Breaking the relay in deregulated cellular signal transduction as a rationale for chemoprevention with anti-inflammatory phytochemicals

Mutation Research 591 (2005) 123–146

Breaking the relay in deregulated cellular signal transduction as a rationale for chemoprevention with anti-inflammatory phytochemicals Joydeb Kumar Kundu, Young-Joon Surh ∗ National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-gu, Seoul 151-742, South Korea Received 14 January 2005; received in revised form 12 April 2005; accepted 13 April 2005 Available online 15 August 2005

Abstract Center to the cancer biology is disrupted intracellular signaling network, which transmits improper signals resulting in abnormal cellular functioning. Therefore, modulation of inappropriate cell signaling cascades might be a rational approach in achieving chemoprevention. Inflammation has long been suspected to contribute to carcinogenesis. A new horizon in chemoprevention research is the recent discovery of molecular links between inflammation and cancer. Components of the cell signaling network, especially those converge on redox-sensitive transcription factor nuclear factor-␬B involved in mediating inflammatory response, have been implicated in carcinogenesis. Intracellular signaling through another redox-sensitive transcription factor AP-1 and that transmitted via a more recently identified oncoprotein ␤-catenin are also considered to be crucial for inflammation-associated cancer. Epidemiological and experimental studies have revealed that a wide variety of phytochemicals present in our daily diet are potential chemopreventive agents that can alter or correct undesired cellular functions caused by abnormal pro-inflammatory signal transmission. Modulation of cellular signaling involved in chronic inflammatory response by anti-inflammatory phytochemicals may comprise a rational and pragmatic strategy in molecular target-based chemoprevention. © 2005 Elsevier B.V. All rights reserved. Keywords: Chemoprevention; Inflammation; NF-␬B; AP-1; ␤-Catenin; Anti-inflammatory phytochemicals

1. Introduction Cancer is a multifactorial heterogeneous disease characterized by multistage nature of pathogenesis. Strategies aimed to control this deadly disease over ∗

Corresponding author. Tel.: +82 2 880 7845; fax: +82 2 874 9775. E-mail address: [email protected] (Y.-J. Surh).

0027-5107/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2005.04.019

several decades have been directed mainly towards developing effective anticancer therapies. However, the success in treating various malignancies is not satisfactory as evidenced by observation that the morbidity and mortality from cancers are still unexpectedly high [1]. Recently, attempts have been made to control cancer at early stages before malignancy manifests [2]. One such strategy is chemoprevention,

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which utilizes non-toxic chemical substances to prevent the progress of cancers either by enhancing detoxification/elimination of carcinogens and their reactive metabolites or by halting/reversing tumor promotion/progression [2–4]. A large pool of convincing data arising from both pre-clinical and clinical studies suggests that plant-based diet rich in a wide variety of fruits and vegetables is effective in preventing cancer [2,5,6]. Examples of chemopreventive dietary phytochemicals are epigallocatechin gallate (EGCG) from green tea, curcumin from turmeric, genistein from soybean, brassinin from cabbage, resveratrol from grapes, lycopene from tomato, diallyl sulfide from garlic, gingerol from ginger, caffeic acid phenethyl ester (CAPE) from honey bee propolis, etc. Since the cellular signaling network often goes awry in various disease processes including cancer, it is fairly rational to target intracellular signaling cascades for achieving chemoprevention. Research directed toward elucidating underlying molecular mechanisms of chemoprevention with dietary phytochemicals has recognized components of signal transduction pathways as potential targets [2–5]. Cellular signaling cascades comprising proline-directed serine/threonine kinases and transcription factors, such as nuclear factor-␬B (NF-␬B), activator protein-1 (AP-1) and ␤catenin–T-cell factor (Tcf), are essential in maintaining cellular homeostasis [2]. Aberrant activation of these signal transduction molecules have been implicated in various cancers associated with inflammation [7–10]. Recent studies have highlighted NF-␬B as a potential link between inflammation and cancer [11,12]. In a seminal article by Philip et al. [13], inflammation has been addressed as a critical event in tumor promotion. The regulation of signal transduction pathways as a basis of chemoprevention with selected anti-inflammatory phytochemicals is the subject of this review.

