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REVIEWS




                               CANCER CHEMOPREVENTION WITH
                               DIETARY PHYTOCHEMICALS
                               Young-Joon Surh
                               Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis.
                               Numerous phytochemicals derived from edible plants have been reported to interfere with a
                               specific stage of the carcinogenic process. Many mechanisms have been shown to account
                               for the anticarcinogenic actions of dietary constituents, but attention has recently been
                               focused on intracellular-signalling cascades as common molecular targets for various
                               chemopreventive phytochemicals.

                              Cancer is a growing health problem around the world             A wide array of substances derived from the diet
                              — particularly with the steady rise in life expectancy,      have been found to stimulate the development, growth
                              increasing urbanization and the subsequent changes in        and spread of tumours in experimental animals, and to
                              environmental conditions, including lifestyle. According     transform normal cells into malignant ones. These are
                              to a recent report by the World Health Organization          regarded as suspected human carcinogens.
                              (WHO), there are now more than 10 million cases of              So, many dietary constituents can increase the risk of
                              cancer per year worldwide. In 2003, it is estimated that     developing cancer, but there is also accumulating evi-
                              approximately 1,300,000 new cases of cancer will be          dence from population as well as laboratory studies to
                              diagnosed, and more than 550,000 people will die from        support an inverse relationship between regular con-
                              cancer in the United States alone.                           sumption of fruit and vegetables and the risk of specific
                                  Although there is no ‘magic bullet’ that can com-        cancers. Several organizations — such as the WHO, the
                              pletely conquer cancer, many types of the disease            American Cancer Society, the American Institute of
                              might be avoidable. Cancer risk can be reduced by            Cancer Research (AICR) and the National Cancer
                              eliminating the identified carcinogens — or at least         Institute (NCI) — have established dietary guidelines to
                              minimizing exposure to them — but, without com-              help people reduce the cancer risk (for further informa-
                              plete identification of the corresponding risk factors,      tion, see the 1997 World Cancer Research Fund and
                              such primary prevention might be difficult to imple-         AICR report in online links box).
                              ment. Furthermore, the avoidance of some risk factors           Many clinical trials on the use of nutritional supple-
                              could require large lifestyle changes, which are not easy    ments and modified diets to prevent cancer are ongo-
                              to implement.                                                ing. It is conceivable that in the future people might only
                                  It has been estimated that more than two-thirds of       need to take specially formulated pills that contain sub-
                              human cancers could be prevented through appropriate         stances derived from edible plants to prevent cancer or
                              lifestyle modification. Richard Doll and Richard Peto        delay its onset2. However, a precise assessment of the
                              have reported that 10–70% (average 35%) of human             mechanisms by which the components of fruit and veg-
                              cancer mortality is attributable to diet1. Their observa-    etables prevent cancer is necessary before they can be
College of Pharmacy,          tions, which are based on statistical and epidemiological    recommended for inclusion in dietary supplements or
Seoul National University,    data, mainly concerned dietary factors that increase risk.   before they can be tested in human intervention trials.
Shinlim-dong, Kwanak-ku,      Although the exact percentage is uncertain, there are           Phytochemicals are non-nutritive components in the
Seoul 151-742, South Korea.
e-mail:                       several lines of compelling evidence from epidemiologi-      plant-based diet (‘phyto’ is from the Greek word mean-
surh@plaza.snu.ac.kr          cal, clinical and laboratory studies that link cancer risk   ing plant) that possess substantial anticarcinogenic and
doi:10.1038/nrc1189           to the nutritional factors.                                  antimutagenic properties. Given the great structural


768   | OCTOBER 2003 | VOLUME 3                                                                                       www.nature.com/reviews/cancer

                                                                                                                                       salutefaq.info
REVIEWS


 Summary                                                                                          diversity of phytochemicals, it is not feasible to define
                                                                                                  structure–activity relationships to deduce their
 • Many population-based studies have highlighted the ability of macronutrients and               underlying molecular mechanisms. A better approach
   micronutrients in vegetables and fruit to reduce the risk of cancer. Recently, attention       is to analyse their effects on cancer-associated
   has been focused on phytochemicals — non-nutritive components in the plant-based               signal-transduction pathways.
   diet that possess cancer-preventive properties.
 • Despite remarkable progress in our understanding of the carcinogenic process,                  Importance of plant-derived foods
   the mechanisms of action of most chemopreventive phytochemicals have not been                  More than 250 population-based studies, including
   fully elucidated.                                                                              case–control and cohort studies, indicate that people
 • Chemopreventive phytochemicals can block initiation or reverse the promotion stage             who eat about five servings of fruit and vegetables a day
   of multistep carcinogenesis. They can also halt or retard the progression of                   have approximately half the risk of developing cancer —
   precancerous cells into malignant ones.                                                        particularly cancers of the digestive and respiratory
 • Many molecular alterations associated with carcinogenesis occur in cell-signalling             tracts — of those who eat fewer than two servings. In
   pathways that regulate cell proliferation and differentiation. One of the central              the United States, these observations led to the develop-
   components of the intracellular-signalling network that maintains homeostasis is the           ment of public-health campaigns such as the ‘Five-a-Day
   family of mitogen-activated protein kinases (MAPKs).                                           for Better Health’ programme and a more recent ‘Savor
 • Numerous intracellular signal-transduction pathways converge with the activation               the Spectrum’ campaign — both were designed to
   of the transcription factors NF-κB and AP1. As these factors mediate pleiotropic               increase the ingestion of fruit and vegetables by the
   effects of both external and internal stimuli in the cellular-signalling cascades, they        population (BOX 1). Increased consumption of fruit and
   are prime targets of diverse classes of chemopreventive phytochemicals.                        vegetables is a global priority in the prevention of cancer
 • Basic helix–loop–helix transcription factors such as NRF2 regulate expression of phase II      and other chronic disorders. According to the WHO
   enzymes, which detoxify carcinogens and protect against oxidative stress. A number of          Report 2002, there are at least 2.7 million deaths globally
   phytochemicals have been shown to induce expression of phase II enzymes via NRF2.              per year, which are primarily attributable to low fruit
 • β-Catenin, a multifunctional protein that was originally identified as a component             and vegetable intake.
   of cell–cell adhesion machinery, is another important molecular target for                        Vegetables and fruit are excellent sources of cancer-
   chemoprevention. Several dietary phytochemicals have been shown to target                      preventive substances. The NCI has identified about
   this molecule.                                                                                 35 plant-based foods that possess cancer-preventive



                                  Box 1 | Chemoprevention initiatives
                                  A number of government programmes have been created in the United States and in Europe to increase vegetable
                                  consumption and decrease cancer incidence. These include the following:
                                  The ‘Five-A-Day for Better Health’ programme
                                  Founded in late 1991, this is the first nationwide health-promotion campaign to encourage people in the United States to
                                  eat fruit and vegetables — at least five servings a day — to reduce the risk of cancer and other chronic diseases. Over the
                                  past decade, there has been a steady increase in both awareness of the health benefits of fruit and vegetables and their
                                  consumption in the United States. The National Cancer Institute (NCI) has recently completed a review of this
                                  programme and reported a series of recommendations for the next round of the initiative (for further information, see
                                  the ‘Five-A-Day for Better Health’ report in online links box).
                                  ‘Savor the Spectrum’
                                  The NCI’s spring 2002 media promotion, entitled ‘Savor the Spectrum’, urges all Americans to eat five to nine
                                  servings of colourful fruit and vegetables a day for better health. The message of this programme is based on current
                                  research showing that phytonutrients from different colour groups are powerful disease fighters that help our body
                                  fight off cancer and heart disease. NCI has produced a series of guidelines featuring each colour of the‘rainbow’ of
                                  fruit and vegetables.
                                  European Prospective Investigation of Cancer and Nutrition (EPIC)
                                  EPIC is one of the most important multicentre prospective cohort studies ever launched worldwide. Beginning in
                                  1992, EPIC has involved more than half a million (520,000) participants recruited by 20 centres in 10 countries under
                                  the coordination of the International Agency for Research on Cancer (IARC) and partly funded by the ‘Europe
                                  Against Cancer’ programme of the European Commission, as well as by the participating countries. EPIC focuses on
                                  identifying the dietary determinants of cancer, and is aimed at expanding the presently limited knowledge of the role
                                  of nutrition and other lifestyle factors in the aetiology and prevention of cancer and other life-threatening diseases.
                                  Global Strategy on Dietary Prevention of Cancer
                                  For a global extension of the ‘Five-A-Day’ concept of boosting increased consumption of fruit and vegetables, the
                                  WHO organized the third Biennial ‘Five-A-Day’ International Symposium on January 14–15 2003 in Berlin,
                                  Germany. At the meeting, Derek Yach, the WHO Executive Director of Noncommunicable Diseases & Mental
                                  Health, said “Increasing the consumption of fruit and vegetables is a necessary part of the effort to reduce the
                                  growing global burden of chronic diseases including cancer.” The guidelines stated “choose most of the foods you eat
                                  from plant sources”.



NATURE REVIEWS | C ANCER                                                                                                  VOLUME 3 | OCTOBER 2003 | 7 6 9
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               Pro-carcinogen                                                                          cancer. Recently, the focus and emphasis have shifted to
                                         Detoxification
                                                                                          Secretion
                                                                                                       the non-nutritive phytochemicals. The NCI has deter-
                                                                                                       mined in laboratory studies that more than 1,000 differ-
                                Metabolic
                                                                                                       ent phytochemicals possess cancer-preventive activity. It
                                activation                                                             is estimated that there could be more than 100 different
 Cancer-blocking                                                                                       phytochemicals in just a single serving of vegetables.
 agents
                                                              Detoxification                               As early as 1980, the NCI’s Chemoprevention
 Ellagic acid
 Indole-3-carbinol                   Ultimate                                                          Programme of the Division of Cancer Prevention and
                                     carcinogen
 Sulphoraphane                                                                                         Control began evaluating phytochemicals for safety, effi-
 Flavonoids
                                                                                                       cacy and applicability for cancer prevention. Michael
                                                                                                       Sporn coined the term ‘chemoprevention’ in the mid-
                                                                                                       1970s to describe the strategy of blocking or slowing the
                                         Normal                                                        onset of premalignant tumours with relatively nontoxic
                                         cell
                                                                                                       chemical substances. To better define and guide research
                                                                                                       in the field of chemoprevention, the NCI Division of
                                Initiation                Preneoplastic                 Neoplastic     Cancer Prevention started the Chemoprevention
                                (1–2 days)                cells                         cells          Implementation Group in 1998, and then the Rapid
                                           Promotion                      Progression                  Access to Preventive Intervention Development pro-
                                           (>10 years)                    (>1 year)
                                                                                                       gramme. The NCI has more than 400 potential agents
                                                                                                       under investigation and is sponsoring more than 65
                        Initiated cell                                                                 Phase I, Phase II and Phase III chemoprevention trials.
                                                                                                       These involve various substances or their mixtures,
                                                          Cancer-suppressing                           many of which are foodborne phytochemicals.
                                                          agents
                                                          β-Carotene
                                                          Curcumin                                     Mechanisms of chemoprevention
                                                          EGCG                                         Carcinogenesis is generally recognized as a multistep
                                                          Genistein
                                                          Resveratrol                                  process in which distinct molecular and cellular alter-
                                                          [6]-Gingerol                                 ations occur. From the study of experimentally induced
                                                          Capsaicin
                                                                                                       carcinogenesis in rodents, tumour development is con-
Figure 1 | Dietary phytochemicals that block or suppress multistage carcinogenesis.                    sidered to consist of several separate, but closely linked,
Carcinogenesis is initiated with the transformation of the normal cell into a cancer cell (initiated   stages — tumour initiation, promotion and progression.
cell). These cells undergo tumour promotion into preneoplastic cells, which progress to neoplastic
cells. Phytochemicals can interfere with different steps of this process. Some chemopreventive
                                                                                                       Although these divisions are an oversimplification of
phytochemicals inhibit metabolic activation of the procarcinogens to their ultimate electrophilic      carcinogenesis, it is useful to think in these stages when
species, or their subsequent interaction with DNA. These agents therefore block tumour initiation      considering possible opportunities for chemoprevention.
(blocking agents). Alternatively, dietary blocking agents can stimulate the detoxification of              Initiation is a rapid and irreversible process that
carcinogens, leading to their secretion from the body. Other phytochemicals suppress the later         involves a chain of extracellular and intracellular
steps (promotion and progression) of multistage carcinogenesis (suppressing agents). Some              events. These include the initial uptake of or exposure
phytochemicals can act as both blocking and suppressing agents. Adapted from REF. 128.
                                                                                                       to a carcinogenic agent, its distribution and transport
                                                                                                       to organs and tissues where metabolic activation and
                                                                                                       detoxification can occur, and the covalent interaction of
                                    properties. These include garlic, soybeans, ginger,                reactive species with target-cell DNA, leading to geno-
                                    onion, turmeric, tomatoes and cruciferous vegetables               toxic damage. In contrast to initiation, tumour promo-
                                    (for example, broccoli, cabbage, cauliflower and                   tion is considered to be a relatively lengthy and
                                    Brussels sprouts). Numerous cell-culture and animal-               reversible process in which actively proliferating pre-
                                    model studies have been conducted to evaluate the                  neoplastic cells accumulate. Progression, the final stage
                                    ability of specific edible plants to prevent cancer.               of neoplastic transformation, involves the growth of a
                                                                                                       tumour with invasive and metastatic potential.
                                    Beyond vitamins to phytochemicals                                      According to the conventional classification origi-
                                    Many population-based studies have highlighted the                 nally proposed by Lee Wattenberg, chemopreventive
                                    ability of macronutrients (for example, carbohydrate,              agents are subdivided into two main categories —
                                    proteins, fat and fibre) and micronutrients (for exam-             blocking agents and suppressing agents3. Blocking
                                    ple, antioxidant vitamins and trace minerals) that are             agents prevent carcinogens from reaching the target
                                    contained in vegetables and fruit to reduce the risk of            sites, from undergoing metabolic activation or from
                                    cancer. The most exciting findings have been achieved              subsequently interacting with crucial cellular macro-
                                    with antioxidant vitamins and their precursors, which              molecules (for example, DNA, RNA and proteins).
                                    are found in dark, leafy green vegetables and                      Suppressing agents, on the other hand, inhibit
                                    yellow/orange fruit and vegetables. The NCI has there-             the malignant transformation of initiated cells, in
                                    fore sponsored a series of human intervention trials               either the promotion or the progression stage.
                                    with individual vitamins and minerals. However, plants             Chemopreventive phytochemicals can block or reverse
                                    contain numerous chemical substances other than these              the premalignant stage (initiation and promotion) of
                                    micronutrients that might also be useful in preventing             multistep carcinogenesis. They can also halt or at least


