechin gallate (EGCG) a popular
component of green tea has been shown to induce apoptosis
in HT-29 cells by damaging the mitochondria and activating
the caspases[15]. It has also been shown to promote
apopto-sis in T24 human bladder cancer cells by modulating the
PI3K/Akt signaling pathway and Bcl-2 family
proteins[16].
It is important to note that though each of these
phyto-chemicals is potent in inhibiting tumor and/or cancer
development, they are also non-toxic to the normal cells.
What really sets apart their differential effects in abnormal
cancer cells versus normal cells is their ability to induce
apoptotic pathways to impede cancer in abnormal cancer
cells and at the same time manipulate levels of metabolizing
enzymes and induce detoxifying enzymes rendering them
non-toxic to normal cells. SFN has been shown to increase
mRNA and protein levels of quinone reductase (QR),
UDP-glucuronyltransferase (UGT) and glutathione-S-transferase
(GST) and heme oxygenase (HO)-1 and this increase is
mediated by the induction of ARE. More recently, work from our
laboratory has demonstrated that the inhibition of p38 MAPK
isoform by SFN contributes to the induction of
ARE-mediated increases in HO-1 gene
expression[17]. SFN has also been shown to decrease the mRNA levels of CYP3A4, which
translates to a decrease in CYP3A4
activity[18]. Likewise PEITC, EGCG, and curcumin have also been shown to
induce phase II detoxifying enzymes _ UGT, GST,
HO-1[19, 20]. Thus it can be inferred that careful manipulation of multiple
signaling cascades by dietary phytochemicals within the cell
contribute to the pleiotropic effects of these potential
chemo-preventive agents.
Nrf2 signaling pathways
Nrf2, a member of the Cap'n'collar family of basic
region-leucine zipper (bZIP) transcription factors (Figure 1A) that
can act as a master regulator of ARE-driven transactivation
of antioxidant genes[21]. Six conserved domains of Nrf2 are
designated Nrf2-epichlorohydrin (ECH) homology (Neh)
1_Neh 6. Neh1 corresponds to the CNC homology region and
bZIP domain. The amino and carboxyl termini of the
proteins are also highly conserved, and are referred to as Neh2
and Neh3, respectively. In addition, there are two conserved
acidic domains (Neh4 and Neh5) as well as a serine-rich
conserved region (Neh6).
Its important role in regulating the expression of many
mammalian detoxifying and antioxidant enzymes under
oxidative or electrophilic stress has been verified in various
Nrf2-deficient mice studies, in which the expression of these
enzymes were dramatically abolished and the Nrf2 knockout
mice were much more susceptible to carcinogen-induced
carcinogenesis[22_24]. As described above, many
phytochemi-cals exert their chemopreventive effects by blocking the
initiation stage of cancer development. For a subset of these
compounds, chemoprotection is mainly derived from the
induction of Nrf2/ARE-regulated genes. For example, the
phase II GST gene can be induced by phenolic antioxidant
butylated hydroxyanisole (BHA) and
ethoxyquin[25] or by
isothiocyanate[26]. The redox-sensitive stress gene HO-1 can
be induced by curcumin and caffeic acid phenethyl ester
(CAPE) through an Nrf2 signaling
pathway[27]. Under basal unstimulated conditions, Nrf2 is sequestered in the
cytoplasm as an inactive complex with its cytosolic repressor
Kelch-like ECH associated protein 1 (Keap1, Figure 1A). Nrf2
is tethered to Keap1 in the cytosol. Most of the Nrf2
proteins are targeted to proteosomal degradation presumably
with low levels of recycling to the
nucleus[28]. Dissociation of Nrf2 from the inhibitory protein Keap1 is a prerequisite for
nuclear translocation and subsequent DNA binding of
Nrf2[29]. Keap1 is a cysteine-rich protein that interacts with
the ETGE motif within the N-terminal Neh2 domain of
Nrf2[30] (Figure 1A). Many studies have shown that challenges with
chemopreventive agents can lead to enhanced nuclear
accumulation of Nrf2, therefore activating Nrf2-dependent gene
transcription[24,25,27,31]. However, the exact mechanisms by
which these phytochemicals or the generated exogenous
and/or endogenous oxidative and/or electrophile stresses
trigger the Nrf2 transactivation activity are still unclear. The
binding of Keap1 to Nrf2 represses Nrf2-mediated gene
transcription under homeostatic conditions. Upon exposure to
above threshold levels of chemopreventive chemicals or
oxidative stress, Nrf2 is able to escape Keap1-mediated
repression, translocate to the nucleus, where Nrf2 binds to
the ARE in association with small Maf proteins inside the
nucleus, and activate expression of its target genes (Figure
1B). Chemopreventive compounds may also directly cause
the cleavage of the disulfide bond between Nrf2 and Keap1.