2. Inflammation and cancer: a deadly duo The association between inflammation and cancer has long been suspected [14]. Population-based studies have suggested that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of certain malignancies [15,16], which frequently occurs in persistently inflamed tissues [17]. There is now

growing evidence supporting that chronic inflammation may lead to cancers of different organs including stomach, colon, breast, skin, prostate, pancreas, etc. [8,18–20]. It has been estimated that approximately 15% of all cancers are somehow linked to inflammation [21]. About 5% of all human colorectal cancer is associated with ulcerative colitis [21]. In addition, experimentally induced colitis by either chemical means such as dietary administration of dextran sulfate sodium in combination with azoxymethane (AOM) or by genetic manipulation through mutation of the ‘gate keeper’ gene adenomatous polyposis coli (APC) have been shown to further progress to colorectal cancer [22]. Persistent inflammation creates an abnormal microenvironment where a distinct set of proinflammatory mediators promote neoplastic transformation of cells. Surrounding these transformed cells are innate immune cells, fibroblasts and endothelial cells, which release numerous inflammatory mediators, such as cytokines, chemokines, prostaglandins (PGs), nitric oxide (NO), leukotrienes, etc. [23]. Most of these pro-inflammatory mediators contribute to tumor promotion by altering normal cellular signaling cascades [23] as schematically represented in Fig. 1. Inflammatory responses are often defective in cancer patients partly due to a failure in the production of anti-inflammatory cytokines and PGs and/or an overproduction of pro-inflammatory mediators. Therefore, one of the plausible actions of chemopreventive phytochemicals would be the suppression of abnormal or improper production of pro-inflammatory mediators. Pro-inflammatory cytokines, such as interleukins (IL) and tumor necrosis factor-alpha (TNF-␣), have been implicated in tumor promotion in various experimental models of tumorigenesis [13]. The incidence and the multiplicity of papillomas in a two-stage mouse skin carcinogenesis model were found to be lowered in TNF-␣−/− animals as compared to TNF-␣ overexpressing mice [24]. Verma et al. [25] have suggested that PGs play a crucial role in the induction of ornithine decarboxylase (ODC) activity and mouse skin tumor promotion induced by phorbol-12-myrstate-13-acetate (PMA). Subsequent studies have suggested that PGs, especially PGE2 and PGF2␣ are functionally related to tumor promotion [26,27]. In response to inflammatory stimuli, PGs are produced in abundance through metabolic conversion of arachidonic acid by the

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Fig. 1. Role of inflammation in tumor promotion.

enzyme cyclooxygenase-2 (COX-2), which is inappropriately up-regulated in various premalignant and malignant tissues [28,29]. Moreover, COX-2 overexpressing transgenic mice [30] are highly susceptible to spontaneous tumor formation, while COX-2 knock out animals [31] are less prone to experimentally induced tumorigenesis. The intestinal adenoma formation in APC mutant mice is strongly reduced in the COX-2−/− [32] as well as in the PG receptor EP−/− background [33]. Therefore, COX-2 is now regarded as a molecular target for chemoprevention. Although a wide array of pro-inflammatory mediators have been identified as potential contributing factors in carcinogenesis, cellular signaling pathways linking inflammation and carcinogenesis have not

been fully elucidated. The following section will address how inappropriate activation of cellular signal transduction pathways is involved in amplifying inflammatory response, particularly via overexpression of COX-2, thereby promoting malignant transformation.

3. Cellular signaling molecules mediating inflammatory response 3.1. Protein kinases A vast variety of cytoplasmic protein kinases are involved in relaying events in the cellular signal-

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ing network. As mentioned earlier, both external and endogenous inflammatory stimuli turn on or switch off certain events of this relay, thereby transmitting improper signaling to diverse downstream target molecules. The resultant effects appear as a disturbance in homeostasis and consequently an abnormal cellular function leading to inflammation and cancer. Components of upstream or cytoplasmic signaling networks include protein kinases, such as the family of proline-directed serine/threonine kinases named mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB)/Akt, glycogen synthase kinase (GSK), etc., which play pivotal roles in maintaining cellular homeostasis. Since inappropriate up-regulation of any of the aforementioned kinases may transmit inflammatory or mitogenic signals to diverse downstream components of cellular signaling network such as a panel of transcription factors, targeted silencing of these upstream kinases by antiinflammatory phytochemicals offers a unique strategy for preventing inflammatory responses, cellular proliferation and ultimately carcinogenesis [2]. 3.1.1. MAPKs Three major enzymes that comprise the MAPK signaling pathway include extracellular signal-regulated protein kinase (ERK), c-Jun NH2 -terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38 MAPK. These MAPKs mediate inflammatory and mitogenic signals to activate transcription factors, particularly NF-␬B and/or AP-1, thereby inducing a battery of pro-inflammatory genes (Fig. 2). The pharmacological inhibition [34] or dominant-negative mutation of the corresponding MAPK [35,36] results in diminished induction of COX-2 and/or PG production, suggesting the role of MAPK cascades in COX-2 regulation. The aberrant activation of MAPKs results in increased production of inflammatory cytokines through induction of NF-␬B and/or AP-1, which are further activated by the cytokines they produce, in either autocrine or paracrine fashion, thereby creating a vicious cycle, which leads to persistent inflammation and tumor promotion [23,37]. 3.1.2. PKCs The persistent activation of PKCs also mediates inappropriate induction of NF-␬B and/or AP-1 (Fig. 2).

