Int. J.
Cancer: 121, 2357–2363 (2007)
' 2007 Wiley-Liss, Inc.
Targeting NOX, INOS and COX-2 in inflammatory cells:
Chemoprevention using food phytochemicals
Akira Murakami* and Hajime Ohigashi
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
Biological, biochemical and physical stimuli activate inflammatory
leukocytes, such as macrophages, resulting in induction and syn-
thesis of proinflammatory proteins and enzymes, together with
free radicals, as innate immune responses. On the other hand,
chronic and dysregulated activation of some inducible enzymes,
including NADPH oxidase (NOX), inducible nitric oxide synthase
(iNOS) and cyclooxygenase (COX)-2, have been shown to play piv-
otal roles in the development of certain inflammatory diseases
such as oncogenesis. While the use of synthetic agents, especially
those targeting molecules, is an attractive and reasonable
approach to prevent carcinogenesis, it should be noted that tradi-
tional herbs and spices also exist along with their active constitu-
ents, which have been demonstrated to disrupt inflammatory sig-
nal transduction pathways. In this mini-review, the molecular
mechanisms of activation or induction of NOX, iNOS and COX-2,
as well as some food phytochemicals with marked potential to reg-
ulate those key inflammatory molecules, are highlighted. For
example, 10 -acetoxychavicol acetate, which occurs in the rhizomes
of the subtropical Zingiberaceae plant, has been shown to attenu-
ate NOX-derived superoxide generation in macrophages, as well
as lipopolysaccharide-induced nitric oxide and prostaglandin E2
production through the suppression of iNOS and COX-2 synthesis,
respectively. Notably, this phytochemical has exhibited a wide
range of cancer prevention activities in several rodent models of
inflammation-associated carcinogenesis. Herein, the cancer pre-
ventive potentials of several food phytochemicals targeting the
induction of NOX, iNOS and COX-2 are described.
' 2007 Wiley-Liss, Inc.
Key words: NOX; iNOS; COX-2; curcumin; resveratrol; acetoxy-
chavicol acetate; zerumbone; chemoprevention; NFjB
Inflammation is a pathophysiological phenomenon known to be
involved in numerous diseases, while it is notable that a consider-
able proportion of chronic inflammatory diseases overlap with the
onset and development of cancer. For example, mechanistic con-
nections between ulcerative colitis/Crohn’s disease and colorectal
cancer, reflux esophagitis/Barrett’s esophagus and esophageal car-
cinoma and hepatitis and hepatocellular carcinoma have been
reported.1 In the process of nonpathologic inflammation, e.g.,
wound healing, platelets are known to release several mediators
that tightly regulate vascular permeability and recruit fibrinogen,
leading to the formation of fibrin clots. These activities also
induce and produce chemotactic factors, including platelet-derived
growth factor, transforming growth factor-b, and interleukin-1b,
which lead to the activation of stromal cells that are responsible
for the release of a cocktail of proteases, such as the matrix metal-
loproteinase (MMP) superfamily that can virtually degrade the
extracellular matrix. Concurrently, neutrophils and monocytes are
maturated and recruited, then infiltrate inflamed tissue as part of
the innate immune machinery, and are well known as biological
sources of reactive oxygen species (ROS), prostaglandins (PGs),
inflammatory cytokines, and chemokines, as well as others. ROS,
which include free radicals, are chemically unstable molecules
able to modify, denature and decompose biological components
such as lipid membranes, proteins, and DNA. Further, PGE2 has
been demonstrated to induce angiogenesis and plays a notable role
in the growth of fibroblasts, as well as endothelial and epithelial
cells. On the other hand, cytokines and chemokines are systemati-
cally activated and released into neighboring tissues in a coordi-
nated manner, after which they circulate in the bloodstream for
further activation of the immune system. All of these biological
Publication of the International Union Against Cancer
phenomena progress in a concerted fashion toward re-epitheliali-
zation and healing resolution.
In pathogenic conditions, most of the above mentioned proc-
esses are shared, though they are sustained and exaggerated in a
dysregulated manner. Further, genetic alterations are frequently
associated in cases of chronic and pathogenic inflammation. It has
also been well documented that infection with microorganisms is
closely related to inflammation-derived carcinogenesis.2 Thus, the
use of synthetic drugs or natural compounds able to suppress
inflammatory processes is considered to be a reasonable approach
to prevent inflammation-associated carcinogenesis.3 In fact, non-
steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, have
received considerable attention for their ability to not only miti-
gate inflammatory responses, but also potentially prevent cancer
incidence in humans, based on the results of several independent
epidemiologic surveys that demonstrated a negative association of
NSAID use with the occurrence of many types of cancer.4 On the
other hand, traditional remedies with natural compounds derived
from herbs, spices, medicinal plants, and others have also been
noted as reliable, particularly in their local regions. Those are typi-
cally low-priced and readily available, however, their modes of
actions are widely ambiguous. Thus, both anti-inflammatory drugs
and natural compounds are considered to have marked potentials
for clinical cancer prevention trials.
NADPH oxidase
Following stimulation from proinflammatory stimuli, activated
leukocytes generate superoxide anion (O2 2 ) from NADPH oxidase
(NOX). A representative biological phenomenon regarding O2 2
generation through NOX is the respiratory burst of neutrophils
and macrophages. NOX comprises a catalytic subunit, gp91phox,
and regulatory proteins, including small GTPase RAC1/2,
p22phox, p47phox, p40phox and p67phox. RAC is associated in a
constitutive manner with the cellular membrane, as are gp91phox
and p22phox, which are collectively termed flavocytochrome
b558, while others are located in the cytoplasm in a resting state.
Among those partner proteins, phosphorylation of p47phox has
been recognized as a critical step for stimuli-induced activation
and assembly of this oxidase, as well as several kinases, including
protein kinase C (PKC) isoforms (bII, d, f), but not a or bI,5
Abbreviations: ACA, 10 -acetoxychavicol acetate; ARE, AU-rich ele-
ment; BITC, benzyl isothiocyanate; COX, cyclooxygenase; eNOS, endothe-
lial NOS; ERK, extracellular signal-regulated kinase; iNOS, inducible NOS;
JNK, c-Jun NH2-terminal kinase; LPS, lipopolysaccharide; MAPK, mito-
gen-activated protein kinase; MAPKAPK2, MAPK-activated protein kinase
2; MMP, matrix metalloproteinase; nNOS, neuronal NOS; NO, nitric oxide;
NOS, nitric oxide synthase; NOX, NADPH oxidase; NSAID, non-steroidal
anti-inflammatory drug; ONOO-, peroxynitrite; O2 2 , superoxide anion; PG,
prostaglandin; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C;
ROS, reactive oxygen species; TLR, toll-like receptor.
Grant sponsor: Ministry of Health, Labor and Welfare of Japan.
Hajime Ohigashi’s current address is: Faculty of Biotechnology, Fukui
Prefectural University, Japan.
*Correspondence to: Division of Food Science and Biotechnology,
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Fax: 181-75-753-6282. E-mail: cancer@kais.kyoto-u.ac.jp
Received 28 June 2007; Accepted after revision 27 August 2007
DOI 10.1002/ijc.23161
Published online 24 September 2007 in Wiley InterScience (www.interscience.
wiley.com).