By inducing the phase II detoxifying and antioxidant
enzyme genes, phytochemicals increase the detoxification of
pro-carcinogens or carcinogens and protect normal cells from
the damage of electrophiles and reactive oxygen
intermedi-ates, thus decreasing the incidence of initiation and
reducing the risk of cancer. Considering the great structural
diversity of the inducers that regulate the Nrf2 signaling
path-way[32], a mechanism of activation requiring the direct
binding or interaction of phytochemicals that activate Nrf2 with a
structurally complementary receptor appears to be quite
unlikely. Therefore, many phytochemicals might regulate
Nrf2-mediated gene transcription by different mechanisms.
It is important to note that many chemopreventive agents
could possess pro-oxidant properties, meaning they can
generate oxidative and/or electrophilic stress by themselves
in the cells. The chemical stress generated by
chemopreven-tive agents appears to be dose-dependent, mild at low
concentrations with sufficient signal strength to activate the
cellular defense systems that lead to the coordinated
activation of the Nrf2 signaling pathway. However, this low stress
is believed to be at a subtoxic level that would not cause any
adverse effects such as DNA damage, mutagenicity, or
degeneration of tissues as traditionally caused by carcinogens.
NF-κB and AP-1 signaling pathways
Nuclear factor-kappaB NF-κB is an ubiquitous
redox-sensitive transcription factor that includes six family members:
NF-κB1 (p50 and its precursor p105), NF-κB2 (p52 and its
precursor p100), RelA (p65), RelB (p68), c-Rel (p75) and
v-Rel (Figure 2). These proteins bind to a specific promoter
of target genes and regulate a wide range of cellular events,
such as cell proliferation, cell cycle control, apoptosis,
differentiation and tumorgenesis by forming homodimers or
heterodimers with each other. In resting or unstimulated
cells, NF-κB is sequestered in the cytoplasm by binding to
IκBa (IκBα, IκBα, IκBα) that masks the nuclear localization
sequence (NLS) in NF-κB. When cells receive the signals
that activate NF-κB signaling pathways, IκB protein will be
phosphorylated at Ser/Thr residues by the upstream
IκB kinase (IKK) complex (consisting of two catalytic subunits,
IKKα and IKKβ, and a regulatory subunit, IKKg or NEMO)
and undergo ubiquitin-mediated proteosomal degradation[33,34], which in turn enables the nuclear import machinery
to recognize the NLS and transports NF-κB to the nucleus.
It is reported that activation of NF-κB can promote or inhibit
apoptosis, depending on the cell type and other conditions[35,36], but activation of NF-κB is generally thought to
protect cells against apoptotic stimuli in most tumor cell lines,
presumably via the induction of cell survival
genes[37]. This notion agrees well with the fact that the
NF-κB signaling pathway is constitutively activated in
leukemia[38], prostate[39], breast[40] and pancreatic
cancers[41] and that the blockade of
NF-κB can increase the sensitivity of cancers to
chemotherapeutic drugs[42]. Therefore, inhibition of the
NF-κB signaling pathway has emerged as an important target of
chemotherapeutic and chemopreventive
compounds[42].
Activator protein-1 is another redox-sensitive
transcription factor that can be regulated by a large variety of stimuli,
including pro-inflammatory cytokines, growth factors,
oxidative stress and tumor
promoters[43] (Figure 2). AP-1 is a dimeric transcription factor that consists of the basic
leucine-zipper family members, including the Jun (c-Jun, JunB
and JunD), Fos (c-Fos, FosB, Fra1 and Fra2), ATF (ATF2,
B-ATF, JDP1 and JDP2), and Maf (MafA, MafB, c-Maf and
MafG/F/K) protein families, in which Jun and Fos dimer is
the most common partner proteins found in the eukaryotes[44,45]. When activated, AP-1 recognizes and binds to
the TPA response element (TRE) or cAMP response element
within the promoter region of target genes. Because of its
implication in a wide variety of cellular responses, the role of
AP-1 in carcinogenesis has been heavily investigated.