According to Catley et al. [38], the induction of NF␬B activity in TNF-␣ treated human airway epithelial A549 cells is mediated by PKC␧. PKC-mediated NF␬B activation is further supported by the fact that in PKC␨-deficient cells, NF-␬B is transcriptionally inactive, and the phosphorylation of the RelA/p65 subunit of NF-␬B in response to TNF-␣ is severely impaired [39]. According to this study, PKC␨ directly phosphorylates RelA/p65 at serine 311 residue. Either an inactivating mutation of this residue in vitro or deletion of PKC␨ in mouse embryo fibroblasts abrogated the interaction of RelA/p65 with CBP leading to impairment of RelA/p65 transcriptional activity. Moreover, the activation of the IKK complex, upstream regulators of NF-␬B [38,39], appeared to be mediated by PKC␣ since both the PKC inhibitor GF109203 and a catalytically inactive PKC␣ mutant nullified activation of endogenous IKK as well as NF-␬B in adenovirus 5E1-transformed baby rat kidney cells stimulated with PMA [40]. Huang et al. [41] have also demonstrated that the TNF-␣induced COX-2 promoter activity in human NCI-H292 cells is attenuated by dominant-negative mutation of upstream kinases including PKC␣, NF-␬B-inducing kinase (NIK) or IKK␣/␤. 3.1.3. PI3K/Akt Signaling through receptor tyrosine kinase mediated via the PI3K/Akt pathway has also been attributed to improper activation of both NF-␬B [42–45] and AP-1 [46,47]. Besides induction of NF-␬B and/or AP1, activated PI3K/Akt plays a regulatory role in stabilizing another oncoprotein ␤-catenin [48], which has recently been suggested to create a link between inflammation and cancer [49]. ␤-Catenin, by forming a complex with T-cell factors, promotes transcriptional activation of pro-inflammatory and proliferative genes [50,51]. Activated PI3K inactivates GSK-3␤, which is an upstream enzyme necessary for ␤-catenin degradation [52,53], via PDK1/2-mediated phosphorylation of Akt [54], thereby augmenting stability and nuclear translocation of ␤-catenin (vide infra). In a recent study, Agarwal et al. suggested a novel signaling cascade involving PI3K–Akt–IKK␣, which in a divergent way may contribute to constitutive activation of both NF-␬B and ␤-catenin in SW480 and RKO colorectal cancer cells [55]. More details on the role of PI3K/Akt in ␤catenin-signaling will be discussed in the later part of this article.

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Fig. 2. Components of intracellular signaling network converging on NF-␬B and AP-1. The signaling molecules and events that can be blocked by anti-inflammatory phytochemicals are marked with a symbol ( ).

3.2. Transcription factors Numerous intracellular signaling pathways mediated via upstream kinases converge on NF-␬B and AP-1, which are evolutionarily conserved transcription factors and act independently or co-ordinately to regulate expression of target genes involved in various physiological processes [2]. Elevated transcriptional activity of these transcription factors has been noted in various human malignancies. Improper activation of NF-␬B and/or AP-1 contributes to tumorigenesis either by transactivating several target genes that have inflammatory (e.g., COX-2, iNOS), anti-apoptotic (e.g., cIAP1, cIAP2, XIAP, Bcl-2, Bcl-3 and Bcl-XL ) and the

cell cycle regulatory functions (e.g., cyclin D1) or by down-regulating apoptosis-inducing genes (e.g., p53) [56–58]. Besides NF-␬B and AP-1, the activation of cellular signaling cascades amplified by soluble Wnt ligands, which are secreted by activated macrophages [9], has also been suggested to play a crucial role in inflammation-associated cancer [7,49]. An inappropriate activation of Wnt-signaling contributes to cellular proliferation through up-regulation of ␤-catenin/Tcfregulated transcription of various proliferative genes [50]. Accumulating data from both in vitro and in vivo studies suggest the implication of ␤-catenin-mediated signaling in tumorigenesis [59,60]. Recently, Araki