770   | OCTOBER 2003 | VOLUME 3                                                                                                   www.nature.com/reviews/cancer
REVIEWS


                           Turmeric                                                                                 Grapes                                                   OH
                                                                       O       O
                                                  O                                                    O
                                            H3C                                                             CH3
                                                                                                                                            HO
                                              HO                                                       OH                                                                    OH
                                                                      Curcumin                                                                         Resveratrol


                           Chilli peppers                                                                           Honey
                                                                           O                                                                                O

                                                      O                                                                                HO
                                              H3C                      N                                                                                        O
                                                                       H
                                                      HO                                                                               HO
                                                                      Capsaicin                                                          Caffeic acid phenethyl ester

                           Ginger                                                                                   Garlic
                                                                               O        OH
                                                        O
                                                  H3C                                                                                                      S

                                                      HO
                                                                   [6]-Gingerol                                                                    Diallyl sulphide


                                                                      HO           OH
                           Green tea                                                                                Cabbage
                                                                                        OH                                                                          OH

                                                                  O                          OH
                                                                               O
                                                                                                                                                            N
                                                      HO                                          OH                                                        H
                                                                               O
                                                                                                                                                  Indole-3-carbinol
                                                                  OH                         OH
                                                            Epigallocatechin-3-gallate

                           Soybeans                                                                                 Broccoli
                                                                                             OH
                                                                 OH        O
                                                                                                                                                                             S
                                                                                                                                                                         C
                                                                                                                                            H3C                     N
                                                                                                                                                   S
                                                            HO             O                                                                       O
                                                                      Genistein                                                                    Sulphoraphane
                               Tomatoes




                                                                                                                  Lycopene

                           Figure 2 | Representative chemopreventive phytochemicals and their dietary sources.




                           retard the development and progression of precancer-                               include carcinogen activation/detoxification by xenobi-
                           ous cells into malignant ones (FIG. 1). Recent advances                            otic metabolizing enzymes; DNA repair; cell-cycle
                           in our understanding of the carcinogenic process at                                progression; cell proliferation, differentiation and apop-
                           the cellular and molecular level have shown this block-                            tosis; expression and functional activation of oncogenes
                           ing and suppressing categorization to be an oversim-                               or tumour-suppressor genes; angiogenesis and metasta-
                           plification, and numerous cellular molecules and                                   sis; and hormonal and growth-factor activity (for
                           events that could be potential targets of chemopreven-                             further information, see ONLINE TABLE 1).
                           tive agents have been more specifically identified4–6.
                           Therefore, the ability of any single chemopreventive                               Cellular signalling molecules as targets
                           phytochemical to prevent tumour development                                        During the past two or three decades, there has been
                           should be recognized as the outcome of the combina-                                substantial progress in identifying the biochemical
                           tion of several distinct sets of intracellular effects,                            events that are associated with the multistage process
                           rather than a single biological response.                                          of carcinogenesis, and we are now better aware of how
                              FIGURE 2 illustrates the chemical structures of repre-                          certain dietary phytochemicals are able to alter this
                           sentative dietary phytochemicals that have been known                              process (FIG. 1). Remarkable advances in the cellular
                           to possess chemopreventive potential and their dietary                             and molecular genetics of carcinogenesis — such as
                           sources. The cellular and molecular events affected or                             the identification of numerous oncogenes and
                           regulated by these chemopreventive phytochemicals                                  tumour-suppressor genes, specific genes encoding


NATURE REVIEWS | C ANCER                                                                                                             VOLUME 3 | OCTOBER 2003 | 7 7 1
REVIEWS


                                                                                                                        Despite this progress, the identification of molecular
                                                                                                                   and cellular targets of chemopreventive phytochemicals
                                                                                                                   is still incomplete. Many of the molecular alterations that
                   PI3K                     MEKK1               RAS                      PKC       Curcumin
                                                                                                   EGCG
                                                                                                                   are associated with carcinogenesis occur in cell-signalling
                                                                                                   Resveratrol     pathways that regulate cell proliferation and differentia-
                                                                                                                   tion. One of the central components of the intracellular-
  EGCG                                                                                                             signalling network that maintains homeostasis is the
                   PDK         NIK          MEK1/2                        RAF                                      family of proline-directed serine/threonine kinases —
                                                                                                       Cytoplasm
                                                          MKK4                                                     the mitogen-activated protein kinases (MAPKs; FIG. 3).
                                                                                                                        Abnormal or improper activation or silencing of the
                                                                                                                   MAPK pathway or its downstream transcription fac-
 Genistein
                                                                                                                   tors can result in uncontrolled cell growth, leading to
 EGCG              AKT      IKK-α/β/γ       ERK1/2         p38                        JNK          Curcumin        malignant transformation. Some phytochemicals
                                                                                                   EGCG
 Curcumin                                                                                          Resveratrol
                                                                                                                   ‘switch on’ or ‘turn off ’ the specific signalling mole-
 EGCG                                                                                                              cule(s), depending on the nature of the signalling cas-
 Genistein                                                                                                         cade they target, preventing abnormal cell proliferation
 Resveratrol
 Capsaicin                                                                                                         and growth4–12. Cell-signalling kinases other than
                                                                                                                   MAPKs, such as protein kinase C (PKC) and phos-
                                                                                                                   phatidylinositol 3-kinase (PI3K), are also important
                                           ELK1/SAP1 SRF                                       c-JUN      ATF2     targets of certain chemopreventive phytochemicals.
         P                                                                                                         These upstream kinases activate a distinct set of tran-
                                                                  c-FOS


                                                                                 c-JUN


                                                   SRE                                                 TRE
 NF-κB       IκB          NF-κB                                                                                    scription factors, including nuclear factor κB (NF-κB)
                                                                                                                   and activator protein 1 (AP1; FIG. 3).
             Ub
                                                                                                                   NF-κB and AP1
                                                                                         AP1
                                                                      c-FOS
                                                                              c-JUN




                                                                                                                   Numerous intracellular signal-transduction pathways
                                                 NF-κB
             26S                                                                                                   converge with the activation of the transcription factors
                          Curcumin            κB binding site             TRE
                                                                                                                   NF-κB and AP1, which act independently or coordinately
                                                                                                                   to regulate target-gene expression (FIG. 3).
                                                                                          Nucleus                      Aberrant activation of NF-κB has been associated
  Proteasome
                                                                                                                   with protection against apoptosis and stimulation of
                                                                                                                   proliferation in malignant cells13,14, and overexpression
Figure 3 | Effect of phytochemicals on activation of NF-κB and AP1. The NF-κB signalling
pathway converges on the multiprotein complex called the IκB kinase (IKK) signalsome,                              of NF-κB is causally linked to the phenotypic changes
leading to IκB phosphorylation (P), ubiquitylation (Ub) and subsequent degradation by the 26S                      that are characteristic of neoplastic transformation15.
proteasome. NF-κB is then released and translocated to the nucleus, where it binds to specific                     Many chemopreventive phytochemicals that are
promoter regions of various genes. The IKK signalsome is activated by the NF-κB-inducing                           derived from the diet have been shown to suppress
kinase (NIK). Pathways that regulate NIK are likely to involve signalling through a family of                      constitutive NF-κB activation in malignant cells or
mitogen-activated protein kinases (MAPKs), such as MAPK kinase kinase-1 (MEKK1) — a
                                                                                                                   NF-κB activation induced by the external tumour pro-
kinase that lies upstream of extracellular signal-regulated kinase (ERK) — MAPK/ERK kinase
(MEK1/2) and p38 MAPK. Recent reports showed that NF-κB activation is also regulated by
                                                                                                                   moter phorbol 12-myristate 13-acetate (PMA) or
the AKT signalling pathway58,59,129. Phosphatidylinositol 3-kinase (PI3K) activates AKT/protein                    tumour-necrosis factor-α (TNF-α)11,16,17.
kinase B via phosphorylation by 3-phosphoinositide-dependent protein kinase-1 (PDK1).                                  AP1 is another transcription factor that regulates
Genistein specifically inhibits AKT activity and AKT-mediated NF-κB activation58,59.                               expression of genes that are involved in cellular adapta-
Epigallocatechin gallate (EGCG) can block the activities of PI3K and AKT49. There is crosstalk                     tion, differentiation and proliferation. Functional activa-
between the AKT and NF-κB signalling pathways — AKT phosphorylation leads to activation of                         tion of AP1 is associated with malignant transformation
NF-κB by stimulating IκB kinase (IKK) activity129. IKK is also a target for chemopreventive
                                                                                                                   as well as tumour promotion18–21. AP1 consists of either
phytochemicals, including curcumin24,28, resveratrol71 and EGCG45,130. The MAPK family
proteins also regulate expression of AP1 — a heterogenous set of dimeric proteins made up of                       homo- or heterodimers between members of the JUN
members of the c-JUN, c-FOS and ATF families. In this pathway, activation of ERK1/2                                and FOS families, which interact via a leucine-zipper
phosphorylates ELK1, c-JUN NH2-terminal kinase (JNK) phosphorylates c-JUN, and p38                                 domain. This transcription factor is also regulated by
phosphorylates both ELK1 and ATF2. This leads to transcriptional activation of target genes.                       the MAPK-signalling cascade21–23.
External stimuli — including phorbol ester and ultraviolet radiation — activate specific isoforms                      As NF-κB and AP1 are ubiquitous eukaryotic tran-
of protein kinase C (PKC), which, in turn, leads to stimulation of the p21 RAS–ERK signalling
                                                                                                                   scription factors that mediate pleiotropic effects of both
pathway via RAF and MEK1/2. Activation of p38 and JNK is mediated by MAPK kinase-4
(MKK4), which is under control of the upstream kinase MEKK.                                                        external and internal stimuli in the cellular-signalling
                                                                                                                   cascades, they are prime targets of diverse classes of
                                                                                                                   chemopreventive phytochemicals (FIG. 3).

                                     carcinogen-metabolizing enzymes, DNA-repair                                   Phytochemicals targeting NF-κB and AP1
                                     enzymes and proteins, and regulators of cell cycle and                        Curcumin, [6]-gingerol and capsaicin. Curcumin — a
                                     apoptosis — have given us a better insight into the                           yellow pigment that is present in the rhizome of
                                     process of neoplastic transformation. Advances have                           turmeric (Curcuma longa L.) and related species — is
                                     also been made in identifying the factors that mediate                        one of the most extensively investigated phytochemicals,
                                     tumour invasion, metastasis and angiogenesis.                                 with regard to chemopreventive potential. Curcumin


772   | OCTOBER 2003 | VOLUME 3                                                                                                               www.nature.com/reviews/cancer
REVIEWS