Inhibition of Fos and Jun expression in mice fibroblasts and
erythroleukaemia cells has indicated that AP-1 is required
for cell proliferation and cell cycle
progression[46]. Using mice overexpressing c-Fos,
Wang et al showed a close relationship between c-Fos expression levels and chondrogenic
tumor development[47]. c-Jun activity suppression, using a
dominant-negative c-Jun in basal keratinocytes or
conditional inactivation of c-Jun in the liver resulted in the
interference of the development of chemically-induced
papillomas and liver tumors,
respectively[48,49]. MAPKs (ERK, JNK and p38 MAPK) are critical mediators of AP-1 activity in
response to pro-inflammatory cytokines or exogenous
stress[50]. Activation of JNK and p38 MAPK phosphorylates and
activates c-Jun and ATF2 proteins, respectively, which in
turn leads to the activation of AP-1 target genes. JNK can
also cross-talk with PI3K to upregulate AP-1
activity[51].
Given that the regulation of NF-κB and AP-1 by
intracellular signaling cascades is complex, it is imperative to know
how dietary chemopreventive compounds modulate the
intracellular signaling cascades to affect the basal and/or
inducible NF-κB and AP-1 activity. At present, a vast number
of studies have reported the regulation of NF-κB and AP-1
activities by chemopreventive compounds. Due to limited
space, however, we will focus on two well-known dietary
chemopreventive compounds (isothiocyanates and curcumin) and discuss how they modulate
NF-κB and AP-1 activities. Isothiocyanates (ITCs) are among a class of
chemopreventive compounds, which abundantly exist in
cruciferous vegetables such as broccoli, watercress, Brussels
sprouts, cabbage and cauliflower. ITCs are characterized by
the chemical structure of R-N=C=S, where R designates an
alkyl or aryl group. We have previously shown that
treatment of ITCs, such as SFN, PEITC and allyl isothiocyanate
(AITC) significantly inhibited the lipopolysaccharide
(LPS)-induced NF-κB-dependent gene expression in human colon
carcinoma HT-29 cells, stably transfected with
NF-κB-luciferase reporter and this event was closely correlated with
the suppression of IκBα
phosphorylation[52]. Similarly, we found that the exposure of SFN and PEITC to human
prostate cancer PC-3 cells strongly suppressed
NF-κB target gene expression by attenuating phosphorylation of upstream
regulatory kinases, IKKα and IKKβ[12]. Likewise, the effects of a
variety of ITCs on AP-1 activity have been intensively
investigated. For example, Zhu et al have shown that SFN
can inhibit UV-induced AP-1 activation in human
keratinocytes[53]. In another study, we found that, while
treatment of PEITC and SFN increased AP-1-dependent gene
expression in HT-29 cells at selected concentrations, AITC
increased AP-1-dependent gene expression in a
dose-dependent manner[54]. Together, these results indicate that the
regulation of NF-κB and AP-1 activity by ITCs is highly
variable, depending on the chemical structures of ITCs, cell
types and/or many other cellular factors.
MAPK signaling pathways
Mitogen-activated protein kinases, characterized as
proline-directed serine/threonine (ProXSer/ThrPro) kinases[55,56], are important cellular signaling components that
convert various extracellular signals into intracellular
responses through serial phosphorylation
cascades[57] (Figure 2). At the present time, three distinct but parallel
MAP kinase cascades (ERK, JNK, and p38) have been
identified in mammalian cells[58,59]. Each consists of a module of
three kinases: a MAPK kinase kinase (MAPKKK), which
phosphorylates and activates a MAPK kinase (MAPKK),
which, in turn, phosphorylates and activates a MAPK.