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et al. [61] have suggested that ␤-catenin may function as a putative regulator of COX-2 [61]. Therefore, ␤-catenin is now recognized as another novel target for chemoprevention by anti-inflammatory substances. 3.2.1. Cellular signaling mediated via NF-κB and/or AP-1 While searching for a molecular link between inflammation and cancer, several recent studies have identified NF-␬B and its upstream regulator IKK as important components to be considered for creating such a link [11,62]. In resting cells, NF-␬B remains sequestered in the cytoplasm by forming an inactive complex with its inhibitory counterpart I␬B proteins. Stimulation with TNF-␣, IL-1, phorbol ester or LPS as well as improper activation of either MAPKs or IKKs leads to phosphorylation and subsequent proteasomal degradation of NF-␬B-bound I␬B␣, allowing free NF-␬B dimers to translocate to the nucleus [2,63] as illustrated in Fig. 2. However, the degradation of I␬B␣ is not necessarily crucial for nuclear translocation of NF-␬B [64,65] as stimuli like H2 O2 or hypoxia followed by reoxygenation may cause phosphorylation of I␬B␣ at tyrosine residue, which facilitates the dissociation of I␬B␣ from NF-␬B without proteasomal degradation of I␬B␣ [66–68]. Moreover, nuclear translocation of NF-␬B does not always appear to be essential for transactivating target genes since inhibitors of several upstream kinases, such as PI3K, p38 MAPK and protein kinase A (PKA), could block the transcriptional activity of NF-␬B without affecting its nuclear translocation [69–72]. It has been suggested that the transcriptional activation of NF-␬B depends on the phosphorylation of its active subunit p65/RelA [73]. The pro-inflammatory cytokines, TNF␣ and IL-1, have been shown to stimulate p65/RelA phosphorylation and subsequent NF-␬B transactivation via mechanisms distinct from those that involve the I␬B␣ phosphorylation and subsequent nuclear translocation of NF-␬B [70,74–76]. An upstream kinase IKK regulates the transcriptional activity of NF-␬B through phosphorylation of both I␬B and NF-␬B [77,78]. We have recently reported that ERK [79] and p38 MAPK [80] can phosphorylate both I␬B␣ and p65 in PMAstimulated mouse skin. In the latter work, phosphorylation of p65 was found to be associated with its interaction with the co-activator CBP/p300. Certain isoforms

of PKC have also been shown to regulate transcriptional activation of NF-␬B as addressed in the previous section. The transcription factor AP-1 exists in about 18 different dimeric combinations of proteins that belong to Jun or Fos family, Jun dimerization partners and the closely related activating transcription factor subfamilies, all of which are basic leucine zipper proteins [81–83]. The activation of AP-1 is mediated predominantly via the MAPK cascades (Fig. 2). The major MAPK-responsive element present in the cfos promoter is the serum response element (SRE) that remains bound to a transcription factor complex including dimeric serum response factor (SRF) and the ternary complex factors Elk-1, Sap1 and Sap2. Of the representative MAP kinases, ERK activates Elk-1 through phosphorylation leading to enhanced SREdependent c-fos expression [84,85]. Both c-Jun and ATF-2, which form heterodimers and preferentially bind to TRE, are phosphorylated by JNK (Fig. 2). ATF-2 is also phosphorylated and activated by p38 MAPK [85]. c-Fos, by forming a heterodimer with c-Jun, binds to AP-1 response element located in the promoter region of target genes [86]. 3.2.2. β-Catenin–Tcf-mediated signaling ␤-Catenin has emerged as a cell membrane-bound adhesion molecule existing largely by forming an adhesion complex with E-cadherin (Fig. 3). Although a minor fraction of free ␤-catenin is present in cytoplasm [50], dissociation of membrane-bound E-cadherin-␤catenin complex may increase the cytosolic pool of ␤-catenin [87–90]. In unstimulated cells, free cytoplasmic ␤-catenin undergoes rapid turnover, which is mediated by a large multiprotein complex consisting of GSK-3␤, APC, axin and conductin [91,92]. GSK-3␤, either directly or through activation of APC, phosphorylates ␤-catenin at N-terminal serine-33, 37, -45 and threonine 41 residues leading to ubiquitination and subsequent proteasomal degradation [52,53,92] of the protein. Recent studies have suggested that phosphorylation of a serine-45 residue of ␤-catenin by casein kinase-I␧ [93–95] or casein kinase-I␣ [96] converts it into a better substrate for GSK-3␤ resulting in the destabilization of the protein. A GSK-3␤-independent pathway of ␤-catenin degradation involves direct phosphorylation of ␤-catenin at its C-terminal domain by activated protein kinase

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Fig. 3. ␤-Catenin–Tcf-mediated signaling as a putative target for chemopreventive phytochemicals with anti-inflammatory properties. Abbreviations: RTK, receptor tyrosine kinase; APC, adenomatous polyposis coli; GBP, GSK, binding protein; u, ubiquitination.