                           has been shown to suppress tumour promotion in a              activation of JNK and p38, and deactivation of ERK41.
                           mouse model of skin carcinogenesis. Furthermore, pre-         Pharmacological inhibition or dominant-negative
                           treatment of human colonic epithelial cells with cur-         forms of JNK and p38, but not of ERK, abrogated the
                           cumin inhibited TNF-α-induced cyclooxygenase-2                capsaicin-induced apoptosis in these cells41.
                           (COX2) gene transcription and NF-κB activation24. In
                           this study, curcumin inhibited IκB degradation by             Epigallocatechin gallate (EGCG). EGCG is an antioxi-
                           downregulation of NF-κB-inducing kinase (NIK) and             dant and chemopreventive polyphenol that is found in
                           IκB kinase (IKK)α/β.                                          green tea. It has been shown to suppress malignant
                               When curcumin was applied topically to the dorsal         transformation in a PMA-stimulated mouse epidermal
                           skin of female ICR mice (a model initially developed at       JB6 cell line, which seemed to be mediated by blocking
                           the Institute of Cancer Research, Fox Chase Cancer            activation of Ap1 (REFS 42,43) or Nf-κb44. More recently,
                           Center), it prevented the PMA-induced activation of           EGCG treatment of human epidermal keratinocytes
                           both Nf-κb and Ap1 (REF. 25). The inhibition of Nf-κb         resulted in significant inhibition of ultraviolet (UV)-
                           was accompanied by blockade of degradation via phos-          B-light-induced activation of IKKα, phosphorylation
                           phorylation of Iκbα and also by reduced nuclear translo-      and subsequent degradation of IκBα and nuclear
                           cation of the p65 subunit of Nf-κb (REF. 26; FIG. 3).         translocation of p65 (REF. 45). In the Hras-transformed
                           Topically applied curcumin inhibited the catalytic activ-     epidermal JB6 cells, EGCG inhibited Ras-activated Ap1
                           ity of epidermal extracellular-signal-regulated kinase        activity 46,47. Similar Ap1 inhibition was observed in the
                           (Erk)1/2, which could account for its ability to inactivate   epidermis of transgenic mice that harbour an Ap1-driven
                           Nf-κb and Cox2 (REF. 26). Curcumin also suppressed the        luciferase reporter gene.
                           TNF-α-induced nuclear translocation and DNA binding               Nomura and colleagues48 have reported the
                           of NF-κB in a human myeloid leukaemia cell line by            inhibitory effect of EGCG on UV-light-induced PI3K
                           blocking phosphorylation and subsequent degradation           activation in mouse epidermal cells. The reduction of
                           of IκB27. PMA- and hydrogen-peroxide-induced activa-          signalling via PI3K–AKT–NF-κB by EGCG was
                           tion of NF-κB was similarly attenuated by curcumin            reported to be mediated through inhibition of ERBB2
                           treatment. In addition, curcumin inhibited IκBα phos-         (also known as HER2/NEU) receptor tyrosine phos-
                           phorylation in human multiple myeolma cells28 and             phorylation49. EGCG also inhibited vascular endothelial
                           murine melanoma cells29 through suppression of IKK            growth factor (VEGF) production by inhibiting consti-
                           activity, which contributed to its antiproliferative,         tutive activation of both STAT3 and NF-κB — but not
                           proapoptotic and/or antimetastatic activities.                of ERK or AKT — in human breast and head and neck
                               [6]-Gingerol — a phenolic substance that is responsi-     cancer cell lines50.
                           ble for the spicy taste of ginger (Zingiber officinale            EGCG treatment resulted in inhibition of cell
                           Roscoe) — was reported to inhibit tumour promotion            growth, G0/G1-phase arrest of the cell cycle and induc-
                           and PMA-induced ornithine decarboxylase (ODC) activ-          tion of apoptosis in human epidermoid carcinoma
                           ity and Tnf-α production in mouse skin30. More recently,      (A431) cells, but not in normal human epidermal ker-
                           [6]-gingerol has been found to inhibit epidermal growth       atinocytes (NHEK)51. A431 cells were more susceptible
                           factor (Egf)-induced Ap1 activation and neoplastic trans-     to EGCG-mediated inhibition of constitutive NF-κB
                           formation in mouse epidermal JB6 cells — this was             expression and activation than NHEK cells, indicating
                           shown using reduced anchorage-independent formation           that EGCG-caused cell-cycle deregulation and apoptosis
                           of cell colonies in soft agar 31.                             of cancer cells might be mediated through NF-κB inhi-
                               Capsaicin — a pungent component of hot chilli pep-        bition. The roles of EGCG and other tea polyphenols on
                           per (Capsicum annuum L.) — has been suspected to act          cellular signalling have been reviewed recently 52,53.
                           as a carcinogen or a co-carcinogen in experimental ani-
                           mals because of its irritant properties, but other studies    Genistein. Genistein — a soy-derived isoflavone — is
                           indicate that the compound has chemopreventive and            believed to contribute to the putative breast- and
                           chemoprotective effects32–35. Topical application of cap-     prostate-cancer-preventive activity of soya. Genistein
                           saicin inhibited PMA-induced mouse-skin tumour for-           inhibited PMA-induced AP1 activity, expression of
                           mation36 and activation of Nf-κb37. This was attributed       c-FOS and ERK activity in certain human mammary
                           to blockade of Iκbα degradation and Nf-κb transloca-          cell lines54. Genistein treatment abrogated NF-κB DNA
                           tion into the nucleus. PMA- or Tnf-α-induced Ap1 acti-        binding in human hepatocarcinoma cells stimulated
                           vation in mouse skin and cultured human leukaemia             with hepatocyte growth factor55. The downregulation
                           HL-60 cells was also blocked by capsaicin38.                  of c-Jun and c-Fos by genistein was also observed in
                               Capsaicin inhibited constitutive and induced acti-        UV-light-stimulated skin of SENCAR (sensitivity to
                           vation of NF-κB in human malignant-melanoma cells,            carcinogenesis) mice56.
                           leading to inhibition of melanoma-cell proliferation39.           Genistein at the apoptogenic concentration also
                           Capsaicin also induced apoptosis in cultured Jurkat           inhibited the H2O2- or TNF-α-induced activation of
                           cells through generation of reactive oxygen species           NF-κB in both the androgen-sensitive (LNCaP) and -
                           (ROS) and rapid activation of c-JUN NH2-terminal              insensitive (PC3) human prostate cancer cell lines by
                           kinase (JNK)40. Similarly, capsaicin caused apoptotic         reducing phosphorylation of IκBα and the nuclear
                           death in HRAS-transformed human mammary                       translocation of NF-κB57. Genistein-mediated inactivation
                           epithelial cells, which was accompanied by marked             of NF-κB was associated with downregulation of AKT in


NATURE REVIEWS | C ANCER                                                                                        VOLUME 3 | OCTOBER 2003 | 7 7 3
REVIEWS


                                     the prostate cancer58 and mammary cancer59 cells. The         HeLa cell cultures, which was associated with inhibition
                                     same studies also revealed that AKT transfection led to       of PKC and protein tyrosine kinase68. Similarly, resvera-
                                     the activation of NF-κB, which was completely blocked         trol blocked UV-light-induced activation of NF-κB
                                     by genistein treatment, indicating that inhibition of the     through suppression of IKK activation69. Resveratrol
                                     crosstalk between AKT and NF-κB could provide a               suppressed TNF-α-induced phosphorylation and
                                     novel mechanism responsible for pro-apoptotic activity        nuclear translocation of p65, and NF-κB-dependent
                                     of genistein.                                                 reporter-gene transcription in myeloid leukaemia
                                         PMA- or TNF-α-induced NF-κB DNA binding                   cells70. The suppression of NF-κB coincided with sup-
                                     and NF-κB-derived COX2 promoter activity, as well as          pression of AP1. Resveratrol also inhibited the TNF-
                                     COX2 expression, were inhibited in human alveolar             induced activation of MAPK kinase (MEK) and JNK,
                                     epithelial carcinoma cells by genistein treatment60. In       and abrogated TNF-induced caspase activation70.
                                     human U937 monocytes, genistein exerted no sub-                   Resveratrol induced apoptosis in fibroblasts after the
                                     stantial inhibitory effect on DNA binding of NF-κB,           induced expression of oncogenic HRAS, possibly
LUCIFERASE-REPORTER-GENE
ASSAY
                                     but markedly attenuated its transcriptional activity 61.      through inhibition of NF-κB activation by blocking
A recombinant method that is         Consistent with this notion, genistein strongly sup-          IKK activity71.
used to measure transcriptional      presses NF-κB transcriptional activity in PMA-stimu-
activity in which the regulatory     lated human mammary epithelial cells, as determined           Miscellaneous phytochemicals. In addition to the
sequence (for example,
                                     by the LUCIFERASE-REPORTER-GENE ASSAY but does not inter-     aforementioned phytochemicals, caffeic acid
promoter or enhancer) of
interest is joined to a firefly      fere with IκB degradation, and subsequent nuclear             phenethyl ester (CAPE), sulphoraphane, silymarin,
luciferase gene that, following      translocation and DNA binding of NF-κB (M.-H.                 apigenin, emodin, quercetin and anethole have also
activation, produces light from      Chung and Y.-J.S., unpublished observations).                 been reported to suppress the activation of NF-κB and
luciferin in the presence of ATP     Genistein might block the phosphorylation of p65              AP1, which might contribute to their chemopreventive
added to the assay mixture. The
relative intensity of the light
                                     without influencing the IKK activity, thereby hamper-         and/or cytostatic effects16.
emission is measured with a          ing its interaction with co-activators such as cyclic
luminometer.                         AMP response element binding protein (CREB)-binding           NRF–KEAP1 complex
                                     protein (CBP/p300), a key element of the transcrip-           Other than suppressing tumour promotion or progres-
CREB
                                     tion-initiation complex that bridges DNA-bound                sion, another important approach to chemoprevention
(Cyclic AMP response element
binding protein). CREB is a          transcription factors to the transcription machinery.         is to block the DNA damage caused by carcinogenic
leucine zipper transcription                                                                       insult — the initiation stage of carcinogenesis. Toxic
factor that binds to DNA at the      Resveratrol. Resveratrol (3,4′,5-trihydroxy-trans-            xenobiotic (‘xeno’, from the Greek word meaning ‘for-
cyclic AMP response element          stilbene) is a phytoalexin that is present in grapes (Vitis   eign’) chemicals, including carcinogens, are detoxified
(CRE) as a homo- or
heterodimer. It has pivotal roles
                                     vinifera) and a key antioxidant ingredient of red wine. It    by PHASE II ENZYMES — such as glutathione S-transferase
in the control of cellular           is believed to be responsible for the so-called ‘French       (GST) and NAD(P)H:quinone oxidoreductase (NQO).
proliferation and differentiation,   paradox’, in which consumption of red wine has been               The phase II enzyme induction system is an
apoptosis, intermediary              shown to reduce the mortality rates from cardiovascular       important component of the cellular stress response
metabolism, inflammation and
                                     diseases and certain cancers. Resveratrol treatment           in which a diverse array of electrophilic and oxidative
numerous other responses,
particularly in hepatocytes,         inhibited PMA-induced COX2 expression and catalytic           toxicants can be removed from the cell before they
adipocytes and haematopoietic        activity, via the cyclic-AMP response element (CRE), in       are able to damage the DNA. Antioxidants exert their
cells.                               human mammary epithelial cells62,63. It also inhibited        protective effects not only by scavenging ROS, but
                                     PKC activation, AP1 transcriptional activity and the          also by inducing de novo expression of genes that
PHASE II ENZYMES
A group of xenobiotic
                                     induction of COX2-promoter activity in PMA-treated            encode detoxifying/defensive proteins, including
metabolizing enzymes that are        cells. Resveratrol induced apoptosis and reduced the          phase II enzymes. Many xenobiotics activate
mainly involved in the               constitutive activation of NF-κB in both rat and human        stress-response genes in a manner similar to that
inactivation and excretion of        pancreatic carcinoma cell lines64. Mammary tumours            achieved by antioxidants. These genes encode
carcinogens and other toxic
                                     isolated from rats treated with resveratrol displayed         enzymes such as glutathione peroxidase, gamma-glu-
chemical substances.
                                     reduced expression of Cox2 and matrix metallopro-             tamylcysteine synthetase (γ-GCS), GST, NQO and
ANTIOXIDANT-RESPONSIVE               teinase (Mmp)-9, as well as reduced Nf-κb activation,         heme oxygenase-1 (HO-1). The 5′-flanking regions
ELEMENT                              compared with controls65. Treatment of human breast           of these genes contain a common cis-element, known
(ARE). A specific DNA-               cancer MCF-7 cells with resveratrol also suppressed           as the ANTIOXIDANT-RESPONSIVE ELEMENT (ARE) (FIG. 4).
promoter-binding region that
can be transcriptionally
                                     NF-κB activation and proliferation65.                         Many basic leucine zipper (bZIP) transcription
activated by numerous                    Treatment of androgen-sensitive prostate cancer           factors — including NRF, JUN, FOS, FRA, MAF and
antioxidants and/or                  cells (LNCaP) with resveratrol caused downregulation          AH receptor — bind to these ARE sequences and
electrophiles. Many stress-          of prostate-specific antigen and p65; these effects were      modulate expression of some of the aforementioned
response genes encoding phase
                                     associated with activation of p53, WAF1, p300/CBP             stress-response genes72 (FIG. 4).
II detoxification or antioxidant
enzymes such as glutathione          and APAF1 (REF. 66). Resveratrol-induced apoptosis in
S-transferase, quinone reductase,    mouse JB6 epidermal cells was associated with phos-           NRF. During oxidative stress or other types of toxic
and heme oxygenase-1 — which         phorylation of p53, which seemed to be mediated               insult that are induced by xenobiotic chemicals, cer-
provide defence against cellular     through activation of Erk and p38 (REF. 67). Yu and col-      tain members of the helix–loop–helix bZIP family of
oxidative stress — have this
element in their 5′-flanking
                                     leagues have shown that resveratrol pretreatment gives        transcription factors — particularly the nuclear fac-
region to facilitate the             rise to suppression of PMA- and UV-light-induced              tor-erythroid 2p45 (NF-E2)-related factors (NRF1
transcription process.               activation of AP1 and MAPKs (ERK2, JNK and p38) in            and NRF2) — heterodimerize and bind to the ARE


774    | OCTOBER 2003 | VOLUME 3                                                                                             www.nature.com/reviews/cancer
REVIEWS


Cell membrane                                                                                      carcinogen benzo[a]pyrene, which was not prevented
                                                                                                   by oltipraz, a chemopreventive agent with phase II
                                                                                                   enzyme inducing activity75,84. Nrf2-null mice also have
           PI3K                     PKC          JNK            ERK           Curcumin
                                                                              CAPE                 defects in detoxifying carcinogens such as aflatoxin B185.
                                                                              Sulphoraphane        Stable transfection of L929 cells with a dominant-
                                                                       p38                         negative mutant form of Nrf2 abolished induction of
                                                 P    P
                               SR                                      SH                          Ho-1 by several toxicants86. Fibroblasts from Nrf2-null
                                                 S    T                                            mice were found to express only about 15% as much
                              KEAP1                                   KEAP1        S   T
                                                 NRF2                                              Gcs mRNA as wild-type cells87. Overexpression of
                                                                                   NRF2            NRF2 activated ARE-mediated transcription in human
  C/EBPβ                                                                                           hepatoma (HepG2) cells, and this activation was
                                                              6-HITC                               further increased by tert-butylhydroquinone88.
                                                                            Sulphoraphane