2358 MURAKAMI AND OHIGASHI
FIGURE 1 – Structures of promising food phytochemicals with cancer preventive potential.
though another research group has proposed the involvement of
PKCa and bII.6 In addition, activation of extracellular signal-
regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase
(MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt, but not
that of c-Jun NH2-terminal kinase (JNK)1/2,7 has been shown to
be involved in NOX activation.7
In some pathological conditions, NOX and related enzymes are
over-expressed. For example, a significant upregulation of
gp91phox in the livers and kidneys, but not xanthine oxidase, was
noted in a rat model of chronic renal failure.8 In addition, experi-
ments with gp91phox-knockout mice have shown that they were
less susceptible to renal artery clipping-induced hypertension and
also indicated that the formation of O2 2 by NOX containing endo-
thelial gp91phox accounts for reduced NO bioavailability, which
may lead to the development of renovascular hypertension and en-
dothelial dysfunction.9,10 However, it is also important to note that
a deficiency in genes coding the NOX units severely affects the
innate immune functions of phagocytes and, as a result, becomes
part of the etiology of chronic granulomatous disease.11
Several phytochemicals have been reported to suppress NOX
activation and resultant O2 2 generation. Genistein (Fig. 1), an iso-
flavone present in soybeans and possibly one of the earliest phyto-
chemicals studied, attenuated phorbol ester-induced O2 2 genera-
tion in differentiated HL-60 cells.12 On the basis of structure-
activity relationship studies, the presence of a 40 -hydroxy group was
suggested as an important moiety, though its purpose and action
mechanism are unclear. Thereafter in 1996, using the same experi-
mental system, we reported that 10 -acetoxychavicol acetate (ACA,
Fig. 1), a phenylpropanoid found in the essential oils of Alipinia
galanga (Zingiberaceae), was a more potent suppressor of O2 2
generation.13 Also, Wei et al. reported that double applications of
14
phorbol ester to mouse skin led to excessive ROS production. Ji
and Marnett15 designated these 2 application stages as ‘‘priming’’
(the first stage, illustrated by leukocyte recruitment, maturation,
and infiltration of inflammatory leukocytes into inflamed lesions)
and ‘‘activation’’ (the second stage, illustrated by ROS production
from accumulated leukocytes). It is important to note that ACA
was able to specifically block the activation stage of the double
application model in mouse skin.16 In addition, we demonstrated
that auraptene17 and nobiletin,18 both citrus constituents, and zer-
umbone (Fig. 1),19 the major component of Zingiber zerumbet,
have similar properties, which were demonstrated in that mouse
skin model. Further, the components of ginger and mioga ginger
have been reported to have remarkable potentials for suppressing
20
O22 generation in leukocytes.
It is also notable that phorbol ester-induced O2
2 generation plays
a major role not only in the tumor promotion stage, but also the
initiation stage, as demonstrated in some in vitro studies.21,22
Unfortunately, there are few reports regarding the molecular
mechanisms underlying the suppressive effects of food phyto-
chemicals on O2 2 generation. Nakamura et al. suggested that ben-
zyl isothiocyanate (BITC, Fig. 1), a well-known sulfur-containing
compound present in cruciferous plants, attenuated phorbol ester-
induced O2 2 generation in differentiated HL-60 cells, presumably
by disrupting the electron transport system of flavocytochrome
b558, whereas it did not have an effect on PKC b translocation
into the cellular membrane.23 BITC was also shown to suppress
infiltrated leukocyte-induced oxidative stress in mouse skin.24
Thus, food phytochemicals in combination with natural or syn-
thetic compounds may be able to scavenge O2 2 more efficiently to
exert antioxidative activity, which is supported by our recent
results.24
Inducible nitric oxide synthase
Nitric oxide synthase (NOS) is an enzyme that catalyzes the
conversion of L-arginine into L-citrulline with stoichiometric for-
mation of nitric oxide (NO), a gaseous radical. NOS is classified
into subfamilies according to the location of expression in the
body and manner of expression, namely, constitutive or inducible.
Constitutive NOS is detected in neuronal tissues (nNOS) and vas-
cular endothelial cells (eNOS), whereas inducible NOS (iNOS) is
expressed in a variety of cell types under both normal and patho-
logical conditions, including macrophages, microglial cells, kera-
tinocytes, hepatocytes, astrocytes and vascular endothelial and
epithelial cells. With infectious and proinflammatory stimuli,
iNOS protein is highly induced to produce NO in a micromolar
range, whereas NO generation from nNOS and eNOS enzymes is
constant and within the nanomolar range.
Various NOS forms have essential roles in the maintenance of
homeostasis, e.g., regulating blood vessel tone (eNOS), and pro-
viding neurotransmitter and neuromodulator (nNOS) functions in
nonadrenergic and noncholinergic nerve endings. On the other
hand, numerous reports have implicated that sustained and/or
excess NO generation, most of which is attributable to iNOS
expression, often occurs in pathogenic conditions. In particular,
iNOS has drawn considerable attention for its critical functions in
inflammation-related diseases.25–28 However, the processes by
which NO generation leads to disease onset remain to be fully elu-
cidated. Nonetheless, it is essential to point out that NO couples
 CHEMOPREVENTION USING FOOD PHYTOCHEMICALS
2 0
with O2
2 to form peroxynitrite (ONOO ) in a diffusion-dependent
manner that is extremely reactive, as compared with NO or O2 2 which has some critical roles in the stability of its mRNA.56 Sev-
alone, while NO has also been shown to have a chemical potential
29
to cause DNA damage by nitration, nitrosation and oxidation.