G leading to proteasomal degradation of the protein [97]. More recently, phosphorylation-independent, but APC-dependent mechanism of ␤-catenin degradation has also been proposed [98]. The binding of Siah protein, which is a human homologue of Drosophila seven in absentia, to the ubiquitin ligase consisting of Fbox protein (Ebi), Skp1 and SIP, and to the C-terminal region of APC results in ubiquitination-mediated proteasomal degradation of ␤-catenin even without prior phosphorylation of the molecule [98,99]. To act as a component of the cellular signaling network, ␤-catenin must be stabilized in the cytoplasm. Various external stimuli including the Wnt signal, growth factors,

platelet derived endothelial factor, LPS, etc. stabilize the protein via multiple mechanisms involving both genetic and epigenetic pathways. The genetic mechanism of ␤-catenin stabilization involves the gain-offunction mutation of ␤-catenin gene (ctnnb1) and/or the loss-of-function mutation of its regulatory partners such as APC or axin [99–103]. The protein may be stabilized by epigenetic mechanisms through inactivation of the upstream regulator GSK-3␤ via phosphorylation at serine-9 residue (GSK-3␤-S9), which is mediated by a series of upstream kinases such as p70S6 kinase, p90Rsk, Akt/PKB, certain isoforms of PKC and cyclic AMP-dependent protein kinase [104].

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Being stabilized in cytosol, ␤-catenin translocates into the nucleus and interacts with lymphoid enhancer factor (Lef)/T-cell factor (Tcf), a family of high mobility group (HMG) Box proteins acting as a docking site for ␤-catenin. However, nuclear localization of ␤-catenin and subsequent interaction with Tcf are not always sufficient for reporter gene activation [105]. It has been reported that ␤-catenin–Tcf transcriptional activity requires derepression of Tcf from transcriptional corepressors (e.g., groucho, histone deacetylase, etc.) and subsequent interaction with transcriptional coactivators (e.g., CBP). The activation of the ␤-catenin–Tcf transcription complex accounts for enhanced transcriptional activity of a variety of genes encoding proteins involved in such processes as inflammation and cell cycle regulation [50,51] (Fig. 3). Genes that undergo ␤-catenin/Tcfmediated transactivation includes c-myc, cyclin D1 [50], gastrin [106], human matrilysin [107,108], keratin1 [108], urokinase plasminogen activated receptor, CD44 [109] and immunoglobulin transcription factor2 [110]. According to Levy et al. [108], IL-8 promoter contains a unique consensus sequence for the Tcf binding that is critical for IL-8 activation by ␤-catenin. Moreover, the existence of a Tcf-binding element in the COX-2 promoter region raises the possibility of ␤catenin-mediated up-regulation of COX-2 [61], which is targeted by a variety of anti-inflammatory substances (Fig. 3).

4. Chemopreventive phytochemicals targeting inflammatory signaling network A great deal of clinical and experimental research conducted over last few decades has provided convincing data suggesting that dietary constituents can prevent multiple forms of cancer. According to a recent report published by American Institute for Cancer Research, about 7–31% of all cancers worldwide could be reduced by diets rich in fruits and vegetables. Taking this fact into account, several public health campaigns such as ‘Five-a-Day for Better Health’ and ‘Savor the Spectrum’ have been launched to encourage the Americans to eat sufficient amounts of fruits and vegetables to reduce the risk of cancer and other chronic diseases. The rapid progress in our understanding of the cellular signal transduction pathways involved in carcino-

genesis process has paved the way to elucidating the molecular mechanism of cancer prevention by dietary constituents. Since alterations in normal cellular signaling network obviously contribute to carcinogenesis, the current chemoprevention strategy focuses on intervening in or correcting improper signal transmission within the cell. The role of chronic inflammation-associated cellular signaling as a critical factor in cancer pathogenesis has already been addressed in the previous section of this review. Certain forms of malignancy can be prevented by intervention with anti-inflammatory therapy. Among the ever-increasing list of dietary chemopreventive agents, anti-inflammatory phytochemicals are, therefore, of particular interest in fighting cancer. The following section describes how selected chemopreventive phytochemicals with anti-inflammatory activity interfere with transmission of inappropriate inflammatory signals. Table 1 summarizes the mode of action of individual anti-inflammatory phytochemicals (structures shown in Fig. 4) listed below in relation to their chemopreventive potential. 4.1. EGCG One of the most extensively investigated dietary sources of chemopreventive agents is green tea. EGCG, the major active component of green tea, has been known to possess anti-oxidant, anti-inflammatory and chemopreventive properties [111]. EGCG suppressed malignant transformation in PMA-stimulated mouse epidermal JB6 cells, which appeared to be associated with its inactivation of AP-1 [112,113] or NF-␬B [114]. The inhibition of AP-1 activity by EGCG in the Hras-transformed epidermal JB6 cells [115] and in the epidermis of transgenic mice bearing an AP-1-driven luciferase reporter gene [116] has also been reported. In contrast, a recent study from our laboratory revealed that oral administration of EGCG failed to affect PMAinduced AP-1 DNA binding, but inhibited activation of NF-␬B in mouse skin in vivo [117]. Several recent studies demonstrated that the inactivation of NF-␬B by EGCG was associated with inhibition of IKK activity, enhancement of phosphorylationdependent degradation of I␬B␣ and subsequent increase in nuclear translocation of p65 protein [118,119]. However, EGCG inhibited LPS-induced phosphorylation of I␬B␣, but did not affect NF-␬B