                                                 P    P                                            KEAP1 — a negative regulator of NRF. A cytosolic
                                                S T                          Phase II enzymes:     actin-binding protein called Kelch-like ECH-associated
                                                NRF2                         GSTA-2                protein 1 (KEAP1) has been identified as a docking site
                                                                             NQO-1
                                                       MAF                   r-GCLC
                                                                                                   at which the bZIP proteins are sequestered under nor-
                   C/EBPβ
                                                                             r-GCLM                mal physiological conditions. For example, KEAP1
                  CCAAT/XRE                          ARE                     HO-1                  suppresses the transcriptional activity of NRF2 by
                                                                                                   retaining the transcription factor in the cytoplasm and
                                                                                                   hampering its nuclear translocation (FIG. 4).
                                                                                                       The mechanisms by which cells recognize chemo-
                                                                                                   preventive antioxidants or phase II enzyme inducers
Figure 4 | Transcriptional activation by NRF2. NRF2 is a transcription factor that regulates       have not been fully elucidated. The KEAP1–NRF2
expression of many detoxification or antioxidant enzymes. The Kelch-like-ECH-associated            complex is an intracellular sensor that recognizes
protein 1 (KEAP1) is a cytoplasmic repressor of NRF2 that inhibits its ability to translocate to   redox signalling by detecting electrophiles or ROS89.
the nucleus. These two proteins interact with each other through the double glycine-rich
                                                                                                   Many phase II gene inducers are able to generate ROS,
domains of KEAP1 and a hydrophilic region in the NEH2 domain of NRF2. KEAP1 contains
many cysteine residues. Phase II enzyme inducers and/or prooxidants can cause oxidation
                                                                                                   or else can be readily converted — nonenzymatically,
or covalent modification (R) of these cysteine residues91. As a result, NRF2 is released from      via REDOX CYCLING — or metabolized to electrophilic
KEAP1. In addition, phosphorylation of NRF2 at serine (S) and threonine (T) residues by            intermediates in the body. Phase II enzyme inducers
kinases such as phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC)131, c-Jun NH2-        mimic pro-oxidants and electrophiles, although most
terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) is assumed to facilitate     of them are antioxidants by nature. Therefore, it might
the dissociation of NRF2 from KEAP1 and subsequent translocation to the nucleus. p38 can           be more appropriate to call ARE an ‘electrophile
both stimulate and inhibit the NRF2 nuclear translocation. In the nucleus, NRF2 associates
                                                                                                   response element’ (EpRE). It is plausible that these
with small MAF (the term is derived from musculoaponeurotic-fibrosarcoma virus), forming a
heterodimer that binds to the antioxidant-responsive element (ARE) to stimulate gene               reactive species interact with thiol groups of KEAP1
expression. NRF2/MAF target genes encode phase II detoxification or antioxidant enzymes            and oxidize or covalently modify the cysteine residues
such as glutathione S-transferase α2 (GSTA2), NAD(P)H:quinone oxidoreductase (NQO1),               within KEAP1 and also, possibly, NRF2 (REFS 90–93).
γ-glutamate cysteine ligase (γ -GCLC and γ -GCLM) and heme oxygenase-1 (HO-1). PI3K                This would cause KEAP1 to release NRF2, so it could
also phosphorylates the CCAAT/enhancer binding protein-β (C/EBPβ), inducing its                    translocate to the nucleus and activate transcription of
translocation to the nucleus and binding to the CCAAT sequence of C/EBP-β response
                                                                                                   phase II enzymes (FIG. 4).
element within the xenobiotic response element (XRE), in conjunction with NRF2 binding to
ARE132. Transfection of human neuroblastoma cells with PI3K activates ARE, which is                    In accordance with this model, sulphydryl-reactive
attenuated by a pharmacological inhibitor of PI3K or dominant-negative NRF2 (REF. 133).            agents — such as diethyl maleate —abrogated
Curcumin and caffeic acid phenethyl ester (CAPE) disrupt the NRF2–KEAP1 complex,                   KEAP1 repression of NRF2, allowing release of the
leading to increased NRF2 binding to ARE99,100. Sulphoraphane directly interacts with KEAP1        transcription factor 89. In this context, the cysteine
by covalent binding to its thiol groups91. 6-(Methylsulfinyl)hexyl isothiocyanate (6-HITC) — a     residues in KEAP1 could serve as a molecular sensor
sulphoraphane analogue from Japanese horseradish wasabi — stimulates nuclear
                                                                                                   of intracellular redox status, ensuring the proper
translocation of NRF2, which subsequently activates ARE 98.
                                                                                                   and timely expression of genes that are involved in
                                                                                                   cellular antioxidant defence or detoxification of
                                                                                                   electrophilic toxicants.
                                 sequence to activate transcription 73. In human
                                 hepatoma cells that are genetically engineered to                 Phytochemicals that activate NRF
                                 overexpress NRF1 or NRF2, both basal and inducible                Exposure of HepG2 cells to the green-tea extract
                                 transcriptional activities of an ARE reporter gene                induces expression of phase II detoxifying enzymes
                                 were increased.                                                   through ARE94. This upregulation was accompanied
                                    A role for NRF2 in the regulation of ARE-mediated              by activation of ERK2 and JNK1, as well as immediate-
REDOX CYCLING                    gene expression has been shown in studies involving               early genes c-JUN and c-FOS. Subsequent studies have
A reciprocal transformation      Nrf2-null mice73. These mice fail to induce many of the           shown that EGCG transcriptionally activated the
between an oxidant and its       genes involved in carcinogen detoxification and protec-           phase II enzyme gene expression in HepG2 cells, as
reductive counterpart. An
example is conversion of
                                 tion against oxidative stress73–83. Most notably, the Nrf2-       determined by the ARE reporter-gene assay95. In this
catechol to quinone via          null mice developed a larger number of tumours in the             experiment, EGCG strongly activated all three MAPKs
semiquinone or vice versa.       forestomach after treatment with the ubiquitous                   (ERK, JNK and p38) and induced caspase-3-mediated


NATURE REVIEWS | C ANCER                                                                                                  VOLUME 3 | OCTOBER 2003 | 7 7 5
REVIEWS


                           cell death. Other phytochemicals such as phenethyl             (CKI) has been shown to convert β-catenin into a
                           isothiocyanate and sulphoraphane also differentially           form that is favoured for phosphorylation by GSK-3β,
                           regulated the activation of MAPKs and NRF, ARE-                and so promotes destabilization of β-catenin107,108. Liu
                           mediated luciferase reporter-gene activity, and phase II       et al. reported a similar function of another isoform of
                           enzyme gene induction96,97.                                    casein kinase, CKIα109.
                               Analysis of gene-expression profiles by an oligonu-            So, β-catenin needs to be stabilized in the cyto-
                           cleotide microarray revealed that sulphoraphane                plasm to escape the degradation pathway. This occurs
                           upregulated expression of Nqo1, Gst and Gcs in the             in response to WNT signalling, as well as signalling by
                           small intestine of wild-type mice, whereas the Nrf2-null       several growth factors, such as platelet-derived
                           mice displayed much lower levels of these enzymes80.           endothelial factor and bacterial lipopolysaccharide.
                           During extensive screening of vegetable extracts for           GSK-3β can be inactivated by phosphorylation of ser-
                           GST-inducing activity in cultured rat liver epithelial         ine-9, either through WNT signalling or through acti-
                           RL-34 cells, Morimitsu and colleagues have identified a        vation of the PI3K–AKT pathway110. Stabilization of
                           sulphoraphane analogue, 6-methylsulphinylhexyl                 β-catenin also occurs in the case of either mutation of
                           isothiocyanate (6-HITC), as a key GST-inducer present          APC111 or axin112. In addition, a point mutation at the
                           in Japanese horseradish, wasabi (Wasabia japonica or           phosphorylation site of the amino-terminal domain
                           Eutrema wasabi Maxim)98. The compound potently                 of β-catenin turns it into an oncoprotein103 that is
                           induced both class α Gsta1 and class π Gstp1 isozymes          resistant to phosphorylation by GSK-3β.
                           in RL-34 cells by stimulating nuclear translocation of             Once β-catenin is stabilized, it translocates into
                           Nrf2 and subsequent activation of Are. Oral adminis-           the nucleus and interacts with lymphoid enhancer
                           tration of 6-HITC resulted in the induction of hepatic         factor (LEF)/T-cell factor (TCF) transcription factors,
                           phase II detoxification enzymes to a greater extent than       resulting in transcriptional activation of various
                           sulphoraphane, whereas this induction was abrogated            genes. Many of these gene products are involved in
                           in Nrf2-null mice98. In porcine renal epithelial cells,        processes such as cell-cycle regulation, cell adhesion
                           both curcumin and CAPE stimulated expression of                and cellular development103,113. Genes that undergo
                           Nrf2 by inactivating the Nrf2–Keap1 complex, which             transactivation mediated by the β-catenin–TCF/LEF
                           was associated with a significant increase in activity and     complex include those encoding c-MYC, cyclin-D1,
                           expression of Ho-1 (REF. 99; FIG. 4). p38 Mapk, which is       gastrin, human matrilysin (MMP7), keratin1,
                           upstream of Nrf2, seems to be involved in curcumin-            urokinase plasminogen-activated receptor (uPAR),
                           induced Ho1 gene induction. In another study, cur-             CD44 and ITF2 (REFS 114,115). Transcription factors
                           cumin increased nuclear translocation of Nrf2, Are             such as c-JUN and FRA1 — two components of AP1
                           DNA binding activity and GCL expression100. It is              — are reported to be regulated by the transcriptional
                           notable that both curcumin and CAPE bear an α,                 activity of the β-catenin–TCF/LEF complex 103.
                           β-unsaturated ketone moiety, and can therefore act as          Recently, a TCF4-binding element (TBE) has been
                           Michael-reaction acceptors that are able to modify cys-        identified in the COX2-promoter region, and the
                           teine thiols located in Keap1. Sulphoraphane also              β-catenin–TCF/LEF complex has been shown to
                           directly reacts with thiol groups of Keap1 (REF. 91) .         upregulate COX2 gene expression in human colorectal
                                                                                          HT29-APC cells116.
                           β-Catenin
                           β-Catenin is another important target of chemopre-             Phytochemicals that target β-catenin
                           ventive phytochemicals. β-Catenin is a multifunctional         Several dietary phytochemicals have been shown to
                           protein that was originally identified as a component          downregulate the β-catenin-mediated signalling
                           of the cell–cell adhesion machinery. It binds with the         pathway as part of their molecular mechanism of
                           cytosolic tail of E-cadherin and connects actin fila-          chemoprevention. Curcumin and CAPE inhibited
                           ments through α-catenin to form the cytoskele-                 tumorigenesis and decreased β-catenin expression in
                           ton101,102 (FIG. 5). It was identified as a component of the   the multiple intestinal neoplasia (Min/+) mouse
                           evolutionarily conserved WNT signalling pathway, and           model117. Moreover, curcumin reduced the cellular
                           is involved in developmental processes in many organ-          leves of β-catenin through caspase-mediated cleavage
                           isms, as well as in tumorigenesis. β-Catenin can also          of the protein118. Downregulation of β-catenin expres-
                           function as a transcription factor, and nuclear translo-       sion by resveratrol was observed in a human colon
                           cation of β-catenin has been associated with various           cancer cell line119. Expression of a β-catenin–
                           human cancers103.                                              TCF4-binding reporter construct was reduced in
                               The cytoplasmic β-catenin undergoes rapid                  HEK293 cells by EGCG 120,121. Indole-3-carbinol
                           turnover by a large multiprotein complex that consists         altered the pattern of β-catenin mutation in chemi-
                           of glycogen synthase kinase-3β (GSK-3β), adenoma-              cally-induced rat colon tumours122, inhibited adhe-
                           tous polyposis coli (APC), axin and conductin104,105.          sion, migration and invasion of cultured human
                           GSK-3β — either directly or through activation of              breast carcinoma cells, and upregulated E-cadherin
                           APC — phosphorylates β-catenin, leading to ubiquity-           and β-catenin123. A similar effect was observed with
                           lation followed by proteasomal degradation of                  tangeretin from citrus124. COX inhibitors have also
                           β-catenin104–106. Recently, the phosphorylation of the         been found to suppress β-catenin signalling and
                           serine-45 residue of β-catenin by casein kinase Iε             β-catenin–TCF/LEF transcriptional activity 125–127.


776   | OCTOBER 2003 | VOLUME 3                                                                                     www.nature.com/reviews/cancer
REVIEWS


             Growth factors                                                                                  As upregulation of COX2 promotes tumorigenesis,
                                                                                                             and β-catenin is found to regulate COX2 expression,
                                                                                WNT ligand                   modulation of β-catenin signalling could be another
                                        RTKs
                                                                                                             molecular target for chemoprevention by dietary
                                                                                 Frizzled receptor
              E-cadherin                                                                                     phytochemicals.