Although the MAPK, in particular the ERK, has been known
to be activated by mitogens and growth factors, many
environmental stress stimuli such as UV and ionizing radiation
can also activate JNK and p38 MAPK, with the consequences
of apoptotic cell death[60]. Many chemotherapeutic drugs
have been known to activate JNK and p38 MAPK and their
activation had been implicated in
apoptosis[61]. Once activated, these three MAPKs (ERK, JNK, and p38) can
phosphorylate many transcription factors, such as c-Myc,
p62TCF/Elk-1, c-Jun, ATF2, CHOP/GADD153, MEF2C, and
SAP-1, and ultimately leading to the changes in gene
expression[62]. Given the fact that MAPKs are activated by such a
wide range of factors, these signaling cascades may serve
as a common mechanism and integrate with other signaling
pathways to control cellular responses to various
extracellular stimuli, including xenobiotics and pharmacological agents.
The ability of curcumin to regulate the MAPKs signaling
pathway might contribute to the suppression of
inflammation by curcumin. Lee et al have reported that curcumin
inhibits phorbol ester-induced upregulation of COX-2 and
matrix metalloproteinase-9 by blocking ERK1/2
phosphorylation and NF-κB transcriptional activity in MCF10A human
breast epithelial cells[63]. Chen et al
found that curcumin inhibits JNK activation induced by various agonists
including PMA plus ionomycin, anisomycin, UV-C, and
g-radiation[64]. Salh et al reported that curcumin is able to
attenuate dinitrobenzene sulfonic acid (DNB)-induced
experimental colitis through a reduction in the activity of p38
MAPK[65]. In addition, Li et al have reported that
indole-3-carbinol (I3C) and its active metabolite 3,3"-diindolylmethane
(DIM) down-regulate the expression of MAP2K3, MAP2K4,
MAP4K3 and MARK3 in PC3 prostate cancer cells. The
results suggest that I3C and DIM suppress MAPK
signaling[66].
Inflammatory mediator-related pathways
Tumor necrosis factor-α (TNF-α), is a pro-inflammatory
cytokine with a wide variety of biological functions in
inflammation like tissue remodeling, alteration of epithelial
barrier permeability, increasing vascular permeability,
activation of macrophages, recruitment of inflammatory cells,
and upregulation of cell adhesion
molecules[67]. TNF-α can be produced and released by activated
monocytes, macro-phages, T cells, and mast cells. The induction of
pro-inflammatory genes by TNF has been linked to most diseases.
Almost all cell types, when exposed to TNF, activate
NF-κB, leading to the expression of inflammatory genes. These
include pro-inflammatory cytokines, chemokines, COX-2,
inducible nitric oxide synthase (iNOS), lipoxygenase-2
(LOX-2), and cell adhesion molecules. TNF has been found to be
a growth factor for most tumor
cells[68]. These include ovarian cancer cells, cutaneous T cell
lymphoma[69], acute myelogenous
leukemia[70], and B cell
lymphoma[71]. Because of the critical role of TNF in mediating tumorigenesis, agents
that can suppress TNF activity have potential for the therapy
of TNF-linked diseases. Moore et al reported that
TNF-α knockout mice have been shown to be resistant to skin
carcinogenesis[72], suggesting that neutralization of
TNF-α production may be useful in cancer treatment and prevention.
Phytochemicals such as curcumin[73], green tea polyphenols
EGCG[74] and resveratrol[75] have been shown to suppress
TNF production.
Arachidonic acid (AA) metabolism diverges into the COX
and the LOX pathways (Figure 3). The COX pathway leads
to prostaglandin (PG) and thromboxane production and the
LOX pathway leads to the leukotrienes (LTs) and
hydro-peroxyeicosatetraenoic acids (HPETEs). These classes of
inflammatory molecules exert profound biological effects that
enhance the development and progression of human cancers.