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Table 1 Components of pro-inflammatory signaling cascades as potential targets for chemoprevention with anti-inflammatory phytochemicals Molecular targets affected

Stimulus

Phytochemicals

LPS plus IFN-␥ LPS PMA

EGCG plus genistein [133] Capsaicin [188], EGCG [131], curcumin [212] Curcumin [212], Yakuchinones [204]

↓ TNF-␣ mRNA

LPS UVB Okadaic acid PMA

EGCG [131] EGCG [132] EGCG [130] Yakuchinones [205]

↓IL-8

TNF-␣ IL-1␤ – PMA/LPS H. pylori

EGCG [134] EGCG [135], resveratrol [213] Curcumin [62] Curcumin [212] Curcumin [146]

↓ IL-8 mRNA

IL-1␤ H. pylori

EGCG [135] Curcumin [146]

↓PGE2

PMA LPS H2 O2 IL-1␤ – UVB

Resveratrol [158,159,164], capsaicin [185], IH-901[210], CAPE [214] Resveratrol [164], capsaicin [185,186], CAPE [201] Resveratrol [164] EGCG [127] Curcumin [62] EGCG [215]

↓NO

LPS

Resveratrol [161,216], curcumin [217], capsaicin [185], [6]-gingerol [218] EGCG [127,136] Capsaicin [185] CAPE [197]

Pro-inflammatory mediators ↓TNF-␣

IL-1␤ IFN-␥ LPS plus IFN-␥ Pro-inflammatory enzymes ↓ COX-2

H2 O2

Resveratrol [164,165] Resveratrol [153,164], [6]-gingerol [80,176], curcumin[79,219], EGCG [117], Rg3 [207], capsaicin [185], IH-901 [210], CAPE [214] Resveratrol [164]

↓ COX-2 mRNA

PMA – TNF-␣

Resveratrol [158], CAPE [214], curcumin [219] EGCG [128], curcumin [220] Curcumin [145]

↓ iNOS

IL-1␤ LPS PMA

EGCG [127,136] Resveratrol [165,169], EGCG [137], curcumin [217,221], [6]-gingerol [218], capsaicin [185] Yakuchinones [205]

LPS LPS plus IFN-␥

Capsaicin [185] CAPE [197]

DMBA IL-1␤ LPS

Resveratrol [222] Resveratrol [155], EGCG [135] Resveratrol [160–162], EGCG [131], capsaicin [185,186], CAPE [196], curcumin [120] Resveratrol [157], EGCG [223], curcumin [145] EGCG [114], curcumin [79,143,144], Yakuchinones [205], [6]-gingerol [80,176], capsaicin [181,184], CAPE [199], Rg3 [207], IH-901 [210]

↓ iNOS mRNA Transcription factors ↓NF-␬B activation

LPS PMA

TNF-␣ PMA

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Table 1 (Conitnued ) Molecular targets affected

↓AP-1 activation

Stimulus

Phytochemicals

UVB H. pylori –

EGCG [224], curcumin [225] Curcumin [146] Curcumin [62,147]

PMA

EGCG [112], curcumin [143], resveratrol [153,158,159,170], [6]gingerol [143], capsaicin [183–185] Capsaicin [184] Capsaicin [185], resveratrol [157] EGCG [113]

TNF-␣ LPS UVB ↓␤-Catenin–Tcf signaling

–

Resveratrol [173], EGCG [138], curcumin [149], Docosahexanoic acid [226], genistein [227]

PMA EGF

Curcumin [228], EGCG [229], resveratrol [159,230] CAPE [231]