                                                                                                             Future directions
                                           PTEN
                                                                                                             Chemoprevention by edible phytochemicals is now
                               PI3K
                                                                                                             considered to be an inexpensive, readily applicable,
     β-cat




                                                                                                             acceptable and accessible approach to cancer control
                                           AKT/PKB                                                   S   P   and management. With healthcare costs being a key
                           β-cat                                  Dishevelled              β-cat
                                                                                                     T   P
                                                                                                             issue today, it would be cost-effective to promote the
                                                                                                             awareness and consumption of phytochemicals as a
                                                                                Ubiquitylation
 Curcumin
                                                                                                             cancer-preventive strategy for the general public.
 CAPE                                                                                                            Several nutrients and non-nutritive phytochemi-
 Resveratrol                                                                                                 cals are being evaluated in intervention trials for their
 COX inhibitors
                                                                                                             potential as cancer chemopreventive agents. Despite
                                                          β-cat




                        β-cat                                                                                significant advances in our understanding of multi-
                                                                                          Ub                 stage carcinogenesis, little is known about the mecha-
                               Indole-3-carbimol         APC GSK-3β                                  S   P   nism of action of most chemopreventive agents. The
                                                                                           β-cat
                                                     Axin/conductin
                                                                                                     T   P
                                                                                                             chemopreventive effects that most dietary phyto-
                                                                                          Ub                 chemicals exert are likely to be the sum of several dis-
                                                                                                             tinct mechanisms. Disruption or deregulation of
                                                                                                   26S       intracellular-signalling cascades often leads to malig-
                                   CBP/p300                                                                  nant transformation of cells, and it is therefore
                                                                     β-cat                                   important to identify the molecules in the signalling
                                                     ?
                                                                                                             network that can be affected by individual chemopre-
    Cell growth-
    regulatory genes                               TCF/LEF
                                                                                                             ventive phytochemicals to allow for better assessment
                                                                                                             of their underlying mechanisms.
                                                                                                                 In many cases, the chemopreventive effects of
                           Activation              Repression                                                dietary chemopreventives in cultured cells or tissues
                                                                                                             are only achievable at supraphysiological concentra-
                                                                                                             tions — such concentrations might not be attained
                                                                                                             when the phytochemicals are administered as part of
                                                                                        Proteasome           diet. Furthermore, phenolic phytochemicals are often
                                                                                                             present as glycosides or are converted to other conju-
Figure 5 | Effect of phytochemicals on β-catenin signalling. β-Catenin (β-cat) mediates                      gated forms after absorption, which might further
both growth-factor- and WNT-mediated signalling pathways. The interaction of a WNT-
                                                                                                             lower the bioavailablity. Both pharmacokinetic prop-
ligand with its transmembrane receptor — ‘frizzled receptor’ — recruits dishevelled protein,
which inactivates glycogen synthase kinase-3β (GSK-3β) by phosphorylation at serine-9. On                    erties and bioavailability are key problems in investi-
the other hand, interaction of a growth factor with receptor tyrosine kinase (RTK) leads to                  gating the dietary prevention of cancer and should be
the activation of phosphatidylinositol 3-kinase (PI3K), which, in turn, phosphorylates                       assessed carefully before undertaking intervention
AKT/protein kinase B (PKB). Phosphorylated AKT also inactivates GSK-3β by serine-9                           trials with dietary supplements.
phosphorylation. A tumour-suppressor protein phosphatase and tensin homologue deleted                            The development and use of chemopreventive
on chromosome 10 (PTEN) blocks AKT-mediated inactivation of GSK-3β. GSK-3β — a
                                                                                                             agents for intervention trials involve many scientific
component of a multiprotein complex that consists of GSK-3β, adenomatous polyposis coli
(APC), axin and conductin — regulates the intracellular fate of β-catenin, which, in its
                                                                                                             disciplines. With the advances in techniques to assess
membrane-bound form, acts as a component of the cell–cell adhesion machinery and, in its                     single nucleotide polymorphisms (SNPs), we are now
free cytosolic form, acts as a signalling molecule. In the absence of a growth factor or WNT                 more aware of the specific genes that can directly and
signal, GSK-3β phosphorylates cytosolic β-catenin at amino-terminal serine (S) and                           indirectly contribute to individual differences in the
threonine (T) residues, which is then targeted for ubiquitylation (Ub) by ubiquitin ligase                   susceptibility to carcinogenesis. When high-risk
followed by proteasomal degradation. In response to the above stimuli, the inactivation of                   groups are identified, practitioners might be able to
GSK-3β results in cytosolic stabilization of β-catenin. Besides inactivation of GSK-3β,
mutation of either APC or axin as well as β-catenin causes its stabilization in the cytoplasm.
                                                                                                             recommend specific dietary supplements that can
Stabilized cytosolic β-catenin translocates to the nucleus and binds to T-cell factor                        modulate or restore the cellular-signalling events that
(TCF)/lymphoid enhancing factor (LEF). The β-catenin–TCF/LEF complex acts as a                               are likely to be disrupted in these individuals. The term
transcription factor and activates transcription of genes that are involved in the regulation of             ‘nutragenomics’ has been coined, and much attention
cellular growth processes. Some chemopreventive phytochemicals have recently been                            is being focused on this relatively new area of research.
reported to target β-catenin-mediated signalling pathways. Curcumin downregulates                            Tailored supplementation with designer foods that
β-catenin through caspase-mediated degradation of the protein, resulting in decreased
                                                                                                             consist of chemopreventive phytochemicals — each
DNA-promoter-binding activity of the β-catenin–TCF/LEF complex and reduced levels of
c-MYC protein. Caffeic acid phenethyl ester (CAPE) and resveratrol also attenuate                            having their own distinct anticancer mechanisms —
expression of β-catenin. Epigallocatechin gallate (EGCG) inhibits β-catenin–TCF4 reporter                    will be available in the near future. These should be
activity and reduces β-catenin protein levels. Indole-3-carbinol shifts the pattern of                       developed in line with advances in the genetic and
β-catenin mutations, thereby hampering its nuclear translocation.                                            molecular epidemiology of carcinogenesis.


NATURE REVIEWS | C ANCER                                                                                                           VOLUME 3 | OCTOBER 2003 | 7 7 7
Cancer Chemoprevention with Dietary Phytochemicals Review
Cancer Chemoprevention with Dietary Phytochemicals Review
Cancer Chemoprevention with Dietary Phytochemicals Review

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Cancer Chemoprevention with Dietary Phytochemicals Review