It is important to note that NO and hypoxia confer tolerance to
tumor cells toward glucose starvation in a 50 -AMP-activated pro-
tein kinase-dependent manner.30 NO is also reported to induce
MMP and vascular endothelial growth factor, which in turn acti-
vate tumor cell invasion and metastasis.31,32 Along a similar line,
Okada et al. presented an interesting finding that NO was involved
in the acquisition of metastatic properties of benign tumors in a
model of inflammation-based tumor progression.33 Intriguingly,
Sawa et al. also demonstrated that nitrosative stress-derived 8-
nitroguanosine is highly redox-active, which results in the genera-
tion of O2 2 from various NADPH-dependent reductases, including
cytochrome P450 reductase and all isoforms of NOS.34
A great number of phytochemicals have been shown to suppress
iNOS induction. The first report may have been by Brouet and
Ohshima, who showed that curcumin (Fig. 1) suppresses lipopoly-
saccharide (LPS)-induced iNOS expression in macrophages.35
That was supported by findings indicating that the most down-
stream target of this compound may be NFjB, a master regulator
for inducing numerous inflammatory and oncogenes.36,37 Indeed,
oral administration of this compound at a dose of 92 ng/g of body
weight attenuated LPS-induced iNOS mRNA expression in sub-
ject livers.38 However, the upstream target of curcumin remains to
be identified. In addition, Camacho-Barquero et al. reported that
disruption of the p38 MAPK pathway, but not of JNK, was associ-
ated with the ameliorative effects of curcumin in chronic experi-
mental colitis in rats.39
Tsai et al. found that resveratrol (Fig. 1), a grape phytoalexin,
suppressed LPS-induced iNOS mRNA expression in macro-
phages,40 which was followed by several other investigations.41,42
Lin et al. also published a pioneering work that showed that cer-
tain food phytochemicals, such as EGCG (Fig. 1), have a pro-
nounced ability to suppress iNOS expression.43 Thereafter, a num-
ber of reports supported those findings,44–46 including those that
showed their in vivo and ex vivo efficacy.47,48 In addition, a recent
study noted that induction of endothelium-dependent vasodilation
was an intriguing property of EGCG, which was implied to be pri-
marily based on rapid activation of eNOS by a phosphatidylinosi-
tol 3-kinase-, PKA- and Akt-dependent increase in eNOS activ-
ity.49 Allyl ITC and BITC have also been indicated as a notable
for iNOS suppression in macrophages.50,51 Further, genistein is
believed to exert iNOS suppressive profiles via inhibition of tyro-
sine kinase,52 while zerumbone has shown potent suppressive
activities toward iNOS expression in macrophages.53
Cyclooxygenase-2
Cyclooxygenase (PGH2 synthase, COX) donates 2 oxygen mol-
ecules to arachidonic acid to form PGG2 by peroxidation, which
in turn is reduced to PGH2. This leads to the formation of PEG2, a
bioactive prostanoid, via concerted activation of PGE synthase
(PGES). COX is the molecular target for analgesic and antiinflam-
matory remedies that have been used for hundreds of years. It is
well known that the COX enzyme consists of at least 2 isoforms,
COX-1 and COX-2, the latter of which has been cloned as a v-src-
inducible gene.54 In humans, the expression of COX-1 is constitu-
tive in many normal tissues at relatively stable levels and believed
to have some housekeeping functions, such as production of PG
precursors for thromboxane in platelets,55 which is vital for the
regulation of blood flow. In contrast to COX-1, COX-2 protein is
only slightly expressed in most normal mammalian tissues in
response to physical, chemical and biological stimuli, including
UV light exposure, dioxin and LPS insult.
COX-2 mRNA expression is regulated during at least 3 distin-
guishable stages in a complex manner. The earliest occurring
induction mechanism is related to the finding that COX-2 mRNA
2359
contains an AU-rich element (ARE) in its 3 -untranslated region,
eral reports of different cell types have shown that activation of
p38 MAPK leads to the stabilization of COX-2 mRNA. Next, a
substrate for p38 MAPK, i.e., MAPK-activated protein kinase 2
(MAPKAPK-2), induces phosphorylation of certain candidate pro-
teins, such as HSP27,57 heterogeneous nuclear ribonucleoprotein
A0,58 and Hu antigen R,59 which bind to AREs, thereby contribut-
ing to a rapid synthesis of COX-2 protein. In macrophages, LPS-
triggered induction and activation of signal transduction pathways
lead to transcriptional activation of the COX-2 gene.
Members of the toll-like receptor (TLR) family, particularly
TLR4, are now recognized as central receptors for LPS.60 TLR4
has several associated proteins, such as MD2 and Myd88, which
are required for full activation, after which it stimulates various
protein kinases, including PI3K and phosphoinositide-dependent
kinase (PDK). The phosphorylated protein kinase B (Akt) in turn
activates IkappaB (IjB) kinase (IKK), which is composed of a, b
and g subunits, and phosphorylates IjB protein,61 leading to its
degradation. Since IjB is a suppressive protein that binds to the
NFjB transcription factor in a normal state, LPS-induced IjB
degradation results in activation of this particular transcription
factor for COX-2 mRNA induction. It is also essential to under-
stand that NFjB-targeted genes include the IjB gene, and this
negative feedback mechanism causes NFjB-induced COX-2
expression to be both intermediate and transient.
For full induction of COX-2, which is recognized as the third
stage, at least in macrophages, several NFjB-targeted genes play
major roles.62 Two of these genes are CCAAT enhancer-binding
protein beta (C/EBPb) and delta (C/EBPd), which form b/b
homodimer and b/d heterodimer, both of which have crucial parts
in late and continuous COX-2 expression.62 In parallel, LPS insult
of macrophages leads to activation of the protein kinase A (PKA)
pathway, in which PKA targets cAMP-responsive element-bind-
ing protein (CREB), another major transcription factor for the
COX-2 gene.63 It is also interesting to note that COX-2-generated
PGE2 binds to its receptors (EP1-EP4)64 for activation of adenylyl
cyclase and thereby increases the level of intracellular cAMP. As
mentioned above, this leads to activation of PKA and, thus, CREB
transcriptional activity. Collectively, these form a positive feed-
back loop in PKA-mediated COX-2 expression.
Resveratrol is a well-known compound that regulates both
COX-1 and COX-2.65 This agent has been shown to have a
marked potential for suppressing several stimuli (phorbol ester,
LPS, H2O2, okadaic acid, ceramide, etc.) that induce NFjB activa-
tion, which leads, at least in part, to COX-2 expression.66 Subbara-
maiah et al. reported that overexpression of protein kinase C-a,
ERK1, and c-jun led to a significant increase in COX-2 promoter
activity, while resveratrol inhibited those molecules.67 Recently, a
unique characteristic of this compound was revealed by Szewczuk
et al., who found that it inactivates COX-1 via a peroxidase-medi-
ated mechanism with concomitant oxidation of resveratrol.68 On
the other hand, resveratrol induced nuclear localization of COX-2
with co-localization of Ser15-phosphorylated p53, which, in turn,
triggered apoptosis in human breast cancer cells.69 There is a lim-
ited number of reports regarding the in vivo efficacy of resveratrol
to suppress COX-2, though Kundu et al. showed that it attenuates
phorbol ester-induced COX-2 expression as well as NFjB activa-
tion in mouse skin.70
The suppressive efficacy of curcumin for COX-2 expression has
also attracted the attention of a large number of researchers. One
of the first groups to report a marked ability of curcumin to sup-
press COX-2 expression is Dannenberg and coworkers, who found
that it decreased chenodeoxycholate- and phorbol ester-mediated
induction of COX-2 in several gastrointestinal cell lines.71 Their
findings were later supported by other similar studies of colon can-
cer cells,72 leukocytes from healthy volunteers,73 Kupffer cells,74
non-small cell lung carcinoma cells,75 microglial cells76 and mac-
rophages.77 Of note, topical application of curcumin attenuated
2360 MURAKAMI AND OHIGASHI

TABLE I – SUMMARY OF CANCER PREVENTIVE ACTIVITIES OF FOOD PHYTOCHEMICALS IN RODENT MODELS

Compounds Organs (ref.) Proposed target molecules1 (ref.) Cancer prevention clinical trials (ref.)