↓IKK phosphorylation and/or activity

TNF-␣ H. pylori UVB LPS

EGCG [223], curcumin [145] Curcumin [146] Resveratrol [163], Curcumin [62] Capsaicin [185]

↓MAPK phosphorylation and/or activity

PMA EGF UVC LPS

EGCG [117,123,232], Curcumin [79], Resveratrol [153,171], [6]gingerol [80,176], Rg3 [207], IH-901 [210] Curcumin [148] Resveratrol [171] Capsaicin [185]

– TGF-␤

EGCG [125], curcumin [148] CAPE [202]

Upstream signaling molecules ↓PKC activity

↓PI3K/Akt phosphorylation and/or activity

Abbreviations: EGF, epidermal growth factor; IFN-␥, interferon-␥; IL-1␤, interleukin-1␤; LPS, lipopolysaccharide; PMA, phorbol-12-myrstate13-acetate; TGF-␤, transforming growth factor-␤; TNF-␣, tumor necrosis factor-␣.

luciferase activity in human colon cancer (HT-29) cells [120], suggesting that EGCG modulation of NF-␬B transcriptional activity does not solely depend on I␬B␣ degradation and subsequent release of NF-␬B proteins. Besides interference with the IKK-I␬B signaling, suppression of NF-␬B activation by EGCG was reported to be associated with its inhibitory effects on MAPKs activation [121,122]. Topical application of a hydrophilic cream containing EGCG prevented UVBinduced phosphorylation of all three MAPKs in SKH1 hairless mouse skin [123]. EGCG inhibited ERK phosphorylation in H-ras-transformed mouse epidermal JB6 cells [124]. Similarly, a recent study from this laboratory revealed that orally administered EGCG inhibited PMA-induced phosphorylation of ERK as well as the activity of both ERK and p38 MAPK in mouse skin [117]. Besides downregulation of signaling through MAPKs, EGCG reduced the constitutively elevated levels of PI3K and phosphorylated Akt in human prostate cancer cells [125]. The inhibition of Her-2/neu

receptor tyrosine phosphorylation by EGCG in human breast cancer cells was attributed to the abrogation of the PI3K/Akt signaling and subsequent inactivation of NF-␬B [126]. The modulation of aforementioned intracellular signaling molecules by EGCG results in the suppression of expression and/or production of various pro-inflammatory mediators by this chemopreventive phytochemical. Several in vivo and in vitro studies revealed that EGCG suppressed COX-2 expression in response to diverse stimuli including PMA [117], 2,2 -azobis(2-amidinopropane)dihydrochloride [118], IL-1␤ [127] and N-nitrosomethylbenzylamine (NMBA) [119]. EGCG suppressed both protein and mRNA expression of COX-2 in human prostate cancer cells [128]. The production of PGE2 , a COX-2 product implicated in tumorigenesis, was also suppressed by EGCG. [119]. Another essential pro-inflammatory factor contributing to tumor promotion is TNF-␣ [129,130]. EGCG inhibited TNF-␣ mRNA expression

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Fig. 4. Chemical structures of representative chemopreventive phytochemicals that can modulate inflammatory signal transduction pathways.

in murine macrophage 264.7 cells [131], keratinocytes [132]and BALB/3T3 cells [130] stimulated with LPS, UVB and okadaic acid, respectively. In contrast, EGCG induced TNF-␣ production in Raw 264.7 cells exposed simultaneously to LPS and interferon-␥ (IFN␥), although in combination with well known tyrosine kinase inhibitor genistein or resveratrol, it reduced LPS plus IFN-␥-induced TNF-␣ production [133], suggesting the complexity of chemopreventive phytochemicals in modulating intracellular signaling. EGCG also attenuated the gene expression and release of IL-8 in normal human keratinocytes [134] and human airway (A549)

cells [135] stimulated with TNF-␣ and IL-1␤, respectively. In addition, the expression of iNOS and production of NO in human osteoarthritic chondrocytes [136] and murine peritoneal macrophages [137] stimulated with IL-1␤ and LPS, respectively, were inhibited by EGCG. EGCG, at a physiologic concentration, suppressed proliferation of human embryonic kidney (HEK293) cells by blocking transcriptional activation of ␤catenin–Tcf and suppressing the expression of ␤catenin and one of its target gene products cyclin D1 [138].