  • 1. REVIEWS CANCER CHEMOPREVENTION WITH DIETARY PHYTOCHEMICALS Young-Joon Surh Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals. Cancer is a growing health problem around the world A wide array of substances derived from the diet — particularly with the steady rise in life expectancy, have been found to stimulate the development, growth increasing urbanization and the subsequent changes in and spread of tumours in experimental animals, and to environmental conditions, including lifestyle. According transform normal cells into malignant ones. These are to a recent report by the World Health Organization regarded as suspected human carcinogens. (WHO), there are now more than 10 million cases of So, many dietary constituents can increase the risk of cancer per year worldwide. In 2003, it is estimated that developing cancer, but there is also accumulating evi- approximately 1,300,000 new cases of cancer will be dence from population as well as laboratory studies to diagnosed, and more than 550,000 people will die from support an inverse relationship between regular con- cancer in the United States alone. sumption of fruit and vegetables and the risk of specific Although there is no ‘magic bullet’ that can com- cancers. Several organizations — such as the WHO, the pletely conquer cancer, many types of the disease American Cancer Society, the American Institute of might be avoidable. Cancer risk can be reduced by Cancer Research (AICR) and the National Cancer eliminating the identified carcinogens — or at least Institute (NCI) — have established dietary guidelines to minimizing exposure to them — but, without com- help people reduce the cancer risk (for further informa- plete identification of the corresponding risk factors, tion, see the 1997 World Cancer Research Fund and such primary prevention might be difficult to imple- AICR report in online links box). ment. Furthermore, the avoidance of some risk factors Many clinical trials on the use of nutritional supple- could require large lifestyle changes, which are not easy ments and modified diets to prevent cancer are ongo- to implement. ing. It is conceivable that in the future people might only It has been estimated that more than two-thirds of need to take specially formulated pills that contain sub- human cancers could be prevented through appropriate stances derived from edible plants to prevent cancer or lifestyle modification. Richard Doll and Richard Peto delay its onset2. However, a precise assessment of the have reported that 10–70% (average 35%) of human mechanisms by which the components of fruit and veg- cancer mortality is attributable to diet1. Their observa- etables prevent cancer is necessary before they can be College of Pharmacy, tions, which are based on statistical and epidemiological recommended for inclusion in dietary supplements or Seoul National University, data, mainly concerned dietary factors that increase risk. before they can be tested in human intervention trials. Shinlim-dong, Kwanak-ku, Although the exact percentage is uncertain, there are Phytochemicals are non-nutritive components in the Seoul 151-742, South Korea. e-mail: several lines of compelling evidence from epidemiologi- plant-based diet (‘phyto’ is from the Greek word mean- surh@plaza.snu.ac.kr cal, clinical and laboratory studies that link cancer risk ing plant) that possess substantial anticarcinogenic and doi:10.1038/nrc1189 to the nutritional factors. antimutagenic properties. Given the great structural 768 | OCTOBER 2003 | VOLUME 3 www.nature.com/reviews/cancer salutefaq.info
  • 2. REVIEWS Summary diversity of phytochemicals, it is not feasible to define structure–activity relationships to deduce their • Many population-based studies have highlighted the ability of macronutrients and underlying molecular mechanisms. A better approach micronutrients in vegetables and fruit to reduce the risk of cancer. Recently, attention is to analyse their effects on cancer-associated has been focused on phytochemicals — non-nutritive components in the plant-based signal-transduction pathways. diet that possess cancer-preventive properties. • Despite remarkable progress in our understanding of the carcinogenic process, Importance of plant-derived foods the mechanisms of action of most chemopreventive phytochemicals have not been More than 250 population-based studies, including fully elucidated. case–control and cohort studies, indicate that people • Chemopreventive phytochemicals can block initiation or reverse the promotion stage who eat about five servings of fruit and vegetables a day of multistep carcinogenesis. They can also halt or retard the progression of have approximately half the risk of developing cancer — precancerous cells into malignant ones. particularly cancers of the digestive and respiratory • Many molecular alterations associated with carcinogenesis occur in cell-signalling tracts — of those who eat fewer than two servings. In pathways that regulate cell proliferation and differentiation. One of the central the United States, these observations led to the develop- components of the intracellular-signalling network that maintains homeostasis is the ment of public-health campaigns such as the ‘Five-a-Day family of mitogen-activated protein kinases (MAPKs). for Better Health’ programme and a more recent ‘Savor • Numerous intracellular signal-transduction pathways converge with the activation the Spectrum’ campaign — both were designed to of the transcription factors NF-κB and AP1. As these factors mediate pleiotropic increase the ingestion of fruit and vegetables by the effects of both external and internal stimuli in the cellular-signalling cascades, they population (BOX 1). Increased consumption of fruit and are prime targets of diverse classes of chemopreventive phytochemicals. vegetables is a global priority in the prevention of cancer • Basic helix–loop–helix transcription factors such as NRF2 regulate expression of phase II and other chronic disorders. According to the WHO enzymes, which detoxify carcinogens and protect against oxidative stress. A number of Report 2002, there are at least 2.7 million deaths globally phytochemicals have been shown to induce expression of phase II enzymes via NRF2. per year, which are primarily attributable to low fruit • β-Catenin, a multifunctional protein that was originally identified as a component and vegetable intake. of cell–cell adhesion machinery, is another important molecular target for Vegetables and fruit are excellent sources of cancer- chemoprevention. Several dietary phytochemicals have been shown to target preventive substances. The NCI has identified about this molecule. 35 plant-based foods that possess cancer-preventive Box 1 | Chemoprevention initiatives A number of government programmes have been created in the United States and in Europe to increase vegetable consumption and decrease cancer incidence. These include the following: The ‘Five-A-Day for Better Health’ programme Founded in late 1991, this is the first nationwide health-promotion campaign to encourage people in the United States to eat fruit and vegetables — at least five servings a day — to reduce the risk of cancer and other chronic diseases. Over the past decade, there has been a steady increase in both awareness of the health benefits of fruit and vegetables and their consumption in the United States. The National Cancer Institute (NCI) has recently completed a review of this programme and reported a series of recommendations for the next round of the initiative (for further information, see the ‘Five-A-Day for Better Health’ report in online links box). ‘Savor the Spectrum’ The NCI’s spring 2002 media promotion, entitled ‘Savor the Spectrum’, urges all Americans to eat five to nine servings of colourful fruit and vegetables a day for better health. The message of this programme is based on current research showing that phytonutrients from different colour groups are powerful disease fighters that help our body fight off cancer and heart disease. NCI has produced a series of guidelines featuring each colour of the‘rainbow’ of fruit and vegetables. European Prospective Investigation of Cancer and Nutrition (EPIC) EPIC is one of the most important multicentre prospective cohort studies ever launched worldwide. Beginning in 1992, EPIC has involved more than half a million (520,000) participants recruited by 20 centres in 10 countries under the coordination of the International Agency for Research on Cancer (IARC) and partly funded by the ‘Europe Against Cancer’ programme of the European Commission, as well as by the participating countries. EPIC focuses on identifying the dietary determinants of cancer, and is aimed at expanding the presently limited knowledge of the role of nutrition and other lifestyle factors in the aetiology and prevention of cancer and other life-threatening diseases. Global Strategy on Dietary Prevention of Cancer For a global extension of the ‘Five-A-Day’ concept of boosting increased consumption of fruit and vegetables, the WHO organized the third Biennial ‘Five-A-Day’ International Symposium on January 14–15 2003 in Berlin, Germany. At the meeting, Derek Yach, the WHO Executive Director of Noncommunicable Diseases & Mental Health, said “Increasing the consumption of fruit and vegetables is a necessary part of the effort to reduce the growing global burden of chronic diseases including cancer.” The guidelines stated “choose most of the foods you eat from plant sources”. NATURE REVIEWS | C ANCER VOLUME 3 | OCTOBER 2003 | 7 6 9
  • 3. REVIEWS Pro-carcinogen cancer. Recently, the focus and emphasis have shifted to Detoxification Secretion the non-nutritive phytochemicals. The NCI has deter- mined in laboratory studies that more than 1,000 differ- Metabolic ent phytochemicals possess cancer-preventive activity. It activation is estimated that there could be more than 100 different Cancer-blocking phytochemicals in just a single serving of vegetables. agents Detoxification As early as 1980, the NCI’s Chemoprevention Ellagic acid Indole-3-carbinol Ultimate Programme of the Division of Cancer Prevention and carcinogen Sulphoraphane Control began evaluating phytochemicals for safety, effi- Flavonoids cacy and applicability for cancer prevention. Michael Sporn coined the term ‘chemoprevention’ in the mid- 1970s to describe the strategy of blocking or slowing the Normal onset of premalignant tumours with relatively nontoxic cell chemical substances. To better define and guide research in the field of chemoprevention, the NCI Division of Initiation Preneoplastic Neoplastic Cancer Prevention started the Chemoprevention (1–2 days) cells cells Implementation Group in 1998, and then the Rapid Promotion Progression Access to Preventive Intervention Development pro- (>10 years) (>1 year) gramme. The NCI has more than 400 potential agents under investigation and is sponsoring more than 65 Initiated cell Phase I, Phase II and Phase III chemoprevention trials. These involve various substances or their mixtures, Cancer-suppressing many of which are foodborne phytochemicals. agents β-Carotene Curcumin Mechanisms of chemoprevention EGCG Carcinogenesis is generally recognized as a multistep Genistein Resveratrol process in which distinct molecular and cellular alter- [6]-Gingerol ations occur. From the study of experimentally induced Capsaicin carcinogenesis in rodents, tumour development is con- Figure 1 | Dietary phytochemicals that block or suppress multistage carcinogenesis. sidered to consist of several separate, but closely linked, Carcinogenesis is initiated with the transformation of the normal cell into a cancer cell (initiated stages — tumour initiation, promotion and progression. cell). These cells undergo tumour promotion into preneoplastic cells, which progress to neoplastic cells. Phytochemicals can interfere with different steps of this process. Some chemopreventive Although these divisions are an oversimplification of phytochemicals inhibit metabolic activation of the procarcinogens to their ultimate electrophilic carcinogenesis, it is useful to think in these stages when species, or their subsequent interaction with DNA. These agents therefore block tumour initiation considering possible opportunities for chemoprevention. (blocking agents). Alternatively, dietary blocking agents can stimulate the detoxification of Initiation is a rapid and irreversible process that carcinogens, leading to their secretion from the body. Other phytochemicals suppress the later involves a chain of extracellular and intracellular steps (promotion and progression) of multistage carcinogenesis (suppressing agents). Some events. These include the initial uptake of or exposure phytochemicals can act as both blocking and suppressing agents. Adapted from REF. 128. to a carcinogenic agent, its distribution and transport to organs and tissues where metabolic activation and detoxification can occur, and the covalent interaction of properties. These include garlic, soybeans, ginger, reactive species with target-cell DNA, leading to geno- onion, turmeric, tomatoes and cruciferous vegetables toxic damage. In contrast to initiation, tumour promo- (for example, broccoli, cabbage, cauliflower and tion is considered to be a relatively lengthy and Brussels sprouts). Numerous cell-culture and animal- reversible process in which actively proliferating pre- model studies have been conducted to evaluate the neoplastic cells accumulate. Progression, the final stage ability of specific edible plants to prevent cancer. of neoplastic transformation, involves the growth of a tumour with invasive and metastatic potential. Beyond vitamins to phytochemicals According to the conventional classification origi- Many population-based studies have highlighted the nally proposed by Lee Wattenberg, chemopreventive ability of macronutrients (for example, carbohydrate, agents are subdivided into two main categories — proteins, fat and fibre) and micronutrients (for exam- blocking agents and suppressing agents3. Blocking ple, antioxidant vitamins and trace minerals) that are agents prevent carcinogens from reaching the target contained in vegetables and fruit to reduce the risk of sites, from undergoing metabolic activation or from cancer. The most exciting findings have been achieved subsequently interacting with crucial cellular macro- with antioxidant vitamins and their precursors, which molecules (for example, DNA, RNA and proteins). are found in dark, leafy green vegetables and Suppressing agents, on the other hand, inhibit yellow/orange fruit and vegetables. The NCI has there- the malignant transformation of initiated cells, in fore sponsored a series of human intervention trials either the promotion or the progression stage. with individual vitamins and minerals. However, plants Chemopreventive phytochemicals can block or reverse contain numerous chemical substances other than these the premalignant stage (initiation and promotion) of micronutrients that might also be useful in preventing multistep carcinogenesis. They can also halt or at least 770 | OCTOBER 2003 | VOLUME 3 www.nature.com/reviews/cancer
  • 4. REVIEWS Turmeric Grapes OH O O O O H3C CH3 HO HO OH OH Curcumin Resveratrol Chilli peppers Honey O O O HO H3C N O H HO HO Capsaicin Caffeic acid phenethyl ester Ginger Garlic O OH O H3C S HO [6]-Gingerol Diallyl sulphide HO OH Green tea Cabbage OH OH O OH O N HO OH H O Indole-3-carbinol OH OH Epigallocatechin-3-gallate Soybeans Broccoli OH OH O S C H3C N S HO O O Genistein Sulphoraphane Tomatoes Lycopene Figure 2 | Representative chemopreventive phytochemicals and their dietary sources. retard the development and progression of precancer- include carcinogen activation/detoxification by xenobi- ous cells into malignant ones (FIG. 1). Recent advances otic metabolizing enzymes; DNA repair; cell-cycle in our understanding of the carcinogenic process at progression; cell proliferation, differentiation and apop- the cellular and molecular level have shown this block- tosis; expression and functional activation of oncogenes ing and suppressing categorization to be an oversim- or tumour-suppressor genes; angiogenesis and metasta- plification, and numerous cellular molecules and sis; and hormonal and growth-factor activity (for events that could be potential targets of chemopreven- further information, see ONLINE TABLE 1). tive agents have been more specifically identified4–6. Therefore, the ability of any single chemopreventive Cellular signalling molecules as targets phytochemical to prevent tumour development During the past two or three decades, there has been should be recognized as the outcome of the combina- substantial progress in identifying the biochemical tion of several distinct sets of intracellular effects, events that are associated with the multistage process rather than a single biological response. of carcinogenesis, and we are now better aware of how FIGURE 2 illustrates the chemical structures of repre- certain dietary phytochemicals are able to alter this sentative dietary phytochemicals that have been known process (FIG. 1). Remarkable advances in the cellular to possess chemopreventive potential and their dietary and molecular genetics of carcinogenesis — such as sources. The cellular and molecular events affected or the identification of numerous oncogenes and regulated by these chemopreventive phytochemicals tumour-suppressor genes, specific genes encoding NATURE REVIEWS | C ANCER VOLUME 3 | OCTOBER 2003 | 7 7 1