COX-1 and 2 are the rate-limiting enzymes in the conversion
of AA to PGs (Figure 3). The two COX isoforms of PGH
synthase have distinct tissue distributions and
physiological functions. COX-1 is constitutively expressed in many
tissues and cell types, whereas the inducible isoenzyme
COX-2 is pro-inflammatory in nature and expressed only in
response to certain stimuli such as mitogens, cytokines,
growth factors, or hormones. COX-2 is overexpressed in
practically every pre-malignant and malignant condition
involving the colon, liver, pancreas, breast, lung, bladder,
skin, stomach, head and neck[76]. Depending on the stimulus
and the cell type, several transcription factors including
AP-1, NF-IL-6, and NF-κB can stimulate COX-2
transcrip-tion[76]. AA can also be converted to leukotrienes (LTs) by
the action of 5-LOX (Figure 3). The first step in the 5-LOX
cascade consists of activation of the enzyme by 5-LOX-activating protein, which leads to the formation of the LTs
and HPETEs. These LTs induce the synthesis and release of
other pro-inflammatory mediators such as IL-8 and
platelet-activating factor. Several dietary components including
curcumin[77], genistein[78], green tea
catechins[79], and
resver-atrol[80] have been shown to suppress COX-2 and LOXs.
Plummer et al. have conducted a dose-escalation pilot study
of a standardized formulation of curcuma extract in 15
patients with advanced colorectal cancer, analysis of basal and
LPS-induced PGE2 production during treatment demonstrated a trend toward dose-dependent
inhibition[81]. Also, Garcea et
al have reported that administration of curcumin
(3 600 mg) significantly decreased M1G levels in human
malignant colorectal tissue but COX-2 protein levels in
malignant colorectal tissue were not affected by
curcumin[82]. Nitric oxide synthase (NOS) is mainly localized in astrocytes
and microglia, and catalyzes the oxidative deamination of
L-arginine to produce nitric oxide (NO), a potent
pro-inflammatory mediator. Excess production of iNOS-mediated NO is
involved in inflammatory and immunological disorders, pain,
neurological diseases, atherosclerosis, and cancer. Several
phytochemicals and dietary agents have been investigated
for their effects on NOS. Recently, Lee et al
have reported that 7-carboxymethyloxy-3',4',5'-trimethoxyflavone have
inhibitory effects on Helicobacter pylori-induced iNOS
expression and NF-κB activation in AGS human gastric
cancer cells[83]. Also, Kim et al
found that Japanese plants strongly inhibited LPS- and
IFN-g-stimulated NO generation in RAW 264.7 murine
macrophages[84].
Animal models in carcinogenesis and cancer chemoprevention
Given the fact that cancer development can be roughly
divided into three stages of initiation, promotion and
progression, control over this disease may only be achieved
if molecular changes underlying each stage can be
well-characterized and recapitulated in animal models of
carcino-genesis. Hence, animal models are critically important and
play a central role in expediting the development of new
chemopreventive approaches and therapies for cancer.
Genetically engineered mouse models of cancer
Once the efficacy of the chemopreventive agents has been
established in nude mice the next logical step would be to attain to
good understanding of the molecular mechanisms
underlying such effects and this is where autochthnous, germ-line
transgenic and knockout animals come into use. These
models are in sharp contrast to in vitro culture or orthotopic
transplantation of cell lines or tumors from clinical specimens,
as described above, because these autochthnous or
trans-genic animals closely mimic the complex interactions that
occur within the tumor microenvironment. By virtue of their
design, these animals could potentially provide a unique
window of opportunity to investigate the molecular events
related to the various stages of cancer development. In other
words, these animal models could potentially recapitulate
some of the salient features of cancer progression in humans.
TRAMP is one such genetically modified mouse model
prostatic intraepithelial neoplasia (PIN) that is commonly used
to study prostate cancer chemoprevention and has received
considerable attention over several past
years[85,86]. The TRAMP model was generated with a probasin (PB)-Tag
transgene containing the SV-40 early genes (T and t antigens,
Tag) under the control of the minimal rat PB gene promoter.
This strategy was designed to target the expression of a
large T antigen to abrogate the function of p53 and Rb tumor
suppressor genes and to target small t antigens to inactivate
protein phosphatase 2A[87]. The TRAMP transgenic mice
develop high-grade PIN within 8_12 weeks of birth and
ultimately develop metastases between 23_30 weeks, primarily
to the lymph nodes, lungs and livers. That is considered the
precursor to invasive carcinoma because it is more often
than not associated with the malignant form of the disease
and the primary architectural and cytological features of PIN
resemble that of invasive carcinoma. Hence, the ability to
retard PIN formation is considered as an important merit in
agents that are tested against prostate
carcinoma[88]. Genis-tein, an abundant soy isoflavone in the diet has been shown
to reduce the incidence of poorly differentiated prostatic
adenocarcinomas in a dose-dependent manner and
down-regulate epidermal growth factor receptor, insulin-like growth
factor-1 (IGF-1), and ERK-1 mRNA
expressions[89]. Likewise, oral consumption of green tea polyphenols has also been
shown to suppress the IGF-1 signaling in TRAMP
mice[90]. Cancer phenotypes have also been described in various
knockout mice. The Nkx 3.1 homeobox gene has been shown
to be essential for prostate differentiation and function.