Curcumin Skin (81), tongue (82), esophagus (83), NOX (89), iNOS (36), COX-2 (72) Phase I (90)
stomach (84), small intestine (85), colon (86),
liver (87), mammary gland (88)
Resveratrol Skin (66), esophagus (91), small intestine (92), NOX (89), iNOS (41), COX-2 (66) No data
colon (93), mammary gland (94)
EGCG Skin (95), stomach (96), small intestine (97), iNOS (44), COX-2 (47) Successful in pilot study of
colon (98) prostate cancer prevention (99)2,
Phase IIa (100)2
BITC Skin (24), small intestine (101), lung (102) NOX (24), iNOS (51), COX-2 (103) No data
Genistein Skin (104), stomach (105), mammary gland NOX (13), iNOS (53), COX-2 (108) Phase I (109, 110)
(106), prostate (107)
ACA Skin (14), tongue (111), esophagus (112), NOX (14), iNOS (80), COX-2 (80) No data
colon (113), liver (114)
Zerumbone Skin (20), colon (80) NOX (54), iNOS (80), COX-2 (80) No data
1 2
Selected from NOX, iNOS and COX-2. Green tea polyphenol mixture.

TABLE II – BIOAVAILABILITY AND METABOLISM OF SELECTED PHYTOCHEMICALS

Phytochemical Typical findings (ref.)

Curcumin Scarcely absorbed, yet detected in colorectal tissues of cancer patient (reviewed in Ref. 115)
Resveratrol Intact structure and its glucuronides detected in sera from healthy human subjects who consumed red wine (116)
EGCG Subjected to intensive metabolism factors, such as glucuronidation, sulfation, methylation and ring fission,
with maximum serum concentration of
1 lM (117)
BITC N-acetyl-S-(N-benzylthiocarbamoyl)-L-cysteine detected in human urinary samples (118)
Genistein May produce equol, an estrogen-like polyphenol (reviewed in Ref. 119)
ACA Unknown
Zerumbone Unknown

phorbol ester-induced COX-2 protein expression in mouse skin,78 CONCLUSION

whereas contrasting findings showed that it increased COX-2
expression when given without a COX-2-inducer.77
In addition, we showed that zerumbone attenuates COX-2
expression in macrophages,53 mouse skin following topical appli-
cation,19 and colonic mucosa in rodents with oral feeding, accom-
panied by decreased PGE2 formation and COX-2 repression.79
The molecular mechanism by which zerumbone suppresses COX-
2 protein expression is suggested to be unique.80 Further, that
report showed that even though abrogation of LPS-induced COX-
2 mRNA expression occurred, zerumbone did not demonstrate
any suppression of the transcriptional activation of NFjB, AP-1
and CREB. These findings raise the possibility that zerumbone
suppresses COX-2 mRNA expression via a posttranscriptional
mechanism. In fact, zerumbone accelerated the spontaneous deg-
radation of COX-2 mRNA in that study, whereas it was virtually
inactive for suppressing p38 MAPK activation.
The food phytochemicals highlighted in this article have been
shown to have notable cancer preventive effects in various rodent
carcinogenesis models (Table I). In addition, as mentioned above,
they are able to suppress NOX, iNOS and COX-2 through multi-
ple molecular mechanisms. However, it remains to be determined
in most cases if the suppression of such proinflammatory mole-
cules by these compounds is the only factor that accounts for their
chemopreventive activities in experimental animals. For example,
it is interesting to consider the selective COX-2 inhibitor cele-
coxib, which seems to occasionally exhibit cancer preventive ac-
tivity in a COX-2-independent manner.115 However, issues related
to the metabolism and bioavailability of these phytochemicals
have not been fully addressed (Table II). Multifaceted approaches
for determining the modes of chemopreventive actions will be in-
dispensable and important to elucidate cancer preventive agents
with reasonable modes of action and low levels of toxicity.

References
1. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:
860–7.
2. Peto J. Cancer epidemiology in the last century and the next decade.
Nature 2001;411:390–5.
3. Kundu JK, Surh YJ. Breaking the relay in deregulated cellular signal
transduction as a rationale for chemoprevention with anti-inflamma-
tory phytochemicals. Mutat Res 2005;591:123–46.
4. Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW. As-
pirin use and risk of fatal cancer. Cancer Res 1993;53:1322–7.
5. Sergeant S, McPhail LC. Opsonized zymosan stimulates the redistribu-
tion of protein kinase C isoforms in human neutrophils. J Immunol
1997;159:2877–85.
6. Nixon JB, McPhail LC. Protein kinase C (PKC) isoforms translocate
to Triton-insoluble fractions in stimulated human neutrophils: correla-
tion of conventional PKC with activation of NADPH oxidase.
J Immunol 1999;163:4574–82.
7. El Benna J, Han J, Park JW, Schmid E, Ulevitch RJ, Babior BM. Acti-
vation of p38 in stimulated human neutrophils: phosphorylation of the
oxidase component p47phox by p38 and ERK but not by JNK. Arch
Biochem Biophys 1996;334:395–400.
8. Vaziri ND, Lin CY, Farmand F, Sindhu RK. Oxidative stress and dys-
regulation of superoxide dismutase and NADPH oxidase in renal
insufficiency. Kidney Int 2003;63:179–94.
9. Hamilton CA, Brosnan MJ, Al-Benna S, Berg G, Dominiczak AF.
NAD(P)H oxidase inhibition improves endothelial function in rat and
human blood vessels. Hypertension 2002;40:755–62.
10. Jung O, Schreiber JG, Geiger H, Pedrazzini T, Busse R, Brandes RP.
gp91phox-containing NADPH oxidase mediates endothelial dysfunc-
tion in renovascular hypertension. Circulation 2004;109:1795–1801.
11. Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous dis-
ease. Curr Opin Immunol 2003;15:578–84.
12. Wei H, Bowen R, Cai Q, Barnes S, Wang Y. Antioxidant and antipro-
motional effects of the soybean isoflavone genistein. Proc Soc Exp
Biol Med 1995;208:124–30.
13. Murakami A, Ohura S, Nakamura Y, Koshimizu K, Ohigashi H. 10 -
Acetoxychavicol acetate, a superoxide anion generation inhibitor,
 CHEMOPREVENTION USING FOOD PHYTOCHEMICALS
potently inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-
acetate in ICR mouse skin. Oncology 1996;53:386–91.
14. Wei H, Wei L, Frenkel K, Bowen R, Barnes S. Inhibition of tumor
promoter-induced hydrogen peroxide formation in vitro and in vivo
by genistein. Nutr Cancer 1993;20:1–12.
15. Ji C, Marnett LJ. Oxygen radical-dependent epoxydation of (7S,8S)-
dihydroxy-7,8-dihydrobenzo[a]pyrene in mouse skin in vivo. Stimula-
tion by phorbol esters and inhibition by antiinflammatory steroids.
J Biol Chem 1992;267:17842–78.
16. Nakamura Y, Murakami A, Ohto Y, Torikai K, Tanaka T, Ohigashi
H. Suppression of tumor promoter-induced oxidative stress and
inflammatory responses in mouse skin by a superoxide generation in-
hibitor 10 -acetoxychavicol acetate. Cancer Res 1998;58:4832–9.
17. Murakami A, Nakamura Y, Tanaka T, Kawabata K, Takahashi D,
Koshimizu K, Ohigashi H. Suppression by citrus auraptene of phorbol
ester-and endotoxin-induced inflammatory responses: role of attenua-
tion of leukocyte activation. Carcinogenesis 2000;21:1843–50.
18. Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba T, Koshi-
mizu K, Kuwahara S, Takahashi Y, Ogawa K, Yano M, Tokuda H,
Nishino H, et al. Inhibitory effect of citrus nobiletin on phorbol ester-
induced skin inflammation, oxidative stress, and tumor promotion in
mice. Cancer Res 2000;60:5059–66.
19. Murakami A, Tanaka T, Lee JY, Surh YJ, Kim HW, Kawabata K,
Nakamura Y, Jiwajinda S, Ohigashi H. Zerumbone, a sesquiterpene in
subtropical ginger, suppresses skin tumor initiation and promotion
stages in ICR mice. Int J Cancer 2004;110:481–90.
20. Kim HW, Murakami A, Abe M, Ozawa Y, Morimitsu Y, Williams
MV, Ohigashi H. Suppressive effects of mioga ginger and ginger con-
stituents on reactive oxygen and nitrogen species generation, and the
expression of inducible pro-inflammatory genes in macrophages.
Antioxid Redox Signal 2005;7:1621–9.
21. Trush MA, Seed JL, Kensler TW. Oxidant-dependent metabolic acti-
vation of polycyclic aromatic hydrocarbons by phorbol ester-stimu-
lated human polymorphonuclear leukocytes: possible link between
inflammation and cancer. Proc Natl Acad Sci USA 1985;82:5194–8.
22. Kim HW, Murakami A, Williams MV, Ohigashi H. Mutagenicity of
reactive oxygen and nitrogen species as detected by co-culture of acti-
vated inflammatory leukocytes and AS52 cells. Carcinogenesis
2003;24:235–41.
23. Miyoshi N, Takabayashi S, Osawa T, Nakamura Y. Benzyl isothiocy-
anate inhibits excessive superoxide generation in inflammatory leuko-
cytes: implication for prevention against inflammation-related carci-
nogenesis. Carcinogenesis 2004;25:567–75.
24. Murakami A, Takahashi D, Koshimizu K, Ohigashi H. Synergistic
suppression of superoxide and nitric oxide generation from inflamma-
tory cells by combined food factors. Mutat Res 2003;523/524:151–61.
25. Cedergren J, Forslund T, Sundqvist T, Skogh T. Inducible nitric oxide
synthase is expressed in synovial fluid granulocytes. Clin Exp Immu-
nol 2002;130:150–5.
26. Donnelly LE, Barnes PJ. Expression and regulation of inducible nitric
oxide synthase from human primary airway epithelial cells. Am J
Respir Cell Mol Biol 2002;26:144–51.
27. Hao XP, Pretlow TG, Rao JS, Pretlow TP. Inducible nitric oxide
synthase (iNOS) is expressed similarly in multiple aberrant crypt foci
and colorectal tumors from the same patients. Cancer Res 2001;61:
419–22.
28. Cross RK, Wilson KT. Nitric oxide in inflammatory bowel disease.
Inflamm Bowel Dis 2003;9:179–89.
29. Szabo C, Ohshima H. DNA damage induced by peroxynitrite: subse-
quent biological effects. Nitric Oxide 1997;1:373–85.
30. Esumi H, Izuishi K, Kato K, Hashimoto K, Kurashima Y, Kishimoto
A, Ogura T, Ozawa T. Hypoxia and nitric oxide treatment confer tol-
erance to glucose starvation in a 50 -AMP-activated protein kinase-
dependent manner. J Biol Chem 2002;277:32791–8.
31. Ishii Y, Ogura T, Tatemichi M, Fujisawa H, Otsuka F, Esumi H.
Induction of matrix metalloproteinase gene transcription by nitric ox-
ide and mechanisms of MMP-1 gene induction in human melanoma
cell lines. Int J Cancer 2003;103:161–168.
32. Kimura H, Ogura T, Kurashima Y, Weisz A, Esumi H. Effects of ni-
tric oxide donors on vascular endothelial growth factor gene induc-
tion. Biochem Biophys Res Commun 2002;296:976–82.
33. Okada F, Tazawa H, Kobayashi T, Kobayashi M, Hosokawa M.
Involvement of reactive nitrogen oxides for acquisition of metastatic
properties of benign tumors in a model of inflammation-based tumor
progression. Nitric Oxide 2006;14:122–9.
34. Sawa T, Akaike T, Ichimori K, Akuta T, Kaneko K, Nakayama H,
Stuehr DJ, Maeda H. Superoxide generation mediated by 8-nitrogua-
nosine, a highly redox-active nucleic acid derivative. Biochem Bio-
phys Res Commun 2003;311:300–6.
35. Brouet I, Ohshima H. Curcumin, an anti-tumour promoter and anti-
inflammatory agent, inhibits induction of nitric oxide synthase in acti-
vated macrophages. Biochem Biophys Res Commun 1995;206:533–
540.
2361
36. Pan MH, Lin-Shiau SY, Lin JK. Comparative studies on the suppres-
sion of nitric oxide synthase by curcumin and its hydrogenated
metabolites through down-regulation of IkappaB kinase and NFkap-
paB activation in macrophages. Biochem Pharmacol 2000;60:1665–
76.
37. Jung KK, Lee HS, Cho JY, Shin WC, Rhee MH, Kim TG, Kang JH,
Kim SH, Hong S, Kang SY. Inhibitory effect of curcumin on nitric
oxide production from lipopolysaccharide-activated primary micro-
glia. Life Sci 2006;79:2022–31.
38. Chan MM, Huang HI, Fenton MR, Fong D. In vivo inhibition of nitric
oxide synthase gene expression by curcumin, a cancer preventive nat-
ural product with anti-inflammatory properties. Biochem Pharmacol
1998;55:1955–62.
39. Camacho-Barquero L, Villegas I, Sanchez-Calvo JM, Talero E, San-
chez-Fidalgo S, Motilva V, Alarcon de la Lastra C. Curcumin, a Cur-
cuma longa constituent, acts on MAPK p38 pathway modulating
COX-2 and iNOS expression in chronic experimental colitis. Int
Immunopharmacol 2007;7:333–42.
40. Tsai SH, Lin-Shiau SY Lin JK. Suppression of nitric oxide synthase
and the down-regulation of the activation of NFkappaB in macro-
phages by resveratrol. Br J Pharmacol 1999;126:673–80.
41. Chan MM, Mattiacci JA, Hwang HS, Shah A, Fong D. Synergy
between ethanol and grape polyphenols, quercetin, and resveratrol, in
the inhibition of the inducible nitric oxide synthase pathway. Biochem
Pharmacol 2000;60:1539–48.
42. Matsuda H, Kageura T, Morikawa T, Toguchida I, Harima S, Yoshi-
kawa M. Effects of stilbene constituents from rhubarb on nitric oxide
production in lipopolysaccharide-activated macrophages. Bioorg Med
Chem Lett 2000;10:323–7.
43. Lin YL, Lin JK. (-)-Epigallocatechin-3-gallate blocks the induction of
nitric oxide synthase by down-regulating lipopolysaccharide-induced
activity of transcription factor nuclear factor-kappaB. Mol Pharmacol
1997;52:465–72.