  • 5. REVIEWS Despite this progress, the identification of molecular and cellular targets of chemopreventive phytochemicals is still incomplete. Many of the molecular alterations that PI3K MEKK1 RAS PKC Curcumin EGCG are associated with carcinogenesis occur in cell-signalling Resveratrol pathways that regulate cell proliferation and differentia- tion. One of the central components of the intracellular- EGCG signalling network that maintains homeostasis is the PDK NIK MEK1/2 RAF family of proline-directed serine/threonine kinases — Cytoplasm MKK4 the mitogen-activated protein kinases (MAPKs; FIG. 3). Abnormal or improper activation or silencing of the MAPK pathway or its downstream transcription fac- Genistein tors can result in uncontrolled cell growth, leading to EGCG AKT IKK-α/β/γ ERK1/2 p38 JNK Curcumin malignant transformation. Some phytochemicals EGCG Curcumin Resveratrol ‘switch on’ or ‘turn off ’ the specific signalling mole- EGCG cule(s), depending on the nature of the signalling cas- Genistein cade they target, preventing abnormal cell proliferation Resveratrol Capsaicin and growth4–12. Cell-signalling kinases other than MAPKs, such as protein kinase C (PKC) and phos- phatidylinositol 3-kinase (PI3K), are also important ELK1/SAP1 SRF c-JUN ATF2 targets of certain chemopreventive phytochemicals. P These upstream kinases activate a distinct set of tran- c-FOS c-JUN SRE TRE NF-κB IκB NF-κB scription factors, including nuclear factor κB (NF-κB) and activator protein 1 (AP1; FIG. 3). Ub NF-κB and AP1 AP1 c-FOS c-JUN Numerous intracellular signal-transduction pathways NF-κB 26S converge with the activation of the transcription factors Curcumin κB binding site TRE NF-κB and AP1, which act independently or coordinately to regulate target-gene expression (FIG. 3). Nucleus Aberrant activation of NF-κB has been associated Proteasome with protection against apoptosis and stimulation of proliferation in malignant cells13,14, and overexpression Figure 3 | Effect of phytochemicals on activation of NF-κB and AP1. The NF-κB signalling pathway converges on the multiprotein complex called the IκB kinase (IKK) signalsome, of NF-κB is causally linked to the phenotypic changes leading to IκB phosphorylation (P), ubiquitylation (Ub) and subsequent degradation by the 26S that are characteristic of neoplastic transformation15. proteasome. NF-κB is then released and translocated to the nucleus, where it binds to specific Many chemopreventive phytochemicals that are promoter regions of various genes. The IKK signalsome is activated by the NF-κB-inducing derived from the diet have been shown to suppress kinase (NIK). Pathways that regulate NIK are likely to involve signalling through a family of constitutive NF-κB activation in malignant cells or mitogen-activated protein kinases (MAPKs), such as MAPK kinase kinase-1 (MEKK1) — a NF-κB activation induced by the external tumour pro- kinase that lies upstream of extracellular signal-regulated kinase (ERK) — MAPK/ERK kinase (MEK1/2) and p38 MAPK. Recent reports showed that NF-κB activation is also regulated by moter phorbol 12-myristate 13-acetate (PMA) or the AKT signalling pathway58,59,129. Phosphatidylinositol 3-kinase (PI3K) activates AKT/protein tumour-necrosis factor-α (TNF-α)11,16,17. kinase B via phosphorylation by 3-phosphoinositide-dependent protein kinase-1 (PDK1). AP1 is another transcription factor that regulates Genistein specifically inhibits AKT activity and AKT-mediated NF-κB activation58,59. expression of genes that are involved in cellular adapta- Epigallocatechin gallate (EGCG) can block the activities of PI3K and AKT49. There is crosstalk tion, differentiation and proliferation. Functional activa- between the AKT and NF-κB signalling pathways — AKT phosphorylation leads to activation of tion of AP1 is associated with malignant transformation NF-κB by stimulating IκB kinase (IKK) activity129. IKK is also a target for chemopreventive as well as tumour promotion18–21. AP1 consists of either phytochemicals, including curcumin24,28, resveratrol71 and EGCG45,130. The MAPK family proteins also regulate expression of AP1 — a heterogenous set of dimeric proteins made up of homo- or heterodimers between members of the JUN members of the c-JUN, c-FOS and ATF families. In this pathway, activation of ERK1/2 and FOS families, which interact via a leucine-zipper phosphorylates ELK1, c-JUN NH2-terminal kinase (JNK) phosphorylates c-JUN, and p38 domain. This transcription factor is also regulated by phosphorylates both ELK1 and ATF2. This leads to transcriptional activation of target genes. the MAPK-signalling cascade21–23. External stimuli — including phorbol ester and ultraviolet radiation — activate specific isoforms As NF-κB and AP1 are ubiquitous eukaryotic tran- of protein kinase C (PKC), which, in turn, leads to stimulation of the p21 RAS–ERK signalling scription factors that mediate pleiotropic effects of both pathway via RAF and MEK1/2. Activation of p38 and JNK is mediated by MAPK kinase-4 (MKK4), which is under control of the upstream kinase MEKK. external and internal stimuli in the cellular-signalling cascades, they are prime targets of diverse classes of chemopreventive phytochemicals (FIG. 3). carcinogen-metabolizing enzymes, DNA-repair Phytochemicals targeting NF-κB and AP1 enzymes and proteins, and regulators of cell cycle and Curcumin, [6]-gingerol and capsaicin. Curcumin — a apoptosis — have given us a better insight into the yellow pigment that is present in the rhizome of process of neoplastic transformation. Advances have turmeric (Curcuma longa L.) and related species — is also been made in identifying the factors that mediate one of the most extensively investigated phytochemicals, tumour invasion, metastasis and angiogenesis. with regard to chemopreventive potential. Curcumin 772 | OCTOBER 2003 | VOLUME 3 www.nature.com/reviews/cancer
  • 6. REVIEWS has been shown to suppress tumour promotion in a activation of JNK and p38, and deactivation of ERK41. mouse model of skin carcinogenesis. Furthermore, pre- Pharmacological inhibition or dominant-negative treatment of human colonic epithelial cells with cur- forms of JNK and p38, but not of ERK, abrogated the cumin inhibited TNF-α-induced cyclooxygenase-2 capsaicin-induced apoptosis in these cells41. (COX2) gene transcription and NF-κB activation24. In this study, curcumin inhibited IκB degradation by Epigallocatechin gallate (EGCG). EGCG is an antioxi- downregulation of NF-κB-inducing kinase (NIK) and dant and chemopreventive polyphenol that is found in IκB kinase (IKK)α/β. green tea. It has been shown to suppress malignant When curcumin was applied topically to the dorsal transformation in a PMA-stimulated mouse epidermal skin of female ICR mice (a model initially developed at JB6 cell line, which seemed to be mediated by blocking the Institute of Cancer Research, Fox Chase Cancer activation of Ap1 (REFS 42,43) or Nf-κb44. More recently, Center), it prevented the PMA-induced activation of EGCG treatment of human epidermal keratinocytes both Nf-κb and Ap1 (REF. 25). The inhibition of Nf-κb resulted in significant inhibition of ultraviolet (UV)- was accompanied by blockade of degradation via phos- B-light-induced activation of IKKα, phosphorylation phorylation of Iκbα and also by reduced nuclear translo- and subsequent degradation of IκBα and nuclear cation of the p65 subunit of Nf-κb (REF. 26; FIG. 3). translocation of p65 (REF. 45). In the Hras-transformed Topically applied curcumin inhibited the catalytic activ- epidermal JB6 cells, EGCG inhibited Ras-activated Ap1 ity of epidermal extracellular-signal-regulated kinase activity 46,47. Similar Ap1 inhibition was observed in the (Erk)1/2, which could account for its ability to inactivate epidermis of transgenic mice that harbour an Ap1-driven Nf-κb and Cox2 (REF. 26). Curcumin also suppressed the luciferase reporter gene. TNF-α-induced nuclear translocation and DNA binding Nomura and colleagues48 have reported the of NF-κB in a human myeloid leukaemia cell line by inhibitory effect of EGCG on UV-light-induced PI3K blocking phosphorylation and subsequent degradation activation in mouse epidermal cells. The reduction of of IκB27. PMA- and hydrogen-peroxide-induced activa- signalling via PI3K–AKT–NF-κB by EGCG was tion of NF-κB was similarly attenuated by curcumin reported to be mediated through inhibition of ERBB2 treatment. In addition, curcumin inhibited IκBα phos- (also known as HER2/NEU) receptor tyrosine phos- phorylation in human multiple myeolma cells28 and phorylation49. EGCG also inhibited vascular endothelial murine melanoma cells29 through suppression of IKK growth factor (VEGF) production by inhibiting consti- activity, which contributed to its antiproliferative, tutive activation of both STAT3 and NF-κB — but not proapoptotic and/or antimetastatic activities. of ERK or AKT — in human breast and head and neck [6]-Gingerol — a phenolic substance that is responsi- cancer cell lines50. ble for the spicy taste of ginger (Zingiber officinale EGCG treatment resulted in inhibition of cell Roscoe) — was reported to inhibit tumour promotion growth, G0/G1-phase arrest of the cell cycle and induc- and PMA-induced ornithine decarboxylase (ODC) activ- tion of apoptosis in human epidermoid carcinoma ity and Tnf-α production in mouse skin30. More recently, (A431) cells, but not in normal human epidermal ker- [6]-gingerol has been found to inhibit epidermal growth atinocytes (NHEK)51. A431 cells were more susceptible factor (Egf)-induced Ap1 activation and neoplastic trans- to EGCG-mediated inhibition of constitutive NF-κB formation in mouse epidermal JB6 cells — this was expression and activation than NHEK cells, indicating shown using reduced anchorage-independent formation that EGCG-caused cell-cycle deregulation and apoptosis of cell colonies in soft agar 31. of cancer cells might be mediated through NF-κB inhi- Capsaicin — a pungent component of hot chilli pep- bition. The roles of EGCG and other tea polyphenols on per (Capsicum annuum L.) — has been suspected to act cellular signalling have been reviewed recently 52,53. as a carcinogen or a co-carcinogen in experimental ani- mals because of its irritant properties, but other studies Genistein. Genistein — a soy-derived isoflavone — is indicate that the compound has chemopreventive and believed to contribute to the putative breast- and chemoprotective effects32–35. Topical application of cap- prostate-cancer-preventive activity of soya. Genistein saicin inhibited PMA-induced mouse-skin tumour for- inhibited PMA-induced AP1 activity, expression of mation36 and activation of Nf-κb37. This was attributed c-FOS and ERK activity in certain human mammary to blockade of Iκbα degradation and Nf-κb transloca- cell lines54. Genistein treatment abrogated NF-κB DNA tion into the nucleus. PMA- or Tnf-α-induced Ap1 acti- binding in human hepatocarcinoma cells stimulated vation in mouse skin and cultured human leukaemia with hepatocyte growth factor55. The downregulation HL-60 cells was also blocked by capsaicin38. of c-Jun and c-Fos by genistein was also observed in Capsaicin inhibited constitutive and induced acti- UV-light-stimulated skin of SENCAR (sensitivity to vation of NF-κB in human malignant-melanoma cells, carcinogenesis) mice56. leading to inhibition of melanoma-cell proliferation39. Genistein at the apoptogenic concentration also Capsaicin also induced apoptosis in cultured Jurkat inhibited the H2O2- or TNF-α-induced activation of cells through generation of reactive oxygen species NF-κB in both the androgen-sensitive (LNCaP) and - (ROS) and rapid activation of c-JUN NH2-terminal insensitive (PC3) human prostate cancer cell lines by kinase (JNK)40. Similarly, capsaicin caused apoptotic reducing phosphorylation of IκBα and the nuclear death in HRAS-transformed human mammary translocation of NF-κB57. Genistein-mediated inactivation epithelial cells, which was accompanied by marked of NF-κB was associated with downregulation of AKT in NATURE REVIEWS | C ANCER VOLUME 3 | OCTOBER 2003 | 7 7 3
  • 7. REVIEWS the prostate cancer58 and mammary cancer59 cells. The HeLa cell cultures, which was associated with inhibition same studies also revealed that AKT transfection led to of PKC and protein tyrosine kinase68. Similarly, resvera- the activation of NF-κB, which was completely blocked trol blocked UV-light-induced activation of NF-κB by genistein treatment, indicating that inhibition of the through suppression of IKK activation69. Resveratrol crosstalk between AKT and NF-κB could provide a suppressed TNF-α-induced phosphorylation and novel mechanism responsible for pro-apoptotic activity nuclear translocation of p65, and NF-κB-dependent of genistein. reporter-gene transcription in myeloid leukaemia PMA- or TNF-α-induced NF-κB DNA binding cells70. The suppression of NF-κB coincided with sup- and NF-κB-derived COX2 promoter activity, as well as pression of AP1. Resveratrol also inhibited the TNF- COX2 expression, were inhibited in human alveolar induced activation of MAPK kinase (MEK) and JNK, epithelial carcinoma cells by genistein treatment60. In and abrogated TNF-induced caspase activation70. human U937 monocytes, genistein exerted no sub- Resveratrol induced apoptosis in fibroblasts after the stantial inhibitory effect on DNA binding of NF-κB, induced expression of oncogenic HRAS, possibly LUCIFERASE-REPORTER-GENE ASSAY but markedly attenuated its transcriptional activity 61. through inhibition of NF-κB activation by blocking A recombinant method that is Consistent with this notion, genistein strongly sup- IKK activity71. used to measure transcriptional presses NF-κB transcriptional activity in PMA-stimu- activity in which the regulatory lated human mammary epithelial cells, as determined Miscellaneous phytochemicals. In addition to the sequence (for example, by the LUCIFERASE-REPORTER-GENE ASSAY but does not inter- aforementioned phytochemicals, caffeic acid promoter or enhancer) of interest is joined to a firefly fere with IκB degradation, and subsequent nuclear phenethyl ester (CAPE), sulphoraphane, silymarin, luciferase gene that, following translocation and DNA binding of NF-κB (M.-H. apigenin, emodin, quercetin and anethole have also activation, produces light from Chung and Y.-J.S., unpublished observations). been reported to suppress the activation of NF-κB and luciferin in the presence of ATP Genistein might block the phosphorylation of p65 AP1, which might contribute to their chemopreventive added to the assay mixture. The relative intensity of the light without influencing the IKK activity, thereby hamper- and/or cytostatic effects16. emission is measured with a ing its interaction with co-activators such as cyclic luminometer. AMP response element binding protein (CREB)-binding NRF–KEAP1 complex protein (CBP/p300), a key element of the transcrip- Other than suppressing tumour promotion or progres- CREB tion-initiation complex that bridges DNA-bound sion, another important approach to chemoprevention (Cyclic AMP response element binding protein). CREB is a transcription factors to the transcription machinery. is to block the DNA damage caused by carcinogenic leucine zipper transcription insult — the initiation stage of carcinogenesis. Toxic factor that binds to DNA at the Resveratrol. Resveratrol (3,4′,5-trihydroxy-trans- xenobiotic (‘xeno’, from the Greek word meaning ‘for- cyclic AMP response element stilbene) is a phytoalexin that is present in grapes (Vitis eign’) chemicals, including carcinogens, are detoxified (CRE) as a homo- or heterodimer. It has pivotal roles vinifera) and a key antioxidant ingredient of red wine. It by PHASE II ENZYMES — such as glutathione S-transferase in the control of cellular is believed to be responsible for the so-called ‘French (GST) and NAD(P)H:quinone oxidoreductase (NQO). proliferation and differentiation, paradox’, in which consumption of red wine has been The phase II enzyme induction system is an apoptosis, intermediary shown to reduce the mortality rates from cardiovascular important component of the cellular stress response metabolism, inflammation and diseases and certain cancers. Resveratrol treatment in which a diverse array of electrophilic and oxidative numerous other responses, particularly in hepatocytes, inhibited PMA-induced COX2 expression and catalytic toxicants can be removed from the cell before they adipocytes and haematopoietic activity, via the cyclic-AMP response element (CRE), in are able to damage the DNA. Antioxidants exert their cells. human mammary epithelial cells62,63. It also inhibited protective effects not only by scavenging ROS, but PKC activation, AP1 transcriptional activity and the also by inducing de novo expression of genes that PHASE II ENZYMES A group of xenobiotic induction of COX2-promoter activity in PMA-treated encode detoxifying/defensive proteins, including metabolizing enzymes that are cells. Resveratrol induced apoptosis and reduced the phase II enzymes. Many xenobiotics activate mainly involved in the constitutive activation of NF-κB in both rat and human stress-response genes in a manner similar to that inactivation and excretion of pancreatic carcinoma cell lines64. Mammary tumours achieved by antioxidants. These genes encode carcinogens and other toxic isolated from rats treated with resveratrol displayed enzymes such as glutathione peroxidase, gamma-glu- chemical substances. reduced expression of Cox2 and matrix metallopro- tamylcysteine synthetase (γ-GCS), GST, NQO and ANTIOXIDANT-RESPONSIVE teinase (Mmp)-9, as well as reduced Nf-κb activation, heme oxygenase-1 (HO-1). The 5′-flanking regions ELEMENT compared with controls65. Treatment of human breast of these genes contain a common cis-element, known (ARE). A specific DNA- cancer MCF-7 cells with resveratrol also suppressed as the ANTIOXIDANT-RESPONSIVE ELEMENT (ARE) (FIG. 4). promoter-binding region that can be transcriptionally NF-κB activation and proliferation65. Many basic leucine zipper (bZIP) transcription activated by numerous Treatment of androgen-sensitive prostate cancer factors — including NRF, JUN, FOS, FRA, MAF and antioxidants and/or cells (LNCaP) with resveratrol caused downregulation AH receptor — bind to these ARE sequences and electrophiles. Many stress- of prostate-specific antigen and p65; these effects were modulate expression of some of the aforementioned response genes encoding phase associated with activation of p53, WAF1, p300/CBP stress-response genes72 (FIG. 4). II detoxification or antioxidant enzymes such as glutathione and APAF1 (REF. 66). Resveratrol-induced apoptosis in S-transferase, quinone reductase, mouse JB6 epidermal cells was associated with phos- NRF. During oxidative stress or other types of toxic and heme oxygenase-1 — which phorylation of p53, which seemed to be mediated insult that are induced by xenobiotic chemicals, cer- provide defence against cellular through activation of Erk and p38 (REF. 67). Yu and col- tain members of the helix–loop–helix bZIP family of oxidative stress — have this element in their 5′-flanking leagues have shown that resveratrol pretreatment gives transcription factors — particularly the nuclear fac- region to facilitate the rise to suppression of PMA- and UV-light-induced tor-erythroid 2p45 (NF-E2)-related factors (NRF1 transcription process. activation of AP1 and MAPKs (ERK2, JNK and p38) in and NRF2) — heterodimerize and bind to the ARE 774 | OCTOBER 2003 | VOLUME 3 www.nature.com/reviews/cancer