Loss-of-function of Nkx 3.1 results in histopathological defects
that resemble prostate cancer initiation and progression in
humans. These mutant mice represent yet another excellent
model to study prostate cancer initiation.
Familial adenomatous polyposis (FAP) is a typical
phenotype that involves the development of several
adenoma-tous polyps carpeting the colonic mucosa. In its classical
form, almost 100% of these adenomatous polyps are
considered cancer prone. FAP is often the result of mutations or
deletions of the adenomatous polyposis coli (Apc) gene.
Because rodents almost never develop spontaneous cancer
in the colon, they often need to be induced or genetically
manipulated to develop colon cancer. This led to the
development of Apc (+/_) min mice that almost spontaneously
develop pre-neoplastic intestinal polyps. These mice present
an excellent model to study intestinal and colon cancer
chemoprevention because alterations in the number of
polyps can be detected with great ease. Recent
work from our laboratory and our unpublished results have shown that low
doses of 300 ppm sulforaphane and 0.5% dibenzoylmethane
(DBM) incorporated in the diet can significantly inhibit polyp
formation in Apc min mice[5]. However adenocarcinomas are
seldom observed and the progression from aberrant crypt
foci (ACF) to aggressive carcinoma is not well established in
this model. Another rodent model that uses
carcinogen-dimethylhydrazine to induce colon cancer is the
azoxymeth-ane (AOM) rat model. Dimethylhydrazine is metabolized to
AOM and AOM-induced tumors share many histopathological characteristics with human tumors. They, like human
tumors, are often mutated on K-ras and b-catenin genes and
display microsatellite instability, but, unlike human colon
cancers, seldom show the mutated Apc gene. This model
allows intervention by dietary phytochemicals prior to each
stage of cancer development and thus, proves to be yet
another valuable tool to study colon cancer
chemopre-vention. Both the Apc min and AOM rat models of colon
cancers could be integrated into other common progression
and promotion models of colon cancer. As an example,
Tanaka et al. investigated the effects of dextran sodium
sulfate (DSS) treatment in the development of colonic neoplasms
in Apc min mice. Apc (+/_) and Apc (+/+) mice were exposed
to 2% DSS in drinking water for 7 days and such treatment
greatly increased the inflammation scores associated with
high levels of b-catenin, cyclooxygenase-2, iNOS and
nitrotyrosine. These results suggest that DSS has a strong
promotion effect in intestinal carcinogenesis of Apc min
mice[92,93]. Most recently, this DSS-induced inflammatory
model has been applied to our Nrf2 _/_
mice[94] and the
results from this study will be discussed later on in this review.
Xenograft models of cancer A very quick though rather
non-mechanistic approach to evaluating the efficacy of
chemopreventive agents in tumor suppression entails the
use of immune suppressed athymic nude mice. Nude mice
often represent a routinely used valuable research tool
because they can receive many types of tissue and tumor
grafts and they offer no rejection response. The effects of
the chemopreventive agents on the xenograft can be easily
monitored by measuring the dimensions and the volume of
the tumor graft. Innumerable researchers have used this
model to evaluate the effectiveness of various anti-cancer
agents. Research from our laboratory has clearly
demonstrated that a combination of dietary agents curcumin and
PEITC can effectively retard tumor formation in nude mice
bearing human prostate cancer PC-3 xenografts and such
inhibition was found at least in part to suppress the Akt and
NF-κB signaling pathways, ultimately resulting in enhanced
expression of apoptosis biomarkers caspase-3 and
caspase-9[14]. Apigenin, a naturally occurring flavonoid compound
has also been shown to suppress hypoxia-inducible
factor-1 (HIF-1) and vascular endothelial growth factor (VEGF)
expression in tumor tissues of nude mice bearing A549
human lung cancer cell xenografts[95]. There are many other
examples of using nude mice xenografts in cancer
chemopre-vention research and these could be found in some of the
companion articles in this Special Issue such as the articles
by Drs Agarwal and Sarkar[96,97].