44. Chan MM, Fong D, Ho CT, Huang HI. Inhibition of inducible nitric
oxide synthase gene expression and enzyme activity by epigallocate-
chin gallate, a natural product from green tea. Biochem Pharmacol
1997;54:1281–96.
45. Singh R, Ahmed S, Islam N, Goldberg VM, Haqqi TM. Epigallocate-
chin-3-gallate inhibits interleukin-1beta-induced expression of nitric
oxide synthase and production of nitric oxide in human chondrocytes:
suppression of nuclear factor kappaB activation by degradation of the
inhibitor of nuclear factor kappaB. Arthritis Rheum 2002;46:2079–
86.
46. Ahmed S, Rahman A, Hasnain A, Lalonde M, Goldberg VM, Haqqi
TM. Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1
beta-induced activity and expression of cyclooxygenase-2 and nitric
oxide synthase-2 in human chondrocytes. Free Radic Biol Med
2002;33:1097–105.
47. Suzuki M, Tabuchi M, Ikeda M, Umegaki K, Tomita T. Protective
effects of green tea catechins on cerebral ischemic damage. Med Sci
Monit 2004;10:BR166–BR74.
48. Song EK, Hur H, Han MK. Epigallocatechin gallate prevents autoim-
mune diabetes induced by multiple low doses of streptozotocin in
mice. Arch Pharm Res 2003;26:559–63.
49. Lorenz M, Wessler S, Follmann E, Michaelis W, D€usterh€oft T, Bau-
mann G, Stangl K, Stangl V. A constituent of green tea, epigallocate-
chin-3-gallate, activates endothelial nitric oxide synthase by a phos-
phatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and
Akt-dependent pathway and leads to endothelial-dependent vasorelax-
ation. J Biol Chem 2004;279:6190–5.
50. Ippoushi K, Itou H, Azuma K, Higashio H. Effect of naturally occur-
ring organosulfur compounds on nitric oxide production in lipopoly-
saccharide-activated macrophages. Life Sci 2002;71:411–9.
51. Chen YH, Dai HJ, Chang HP. Suppression of inducible nitric oxide
production by indole and isothiocyanate derivatives from Brassica
plants in stimulated macrophages. Planta Med 2003;69:696–700.
52. Marczin N, Papapetropoulos A, Catravas JD. Tyrosine kinase inhibi-
tors suppress endotoxin- and IL-1 beta-induced NO synthesis in aor-
tic smooth muscle cells. Am J Physiol 1993;265(3, Part 2):H1014–
H8.
53. Murakami A, Takahashi D, Kinoshita T, Koshimizu K, Kim HW,
Yoshihiro A, Nakamura Y, Jiwajinda S, Terao J, Ohigashi H. Zerum-
bone, a Southeast Asian ginger sesquiterpene, markedly suppresses
free radical generation, proinflammatory protein production, and can-
cer cell proliferation accompanied by apoptosis: the alpha,beta-unsat-
urated carbonyl group is a prerequisite. Carcinogenesis 2002;23:795–
802.
54. Simmons DL, Levy DB, Yannoni Y, Erikson RL. Identification of a
phorbol ester-repressible v-src-inducible gene. Proc Natl Acad Sci
USA 1989;86:1178–82.
55. Schafter AI. Effects of nonsteroidal antiinflammatory drugs on plate-
let function and systemic hemostasis. J Clin Pharmacol 1995;35:209–
19.
2362 MURAKAMI AND OHIGASHI
56. Xu K, Robida AM, Murphy TJ. Immediate-early MEK-1-dependent
stabilization of rat smooth muscle cell cyclooxygenase-2 mRNA
by Galpha(q)-coupled receptor signaling. J Biol Chem 2000;275:
23012–9.
57. Lasa M, Mahtani KR, Finch A, Brewer G, Saklatvala J, Clark AR.
Regulation of cyclooxygenase 2 mRNA stability by the mitogen-
activated protein kinase p38 signaling cascade. Mol Cell Biol 2000;
20:4265–74.
58. Rousseau S, Morrice N, Peggie M, Campbell DG, Gaestel M, Cohen
P. Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by
MAPKAP-K2 and its interaction with cytokine mRNAs. EMBO J
2002;21:6505–14.
59. Subbaramaiah K, Marmo TP, Dixon DA, Dannenberg AJ. Regulation
of cyclooxgenase-2 mRNA stability by taxanes: evidence for involve-
ment of p38, MAPKAPK-2, and HuR. J Biol Chem 2003;278:37637–
47.
60. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-
like receptor-4 mediates lipopolysaccharide-induced signal transduc-
tion. J Biol Chem 1999;274:10689–92.
61. Karin M. How NF-kappaB is activated: the role of the IkappaB kinase
(IKK) complex. Oncogene 1999;18:6867–74.
62. Caivano M, Gorgoni B, Cohen P, Poli V. The induction of cyclooxy-
genase-2 mRNA in macrophages is biphasic and requires both
CCAAT enhancer-binding protein beta (C/EBP beta) and C/EBP delta
transcription factors. J Biol Chem 2001;276:48693–701.
63. Caivano M, Cohen P. Role of mitogen-activated protein kinase cas-
cades in mediating lipopolysaccharide-stimulated induction of cyclo-
oxygenase-2 and IL-1 beta in RAW264 macrophages. J Immunol
2000;164:3018–25.
64. Narumiya S. Prostanoids in immunity: roles revealed by mice defi-
cient in their receptors. Life Sci 2003;74:391–5.
65. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW,
Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pez-
zuto JM. Cancer chemopreventive activity of resveratrol, a natural
product derived from grapes. Science 1997;275:218–20.
66. Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses
TNF-induced activation of nuclear transcription factors NF-kappa B,
activator protein-1, and apoptosis: potential role of reactive oxygen
intermediates and lipid peroxidation. J Immunol 2000;164:6509–19.
67. Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T,
Inoue H, Jang M, Pezzuto JM, Dannenberg AJ. Resveratrol inhibits
cyclooxygenase-2 transcription and activity in phorbol ester-treated
human mammary epithelial cells. J Biol Chem 1998;273:21875–82.
68. Szewczuk LM, Forti L, Stivala LA, Penning TM. Resveratrol is a per-
oxidase-mediated inactivator of COX-1 but not COX-2: a mechanistic
approach to the design of COX-1 selective agents. J Biol Chem
2004;279:22727–37.
69. Tang HY, Shih A, Cao HJ, Davis FB, Davis PJ, Lin HY. Resveratrol-
induced cyclooxygenase-2 facilitates p53-dependent apoptosis in
human breast cancer cells. Mol Cancer Ther 2006;5:2034–42.
70. Kundu JK, Shin YK, Kim SH, Surh YJ. Resveratrol inhibits phorbol
ester-induced expression of COX-2 and activation of NF-kappaB in
mouse skin by blocking IkappaB kinase activity. Carcinogenesis
2006;27:1465–74.
71. Zhang F, Altorki NK, Mestre JR, Subbaramaiah K, Dannenberg AJ.
Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and
phorbol ester-treated human gastrointestinal epithelial cells. Carcino-
genesis 1999;20:445–51.