  • 8. REVIEWS Cell membrane carcinogen benzo[a]pyrene, which was not prevented by oltipraz, a chemopreventive agent with phase II enzyme inducing activity75,84. Nrf2-null mice also have PI3K PKC JNK ERK Curcumin CAPE defects in detoxifying carcinogens such as aflatoxin B185. Sulphoraphane Stable transfection of L929 cells with a dominant- p38 negative mutant form of Nrf2 abolished induction of P P SR SH Ho-1 by several toxicants86. Fibroblasts from Nrf2-null S T mice were found to express only about 15% as much KEAP1 KEAP1 S T NRF2 Gcs mRNA as wild-type cells87. Overexpression of NRF2 NRF2 activated ARE-mediated transcription in human C/EBPβ hepatoma (HepG2) cells, and this activation was 6-HITC further increased by tert-butylhydroquinone88. Sulphoraphane P P KEAP1 — a negative regulator of NRF. A cytosolic S T Phase II enzymes: actin-binding protein called Kelch-like ECH-associated NRF2 GSTA-2 protein 1 (KEAP1) has been identified as a docking site NQO-1 MAF r-GCLC at which the bZIP proteins are sequestered under nor- C/EBPβ r-GCLM mal physiological conditions. For example, KEAP1 CCAAT/XRE ARE HO-1 suppresses the transcriptional activity of NRF2 by retaining the transcription factor in the cytoplasm and hampering its nuclear translocation (FIG. 4). The mechanisms by which cells recognize chemo- preventive antioxidants or phase II enzyme inducers Figure 4 | Transcriptional activation by NRF2. NRF2 is a transcription factor that regulates have not been fully elucidated. The KEAP1–NRF2 expression of many detoxification or antioxidant enzymes. The Kelch-like-ECH-associated complex is an intracellular sensor that recognizes protein 1 (KEAP1) is a cytoplasmic repressor of NRF2 that inhibits its ability to translocate to redox signalling by detecting electrophiles or ROS89. the nucleus. These two proteins interact with each other through the double glycine-rich Many phase II gene inducers are able to generate ROS, domains of KEAP1 and a hydrophilic region in the NEH2 domain of NRF2. KEAP1 contains many cysteine residues. Phase II enzyme inducers and/or prooxidants can cause oxidation or else can be readily converted — nonenzymatically, or covalent modification (R) of these cysteine residues91. As a result, NRF2 is released from via REDOX CYCLING — or metabolized to electrophilic KEAP1. In addition, phosphorylation of NRF2 at serine (S) and threonine (T) residues by intermediates in the body. Phase II enzyme inducers kinases such as phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC)131, c-Jun NH2- mimic pro-oxidants and electrophiles, although most terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) is assumed to facilitate of them are antioxidants by nature. Therefore, it might the dissociation of NRF2 from KEAP1 and subsequent translocation to the nucleus. p38 can be more appropriate to call ARE an ‘electrophile both stimulate and inhibit the NRF2 nuclear translocation. In the nucleus, NRF2 associates response element’ (EpRE). It is plausible that these with small MAF (the term is derived from musculoaponeurotic-fibrosarcoma virus), forming a heterodimer that binds to the antioxidant-responsive element (ARE) to stimulate gene reactive species interact with thiol groups of KEAP1 expression. NRF2/MAF target genes encode phase II detoxification or antioxidant enzymes and oxidize or covalently modify the cysteine residues such as glutathione S-transferase α2 (GSTA2), NAD(P)H:quinone oxidoreductase (NQO1), within KEAP1 and also, possibly, NRF2 (REFS 90–93). γ-glutamate cysteine ligase (γ -GCLC and γ -GCLM) and heme oxygenase-1 (HO-1). PI3K This would cause KEAP1 to release NRF2, so it could also phosphorylates the CCAAT/enhancer binding protein-β (C/EBPβ), inducing its translocate to the nucleus and activate transcription of translocation to the nucleus and binding to the CCAAT sequence of C/EBP-β response phase II enzymes (FIG. 4). element within the xenobiotic response element (XRE), in conjunction with NRF2 binding to ARE132. Transfection of human neuroblastoma cells with PI3K activates ARE, which is In accordance with this model, sulphydryl-reactive attenuated by a pharmacological inhibitor of PI3K or dominant-negative NRF2 (REF. 133). agents — such as diethyl maleate —abrogated Curcumin and caffeic acid phenethyl ester (CAPE) disrupt the NRF2–KEAP1 complex, KEAP1 repression of NRF2, allowing release of the leading to increased NRF2 binding to ARE99,100. Sulphoraphane directly interacts with KEAP1 transcription factor 89. In this context, the cysteine by covalent binding to its thiol groups91. 6-(Methylsulfinyl)hexyl isothiocyanate (6-HITC) — a residues in KEAP1 could serve as a molecular sensor sulphoraphane analogue from Japanese horseradish wasabi — stimulates nuclear of intracellular redox status, ensuring the proper translocation of NRF2, which subsequently activates ARE 98. and timely expression of genes that are involved in cellular antioxidant defence or detoxification of electrophilic toxicants. sequence to activate transcription 73. In human hepatoma cells that are genetically engineered to Phytochemicals that activate NRF overexpress NRF1 or NRF2, both basal and inducible Exposure of HepG2 cells to the green-tea extract transcriptional activities of an ARE reporter gene induces expression of phase II detoxifying enzymes were increased. through ARE94. This upregulation was accompanied A role for NRF2 in the regulation of ARE-mediated by activation of ERK2 and JNK1, as well as immediate- REDOX CYCLING gene expression has been shown in studies involving early genes c-JUN and c-FOS. Subsequent studies have A reciprocal transformation Nrf2-null mice73. These mice fail to induce many of the shown that EGCG transcriptionally activated the between an oxidant and its genes involved in carcinogen detoxification and protec- phase II enzyme gene expression in HepG2 cells, as reductive counterpart. An example is conversion of tion against oxidative stress73–83. Most notably, the Nrf2- determined by the ARE reporter-gene assay95. In this catechol to quinone via null mice developed a larger number of tumours in the experiment, EGCG strongly activated all three MAPKs semiquinone or vice versa. forestomach after treatment with the ubiquitous (ERK, JNK and p38) and induced caspase-3-mediated NATURE REVIEWS | C ANCER VOLUME 3 | OCTOBER 2003 | 7 7 5
  • 9. REVIEWS cell death. Other phytochemicals such as phenethyl (CKI) has been shown to convert β-catenin into a isothiocyanate and sulphoraphane also differentially form that is favoured for phosphorylation by GSK-3β, regulated the activation of MAPKs and NRF, ARE- and so promotes destabilization of β-catenin107,108. Liu mediated luciferase reporter-gene activity, and phase II et al. reported a similar function of another isoform of enzyme gene induction96,97. casein kinase, CKIα109. Analysis of gene-expression profiles by an oligonu- So, β-catenin needs to be stabilized in the cyto- cleotide microarray revealed that sulphoraphane plasm to escape the degradation pathway. This occurs upregulated expression of Nqo1, Gst and Gcs in the in response to WNT signalling, as well as signalling by small intestine of wild-type mice, whereas the Nrf2-null several growth factors, such as platelet-derived mice displayed much lower levels of these enzymes80. endothelial factor and bacterial lipopolysaccharide. During extensive screening of vegetable extracts for GSK-3β can be inactivated by phosphorylation of ser- GST-inducing activity in cultured rat liver epithelial ine-9, either through WNT signalling or through acti- RL-34 cells, Morimitsu and colleagues have identified a vation of the PI3K–AKT pathway110. Stabilization of sulphoraphane analogue, 6-methylsulphinylhexyl β-catenin also occurs in the case of either mutation of isothiocyanate (6-HITC), as a key GST-inducer present APC111 or axin112. In addition, a point mutation at the in Japanese horseradish, wasabi (Wasabia japonica or phosphorylation site of the amino-terminal domain Eutrema wasabi Maxim)98. The compound potently of β-catenin turns it into an oncoprotein103 that is induced both class α Gsta1 and class π Gstp1 isozymes resistant to phosphorylation by GSK-3β. in RL-34 cells by stimulating nuclear translocation of Once β-catenin is stabilized, it translocates into Nrf2 and subsequent activation of Are. Oral adminis- the nucleus and interacts with lymphoid enhancer tration of 6-HITC resulted in the induction of hepatic factor (LEF)/T-cell factor (TCF) transcription factors, phase II detoxification enzymes to a greater extent than resulting in transcriptional activation of various sulphoraphane, whereas this induction was abrogated genes. Many of these gene products are involved in in Nrf2-null mice98. In porcine renal epithelial cells, processes such as cell-cycle regulation, cell adhesion both curcumin and CAPE stimulated expression of and cellular development103,113. Genes that undergo Nrf2 by inactivating the Nrf2–Keap1 complex, which transactivation mediated by the β-catenin–TCF/LEF was associated with a significant increase in activity and complex include those encoding c-MYC, cyclin-D1, expression of Ho-1 (REF. 99; FIG. 4). p38 Mapk, which is gastrin, human matrilysin (MMP7), keratin1, upstream of Nrf2, seems to be involved in curcumin- urokinase plasminogen-activated receptor (uPAR), induced Ho1 gene induction. In another study, cur- CD44 and ITF2 (REFS 114,115). Transcription factors cumin increased nuclear translocation of Nrf2, Are such as c-JUN and FRA1 — two components of AP1 DNA binding activity and GCL expression100. It is — are reported to be regulated by the transcriptional notable that both curcumin and CAPE bear an α, activity of the β-catenin–TCF/LEF complex 103. β-unsaturated ketone moiety, and can therefore act as Recently, a TCF4-binding element (TBE) has been Michael-reaction acceptors that are able to modify cys- identified in the COX2-promoter region, and the teine thiols located in Keap1. Sulphoraphane also β-catenin–TCF/LEF complex has been shown to directly reacts with thiol groups of Keap1 (REF. 91) . upregulate COX2 gene expression in human colorectal HT29-APC cells116. β-Catenin β-Catenin is another important target of chemopre- Phytochemicals that target β-catenin ventive phytochemicals. β-Catenin is a multifunctional Several dietary phytochemicals have been shown to protein that was originally identified as a component downregulate the β-catenin-mediated signalling of the cell–cell adhesion machinery. It binds with the pathway as part of their molecular mechanism of cytosolic tail of E-cadherin and connects actin fila- chemoprevention. Curcumin and CAPE inhibited ments through α-catenin to form the cytoskele- tumorigenesis and decreased β-catenin expression in ton101,102 (FIG. 5). It was identified as a component of the the multiple intestinal neoplasia (Min/+) mouse evolutionarily conserved WNT signalling pathway, and model117. Moreover, curcumin reduced the cellular is involved in developmental processes in many organ- leves of β-catenin through caspase-mediated cleavage isms, as well as in tumorigenesis. β-Catenin can also of the protein118. Downregulation of β-catenin expres- function as a transcription factor, and nuclear translo- sion by resveratrol was observed in a human colon cation of β-catenin has been associated with various cancer cell line119. Expression of a β-catenin– human cancers103. TCF4-binding reporter construct was reduced in The cytoplasmic β-catenin undergoes rapid HEK293 cells by EGCG 120,121. Indole-3-carbinol turnover by a large multiprotein complex that consists altered the pattern of β-catenin mutation in chemi- of glycogen synthase kinase-3β (GSK-3β), adenoma- cally-induced rat colon tumours122, inhibited adhe- tous polyposis coli (APC), axin and conductin104,105. sion, migration and invasion of cultured human GSK-3β — either directly or through activation of breast carcinoma cells, and upregulated E-cadherin APC — phosphorylates β-catenin, leading to ubiquity- and β-catenin123. A similar effect was observed with lation followed by proteasomal degradation of tangeretin from citrus124. COX inhibitors have also β-catenin104–106. Recently, the phosphorylation of the been found to suppress β-catenin signalling and serine-45 residue of β-catenin by casein kinase Iε β-catenin–TCF/LEF transcriptional activity 125–127. 776 | OCTOBER 2003 | VOLUME 3 www.nature.com/reviews/cancer
  • 10. REVIEWS Growth factors As upregulation of COX2 promotes tumorigenesis, and β-catenin is found to regulate COX2 expression, WNT ligand modulation of β-catenin signalling could be another RTKs molecular target for chemoprevention by dietary Frizzled receptor E-cadherin phytochemicals. Future directions PTEN Chemoprevention by edible phytochemicals is now PI3K considered to be an inexpensive, readily applicable, β-cat acceptable and accessible approach to cancer control AKT/PKB S P and management. With healthcare costs being a key β-cat Dishevelled β-cat T P issue today, it would be cost-effective to promote the awareness and consumption of phytochemicals as a Ubiquitylation Curcumin cancer-preventive strategy for the general public. CAPE Several nutrients and non-nutritive phytochemi- Resveratrol cals are being evaluated in intervention trials for their COX inhibitors potential as cancer chemopreventive agents. Despite β-cat β-cat significant advances in our understanding of multi- Ub stage carcinogenesis, little is known about the mecha- Indole-3-carbimol APC GSK-3β S P nism of action of most chemopreventive agents. The β-cat Axin/conductin T P chemopreventive effects that most dietary phyto- Ub chemicals exert are likely to be the sum of several dis- tinct mechanisms. Disruption or deregulation of 26S intracellular-signalling cascades often leads to malig- CBP/p300 nant transformation of cells, and it is therefore β-cat important to identify the molecules in the signalling ? network that can be affected by individual chemopre- Cell growth- regulatory genes TCF/LEF ventive phytochemicals to allow for better assessment of their underlying mechanisms. In many cases, the chemopreventive effects of Activation Repression dietary chemopreventives in cultured cells or tissues are only achievable at supraphysiological concentra- tions — such concentrations might not be attained when the phytochemicals are administered as part of Proteasome diet. Furthermore, phenolic phytochemicals are often present as glycosides or are converted to other conju- Figure 5 | Effect of phytochemicals on β-catenin signalling. β-Catenin (β-cat) mediates gated forms after absorption, which might further both growth-factor- and WNT-mediated signalling pathways. The interaction of a WNT- lower the bioavailablity. Both pharmacokinetic prop- ligand with its transmembrane receptor — ‘frizzled receptor’ — recruits dishevelled protein, which inactivates glycogen synthase kinase-3β (GSK-3β) by phosphorylation at serine-9. On erties and bioavailability are key problems in investi- the other hand, interaction of a growth factor with receptor tyrosine kinase (RTK) leads to gating the dietary prevention of cancer and should be the activation of phosphatidylinositol 3-kinase (PI3K), which, in turn, phosphorylates assessed carefully before undertaking intervention AKT/protein kinase B (PKB). Phosphorylated AKT also inactivates GSK-3β by serine-9 trials with dietary supplements. phosphorylation. A tumour-suppressor protein phosphatase and tensin homologue deleted The development and use of chemopreventive on chromosome 10 (PTEN) blocks AKT-mediated inactivation of GSK-3β. GSK-3β — a agents for intervention trials involve many scientific component of a multiprotein complex that consists of GSK-3β, adenomatous polyposis coli (APC), axin and conductin — regulates the intracellular fate of β-catenin, which, in its disciplines. With the advances in techniques to assess membrane-bound form, acts as a component of the cell–cell adhesion machinery and, in its single nucleotide polymorphisms (SNPs), we are now free cytosolic form, acts as a signalling molecule. In the absence of a growth factor or WNT more aware of the specific genes that can directly and signal, GSK-3β phosphorylates cytosolic β-catenin at amino-terminal serine (S) and indirectly contribute to individual differences in the threonine (T) residues, which is then targeted for ubiquitylation (Ub) by ubiquitin ligase susceptibility to carcinogenesis. When high-risk followed by proteasomal degradation. In response to the above stimuli, the inactivation of groups are identified, practitioners might be able to GSK-3β results in cytosolic stabilization of β-catenin. Besides inactivation of GSK-3β, mutation of either APC or axin as well as β-catenin causes its stabilization in the cytoplasm. recommend specific dietary supplements that can Stabilized cytosolic β-catenin translocates to the nucleus and binds to T-cell factor modulate or restore the cellular-signalling events that (TCF)/lymphoid enhancing factor (LEF). The β-catenin–TCF/LEF complex acts as a are likely to be disrupted in these individuals. The term transcription factor and activates transcription of genes that are involved in the regulation of ‘nutragenomics’ has been coined, and much attention cellular growth processes. Some chemopreventive phytochemicals have recently been is being focused on this relatively new area of research. reported to target β-catenin-mediated signalling pathways. Curcumin downregulates Tailored supplementation with designer foods that β-catenin through caspase-mediated degradation of the protein, resulting in decreased consist of chemopreventive phytochemicals — each DNA-promoter-binding activity of the β-catenin–TCF/LEF complex and reduced levels of c-MYC protein. Caffeic acid phenethyl ester (CAPE) and resveratrol also attenuate having their own distinct anticancer mechanisms — expression of β-catenin. Epigallocatechin gallate (EGCG) inhibits β-catenin–TCF4 reporter will be available in the near future. These should be activity and reduces β-catenin protein levels. Indole-3-carbinol shifts the pattern of developed in line with advances in the genetic and β-catenin mutations, thereby hampering its nuclear translocation. molecular epidemiology of carcinogenesis. NATURE REVIEWS | C ANCER VOLUME 3 | OCTOBER 2003 | 7 7 7