Knockout rodent models of cancer To date, most of the
knockout rodent models are tissue- or site-specific. However,
it is well understood that most cancers are multi-factorial
and arise from multiple mutations. Hence, knocking out a
gene that exerts pleitropic effects or is central to the
development of several cancers presents a model that offers a
more mechanistic approach to cancer development and
chemoprevention. Nuclear factor E2 related factor 2, Nrf2, as
described above is a master transcription factor that has
been shown to regulate the expression of more than 200 genes,
including those involved in Phase II detoxifying and
antioxidant genes[20,98,99]. One of the most prevalent mechanisms
by which dietary phytochemicals effectively halt cancer
initiation, formation and development is by manipulating the
levels of detoxifying and antioxidant cellular defense
enzymes. This manipulation mainly involves the regulation
via Nrf2 of the ARE that flanks the 5'-flanking region of
almost all detoxifying and antioxidant response elements.
Hence the use of Nrf2 disrupted mice sheds light on the
mechanistic details of cancer chemoprevention by these
dietary agents. Because Nrf2 exerts pleiotropic effects, mice
that lack this gene are spontaneously predisposed to a
variety of carcinogen-induced cancers. Subjecting these mice
to the putative chemopreventive agents aids in elucidating
the role of Nrf2 in chemoprevention. SFN and dithiolthiones
have been shown to transcriptionally induce the expression
of detoxifying and antioxidant enzymes through the
activation of Nrf2[100]. SFN blocked carcinogen
benzo[a]pyrene-induced forestomach tumors and this effect was abrogated
in mice lacking the Nrf2 gene[101]. The Nrf2 knockout mouse
model allows integration with other cancer models. Recent
work from our laboratory established that Nrf2-deficient mice
are more susceptible to DSS-induced colitis and this was
associated with increased levels of pro-inflammatory
mediators such as COX-2, iNOS, IL-6 and TNF-α and a
concomitant decrease in antioxidant enzymes such as HO-1,
NAD(P)H quinone oxidoreductase 1 (NQO1), UGT and
GST[94]. The Nrf2 knockout mouse model has been successfully integrated
into skin cancer models that involve initiation with DMBA
and promotion by TPA. Work from our laboratory has
demonstrated that Nrf2-deficient mice are greatly susceptible to
the development of skin cancer by DMBA/TPA applications
as compared to the wild type mice and importantly dietary
agent SFN, which could effectively suppress
carcinogenesis in the wild type mice in part by enhancing the
expression of the antioxidant enzyme HO-1, lost its preventive
effect in the Nrf2 _/_ mice[102]. Surprisingly, in the skin
tumors of DMBA/TPA treated Nrf2+/+ mice, there was a loss
of expression of both Nrf2 and HO-1 proteins
(Yu et al,
unpublished data), suggesting potential methylation of the
CpG island of Nrf2, thereby inactivating Nrf2 expression with
the subsequent decrease in expression of defensive enzymes
such as HO-1, that may contribute to the overall
carcinogenesis[102].
Each animal model discussed above has immense
relevance and potential application in the field of cancer
chemoprevention and these animal models will undoubtedly
facilitate our ability to discover other dietary factors or
synthetic compounds that would be effective at preventing
cancer as well as the specific stage(s) of carcinogenesis at which
they become effective. Almost every model discussed may
seem imperfect in one sense or another, however, each model
has contributed significantly to our current knowledge of
chemoprevention. Furthermore, cross-breeding to obtain
double or triple knockout mice may also greatly help in
elucidating the mechanism of chemoprevention by dietary agents
in the future. The primary objective for the use of animal
models is to ultimately understand the causal relationship
between human exposure to dietary phytochemicals and
reduced cancer risk. Although many studies have shown the
protective effects of these phytochemicals in human clinical
trials, not many of these agents have received FDA approval.