72. Goel A, Boland CR, Chauhan DP. Specific inhibition of cyclooxygen-
ase-2 (COX-2) expression by dietary curcumin in HT-29 human colon
cancer cells. Cancer Lett 2001;172:111–18.
73. Plummer SM, Hill KA, Festing MF, Steward WP, Gescher AJ,
Sharma RA. Clinical development of leukocyte cyclooxygenase 2 ac-
tivity as a systemic biomarker for cancer chemopreventive agents.
Cancer Epidemiol Biomarkers Prev 2001;10:1295–9.
74. Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Thomas P, Dan-
nenberg AJ. Curcumin prevents alcohol-induced liver disease in rats
by inhibiting the expression of NF-kappa B-dependent genes. Am J
Physiol Gastrointest Liver Physiol 2003;284:G321–G7.
75. Shishodia S, Potdar P, Gairola CG, Aggarwal BB. Curcumin (diferu-
loylmethane) down-regulates cigarette smoke-induced NF-kappaB
activation through inhibition of IkappaBalpha kinase in human lung
epithelial cells: correlation with suppression of COX-2, MMP-9 and
cyclin D1. Carcinogenesis 2003;24:1269–79.
76. Kang G, Kong PJ, Yuh YJ, Lim SY, Yim SV, Chun W, Kim SS.
Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2
expression by inhibiting activator protein 1 and nuclear factor kappab
bindings in BV2 microglial cells. J Pharmacol Sci 2004;94:325–328.
77. Hong J, Bose M, Ju J, Ryu JH, Chen X, Sang S, Lee MJ, Yang CS.
Modulation of arachidonic acid metabolism by curcumin and related
{beta}-diketone derivatives: effects on cytosolic phospholipase A2,
cyclooxygenases, and 5-lipoxygenase. Carcinogenesis 2004;25:1671–
179.
78. Chun KS, Keum YS, Han SS, Song YS, Kim SH, Surh YJ. Curcumin
inhibits phorbol ester-induced expression of cyclooxygenase-2 in
mouse skin through suppression of extracellular signal-regulated ki-
nase activity and NF-kappaB activation. Carcinogenesis 2003;24:
1515–24.
79. Tanaka T, Shimizu M, Kohno H, Yoshitani S, Tsukio Y, Murakami
A, Safitri R, Takahashi D, Yamamoto K, Koshimizu K, Ohigashi H,
Mori H. Chemoprevention of azoxymethane-induced rat aberrant
crypt foci by dietary zerumbone isolated from Zingiber zerumbet.
Life Sci 2001;69:1935–45.
80. Murakami A, Shigemori T, Ohigashi H. Zingiberaceous and citrus
constituents, 10 -acetoxychavicol acetate, zerumbone, auraptene, and
nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2
expression in RAW264.7 murine macrophages through different
modes of action. J Nutr 2005;135:2987S–92S.
81. Huang MT, Smart RC, Wong CQ, Conney AH. Inhibitory effect of
curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor
promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate.
Cancer Res 1988;48:5941–6.
82. Tanaka T, Makita H, Ohnishi M, Hirose Y, Wang A, Mori H, Satoh
K, Hara A, Ogawa H. Chemoprevention of 4-nitroquinoline 1-oxide-
induced oral carcinogenesis by dietary curcumin and hesperidin: com-
parison with the protective effect of beta-carotene. Cancer Res
1994;54:4653–9.
83. Ushida J, Sugie S, Kawabata K, Pham QV, Tanaka T, Fujii K, Takeu-
chi H, Ito Y, Mori H. Chemopreventive effect of curcumin on N-nitro-
somethylbenzylamine-induced esophageal carcinogenesis in rats. Jpn
J Cancer Res 2000;91:893–8.
84. Singh SV, Hu X, Srivastava SK, Singh M, Xia H, Orchard JL, Zaren
HA. Mechanism of inhibition of benzo[a]pyrene-induced forestomach
cancer in mice by dietary curcumin. Carcinogenesis 1998;19:1357–
60.
85. Collett GP, Robson CN, Mathers JC, Campbell FC. Curcumin modi-
fies Apc(min) apoptosis resistance and inhibits 2-amino 1-methyl-6-
phenylimidazo[4,5-b]pyridine (PhIP) induced tumour formation in
Apc(min) mice. Carcinogenesis 2001;22:821–5.
86. Rao CV, Rivenson A, Simi B, Reddy BS. Chemoprevention of colon
carcinogenesis by dietary curcumin, a naturally occurring plant phe-
nolic compound. Cancer Res 1995;55:259–66.
87. Chuang SE, Kuo ML, Hsu CH, Chen CR, Lin JK, Lai GM, Hsieh CY,
Cheng AL. Curcumin-containing diet inhibits diethylnitrosamine-
induced murine hepatocarcinogenesis. Carcinogenesis 2000;21:331–5.
88. Singletary K, MacDonald C, Iovinelli M, Fisher C, Wallig M. Effect
of the beta-diketones diferuloylmethane (curcumin) and dibenzoylme-
thane on rat mammary DNA adducts and tumors induced by 7,12-
dimethylbenz[a]anthracene. Carcinogenesis 1998;19:1039–43.
89. Deby-Dupont G, Mouithys-Mickalad A, Serteyn D, Lamy M, Deby C.
Resveratrol and curcumin reduce the respiratory burst of Chlamydia-
primed THP-1 cells. Biochem Biophys Res Commun 2005;333:21–7.
90. Hsu CH, Cheng AL. Clinical studies with curcumin. Adv Exp Med
Biol 2007;595:471–80.
91. Li ZG, Hong T, Shimada Y, Komoto I, Kawabe A, Ding Y, Kaganoi
J, Hashimoto Y, Imamura M. Suppression of N-nitrosomethylbenzyl-
amine (NMBA)-induced esophageal tumorigenesis in F344 rats by
resveratrol. Carcinogenesis 2002;23:1531–6.
92. Schneider Y, Duranton B, Gosse F, Schleiffer R, Seiler N, Raul F.
Resveratrol inhibits intestinal tumorigenesis and modulates host-
defense-related gene expression in an animal model of human familial
adenomatous polyposis. Nutr Cancer 2001;39:102–7.
93. Sengottuvelan M, Viswanathan P, Nalini N. Chemopreventive effect
of trans-resveratrol—a phytoalexin against colonic aberrant crypt foci
and cell proliferation in 1,2-dimethylhydrazine induced colon carcino-
genesis. Carcinogenesis 2006;27:1038–46.
94. Banerjee S, Bueso-Ramos C, Aggarwal BB. Suppression of 7,12-
dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats
by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and
matrix metalloprotease 9. Cancer Res 2002;62:4945–54.
95. Fujiki H, Yoshizawa S, Horiuchi T, Suganuma M, Yatsunami J, Nish-
iwaki S, Okabe S, Nishiwaki-Matsushima R, Okuda T, Sugimura T.
Anticarcinogenic effects of (-)-epigallocatechin gallate. Prev Med
1992;21:503–9.