Some of the main challenges are that while the beneficial
effects of these agents are very well studied, the possible
adverse side-effects of these compounds are lagging behind,
although their elucidation is being pursued at a rapid pace.
These adverse side-effects may in part be due to the ability
of these agents to cause various drug to drug interactions
due to unwarranted inhibition or activation of various drug
metabolizing enzymes other than the detoxifying enzymes.
Successful prediction of the consequences of human
consumption of these phytochemicals will be possible only
after appropriate doses are designed and the safety issues are
taken care of.
Conclusion
The modulation of cellular signal transduction pathways
by naturally occurring phytochemicals has recently been
extended to elucidate the molecular basis of cancer
chemopre-vention with dietary factors. Dietary chemopreventive agents
derived from the human dietary fruits, vegetables and tea
and coffee beverages have gained much attention recently, in
lieu of the fact that cancer incidence remains high throughout
the world as well as in China
(http://english.people.com.cn/200705/21/eng20070521_376395.html
) and the concept of cancer intervention by means of dietary phytochemicals needs
to be more widely accepted. Because of the rapid progress
in our understanding of the genetic and epigenetic
mechanisms of carcinogenesis at the signal transduction level,
additional molecular targets have been and will be identified
for the potential intervention at the initiation, promotion and
progression steps of carcinogenesis and cancer development.
So far, these include transcription factors such as Nrf2,
NF-κB, AP-1, and MAPKs. The signaling pathways mediated
by these transcription factors in response to
pro-inflammatory cytokines, growth factors, xenobiotics, oxidative stress
and tumor promoters can regulate a wide array of genes
involved in many cellular events such as cell cycle control,
differentiation, transformation, apoptosis and tumorigenesis.
Because of their potential role in preventing cancer
development, the mechanisms by which phytochemicals
regulate signaling pathways have been extensively studied.
Dietary chemopreventive agents activate Nrf2-mediated gene
expression either by directly modifying the cysteine
residues on Keap1 to disrupt the Nrf2-Keap1 complex or by
activating kinase signaling pathways such as MAPKs,
protein kinase C (PKC), and PI3K to phosphorylate Nrf2/Keap1
complex and/or facilitate the release of Nrf2 or to increase
the nuclear translocation of Nrf2 and regulate the
transcriptional activity of Nrf2 nuclear co-activators. While many
chemopreventive agents directly act on the Nrf2/ARE
signaling pathway to induce detoxification and antioxidant
enzyme systems, which may block tumor initiation in normal
cells, the same compounds and/or others may exert
anti-promotion or anti-progression effects by modulating the
NF-κB and AP-1 signaling pathways in abnormal pre-initiated
cancer cells[103]. Cellular signaling cascades mediated by
NF-κB and AP-1 generally act as key regulators of many of
the aforementioned biochemical processes. Results from both
in vitro and in vivo studies suggest that phytochemicals can
inhibit the activation of NF-κB and/or AP-1 in a cell- or
tissue-specific manner. Although experimental data from cell
culture models provide valuable information regarding the
molecular and cellular mechanisms involved in the modulation
of Nrf2, NF-κB and AP-1 signaling pathways, the precise
chemical mechanisms and the signal transduction cascades
between the interplay of phytochemicals and transcription
factors are still not fully understood. For instance, although
NF-κB and AP-1 may be considered as prime molecular
targets for chemoprevention by dietary phytochemicals, cell
type- and stimuli-dependency between these two
transcription factors often makes it complicated to deduce a unique
mechanism for the chemopreventive activity of
phyto-chemicals. While chemoprevention studies using animal
models certainly provide promising results for the
chemopreventive agents discussed in this review article,
future confirmatory human clinical trials coupled with
epidemiological data would be needed to support their eventual
chemopreventive potentials. The modulation of the above
signaling pathways, transcription factors and genes
expression by cancer chemopreventive phytochemicals would
provide potential opportunities for future design of
chemopreventive agents based on molecular targeting.
Acknowledgments
The authors are grateful to all members of Dr Ah-Ng
Tony Kong's laboratory as well as researchers in the
scientific community whose works have been cited here. The
authors also regret the inability to include many other
excellent relevant citations in the interests of comprehensive
abridgement.
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