96. Yamane T, Takahashi T, Kuwata K, Oya K, Inagake M, Kitao Y,
Suganuma M, Fujiki H. Inhibition of N-methyl-N0 -nitro-N-nitrosogua-
nidine-induced carcinogenesis by (-)-epigallocatechin gallate in the
rat glandular stomach. Cancer Res 1995;55:2081–4.
97. Ju J, Hong J, Zhou JN, Pan Z, Bose M, Liao J, Yang GY, Liu YY,
Hou Z, Lin Y, Ma J, Shih WJ, et al. Inhibition of intestinal tumorigen-
esis in Apcmin/1 mice by (-)-epigallocatechin-3-gallate, the major
catechin in green tea. Cancer Res 2005;65:10623–31.
98. Ohishi T, Kishimoto Y, Miura N, Shiota G, Kohri T, Hara Y, Hase-
gawa J, Isemura M. Synergistic effects of (-)-epigallocatechin gallate
with sulindac against colon carcinogenesis of rats treated with azoxy-
methane. Cancer Lett 2002;177:49–56.
 CHEMOPREVENTION USING FOOD PHYTOCHEMICALS
99. Bettuzzi S, Rizzi F, Belloni L. Clinical relevance of the inhibitory
effect of green tea catechins (GtCs) on prostate cancer progression in
combination with molecular profiling of catechin-resistant tumors: an
integrated view. Pol J Vet Sci 2007;10:57–60.
100. Luo H, Tang L, Tang M, Billam M, Huang T, Yu J, Wei Z, Liang Y,
Wang K, Zhang ZQ, Zhang L, Wang JS. Phase IIa chemoprevention
trial of green tea polyphenols in high-risk individuals of liver cancer:
modulation of urinary excretion of green tea polyphenols and 8-
hydroxydeoxyguanosine. Carcinogenesis 2006;27:262–8.
101. Sugie S, Okamoto K, Okumura A, Tanaka T, Mori H. Inhibitory
effects of benzyl thiocyanate and benzyl isothiocyanate on methyla-
zoxymethanol acetate-induced intestinal carcinogenesis in rats. Carci-
nogenesis 1994;15:1555–60.
102. Lin JM, Amin S, Trushin N, Hecht SS. Effects of isothiocyanates on
tumorigenesis by benzo[a]pyrene in murine tumor models. Cancer
Lett 1993;74:151–9.
103. Kuroiwa Y, Nishikawa A, Kitamura Y, Kanki K, Ishii Y, Umemura
T, Hirose M. Protective effects of benzyl isothiocyanate and sulfora-
phane but not resveratrol against initiation of pancreatic carcinogene-
sis in hamsters. Cancer Lett 2006;241:275–80.
104. Wei H, Bowen R, Zhang X, Lebwohl M. Isoflavone genistein inhibits
the initiation and promotion of two-stage skin carcinogenesis in mice.
Carcinogenesis 1998;19:1509–14.
105. Tatsuta M, Iishi H, Baba M, Yano H, Uehara H, Nakaizumi A.
Attenuation by genistein of sodium-chloride-enhanced gastric carci-
nogenesis induced by N-methyl-N0 -nitro-N-nitrosoguanidine in Wistar
rats. Int J Cancer 1999;80:396–9.
106. Lamartiniere CA, Moore JB, Brown NM, Thompson R, Hardin MJ,
Barnes S. Genistein suppresses mammary cancer in rats. Carcinogene-
sis 1995;16:2833–40.
107. Mentor-Marcel R, Lamartiniere CA, Eltoum IE, Greenberg NM,
Elgavish A. Genistein in the diet reduces the incidence of poorly dif-
ferentiated prostatic adenocarcinoma in transgenic mice (TRAMP).
Cancer Res 2001;61:6777–82.
108. Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF, Lin JK. Sup-
pression of inducible cyclooxygenase and inducible nitric oxide
synthase by apigenin and related flavonoids in mouse macrophages.
Carcinogenesis 1999;20:1945–52.
109. Fischer L, Mahoney C, Jeffcoat AR, Koch MA, Thomas BE, Valen-
tine JL, Stinchcombe T, Boan J, Crowell JA, Zeisel SH. Clinical
2363
characteristics and pharmacokinetics of purified soy isoflavones: mul-
tiple-dose administration to men with prostate neoplasia. Nutr Cancer
2004;48:160–70.
110. Takimoto CH, Glover K, Huang X, Hayes SA, Gallot L, Quinn M,
Jovanovic BD, Shapiro A, Hernandez L, Goetz A, Llorens V, Lieber-
man R, et al. Phase I pharmacokinetic and pharmacodynamic analysis
of unconjugated soy isoflavones administered to individuals with can-
cer. Cancer Epidemiol Biomarkers Prev 2003;12:1213–21.
111. Ohnishi M, Tanaka T, Makita H, Kawamori T, Mori H, Satoh K, Hara
A, Murakami A, Ohigashi H, Koshimizu K. Chemopreventive effect
of a xanthine oxidase inhibitor, 10 -acetoxychavicol acetate, on rat oral
carcinogenesis. Jpn J Cancer Res 1996;87:349–56.
112. Kawabata K, Tanaka T, Yamamoto T, Ushida J, Hara A, Murakami
A, Koshimizu K, Ohigashi H, Stoner GD, Mori H. Suppression of N-
nitrosomethylbenzylamine-induced rat esophageal tumorigenesis by
dietary feeding of 10 -acetoxychavicol acetate. Jpn J Cancer Res
2000;91:148–55.
113. Tanaka T, Kawabata K, Kakumoto M, Makita H, Matsunaga K, Mori
H, Satoh K, Hara A, Murakami A, Koshimizu K, Ohigashi H. Chemo-
prevention of azoxymethane-induced rat colon carcinogenesis by a
xanthine oxidase inhibitor, 10 -acetoxychavicol acetate. Jpn J Cancer
Res 1997;88:821–30.
114. Kobayashi Y, Nakae D, Akai H, Kishida H, Okajima E, Kitayama W,
Denda A, Tsujiuchi T, Murakami A, Koshimizu K, Ohigashi H,
Konishi Y. Prevention by 10 -acetoxychavicol acetate of the induction
but not growth of putative preneoplastic, glutathione S-transferase pla-
cental form-positive, focal lesions in the livers of rats fed a choline-
deficient, L-amino acid-defined diet. Carcinogenesis 1998;19:1809–14.
115. Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharma-
codynamics of curcumin. Adv Exp Med Biol 2007;595:453–70.
116. Vitaglione P, Sforza S, Galaverna G, Ghidini C, Caporaso N, Vescovi
PP, Fogliano V, Marchelli R. Bioavailability of trans-resveratrol from
red wine in humans. Mol Nutr Food Res 2005;49:495–504.
117. Lambert JD, Yang CS. Mechanisms of cancer prevention by tea con-
stituents. J Nutr 2003;133:3262S–7S.
118. Mennicke WH, Gorler K, Krumbiegel G, Lorenz D, Rittmann N.
Studies on the metabolism and excretion of benzyl isothiocyanate in
man. Xenobiotica 1988;18:441–7.
119. Nielsen IL, Williamson G. Review of the factors affecting bioavaila-
bility of soy isoflavones in humans. Nutr Cancer 2007;57:1–10.