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4.2. Curcumin Curcumin, a yellow pigment present in the rhizome of turmeric (Curcuma longa L., Zingiberaceae), has been extensively investigated with regard to its antitumor promoting as well as anti-inflammatory activity. The compound strongly inhibited the PMA-induced inflammation, hyperplasia, proliferation, activity and expression of ODC, reactive oxygen species (ROS) generation and oxidative DNA damage as well as papilloma formation in mouse skin [139,140], and reduced anchorage-independent colony formation in mouse epidermal JB6 cells [141]. The anti-tumor promoting effect of curcumin is largely attributable to its inhibition of cellular signaling mediated by NF-␬B, AP-1, ␤-catenin–Tcf and the upstream kinases. Curcumin inhibited the expression of c-Jun and c-Fos proteins and mRNA as well as AP1 DNA binding in NIH3T3 cells [142] and lowered the levels of c-Jun and c-Fos proteins in CD-1 mouse skin after treatment with PMA [141]. Previous studies from this laboratory demonstrated that curcumin inhibited activation of AP-1 and NF-␬B in PMA-stimulated mouse skin in vivo as well as in cultured HL-60 cells [143]. Curcumin blocked stimuli-induced phosphorylation and degradation of I␬B␣, thereby inhibiting nuclear translocation of p65 [79,144]. Similarly, inhibition of I␬B␣ degradation via downregulation of NIK and IKK contributes to curcumin inhibition of TNF␣-induced COX-2 gene transcription as well as NF-␬B activation in human colonic epithelial cells [145]. Curcumin targeted IKK in Helicobacter pylori-treated gastric epithelial (AGS) [146], multiple myeloma [147] and pancreatic cancer cells [62] to confer chemoprventive activity. Besides IKKs, the activation of ERK was also blocked by curcumin in PMA-treated mouse skin and growth factor-stimulated human mammary epithelial cells [79,148]. Squires et al. demonstrated that curcumin could inhibit basal phosphorylation of Akt/PKB in both tumorigenic and non-tumorigenic human breast epithelial cells [148]. In relation to such modulation of intracellular signaling molecules, curcumin was reported to inhibit expression of COX-2 and generation of PGE2 in PMA-stimulated mouse skin [79] and human pancreatic cancer cells [62]. In addition, curcumin down-regulated H. pylori-induced IL-8 mRNA expression in AGS cells [146] and IL8 production in human pancreatic cancer cells [62].

Curcumin induced apoptosis of human colorectal cancer (HCT-116) cells by inhibiting ␤-catenin–Tcf DNA binding and transactivation, resulting in diminished cMyc expression and elevated degradation of ␤-catenin [149,150]. 4.3. Resveratrol Resveratrol, a phytoallexin present in grapes and other plant species, exerts anti-oxidant, antiinflammatory and chemopreventive activities by modulating various events in cellular signaling. The inhibition of cytokine release and pro-inflammatory gene expression, downregulation of intracellular signal transduction molecules and transcription factors that regulate expression of pro-inflammatory genes are key molecular mechanisms underlying anti-inflammatory and anti-tumor promoting activities of resveratrol. The molecular basis of chemoprevention by resveratrol has been reviewed recently [151,152]. Resveratrol inhibited PMA-stimulated activation of AP-1 in mouse skin in vivo [153] and U937 cells [154] in culture. Resveratrol also suppressed activation of NF␬B in acute myeloid leukemia (OCIM2) cells [155] and mouse epidermal JB6 cells stimulated with IL-1␤ and Cr(VI) [156], respectively. Moreover, the compound inhibited NF-␬B activation induced by other stimuli such as PMA, LPS, H2 O2 , okadaic acid and ceramide in Jurkat-T, HeLa and glioma cells [157]. While several studies reported that resveratrol attenuated PMA-induced transcriptional activity of AP-1 in human mammary epithelial cells [158,159], the compound failed to suppress AP-1-driven transcriptional activity in LPS-stimulated THP-1 cells [160]. According to the latter study, resveratrol blocked LPSinduced activation of NF-␬B by inhibiting phosphorylation and transactivation potential of p65, but failed to inhibit nuclear translocation of NF-␬B/Rel proteins. In contrast, resveratrol inhibited nuclear translocation and DNA binding of NF-␬B subunits in LPSstimulated Raw 264.7 cells by blocking phosphorylation and degradation of I␬B␣ [161,162]. On the other hand, resveratrol attenuated TNF-␣-induced activation of NF-␬B in U937 cells by suppressing phosphorylation and nuclear translocation of p65 without affecting I␬B␣ degradation [157]. In normal human epidermal keratinocytes, resveratrol inhibited UVB-induced activation of NF-␬B by blocking the activation of IKK␣

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as well as phosphorylation and degradation of I␬B␣ [163]. The differential regulation of signaling via AP1 or NF-␬B by resveratrol appeared to be cell type- and stimuli-specific. Resveratrol has been shown to inhibit expression and activity of COX-2 [153,159,164,165]. While resveratrol downregulated the expression of both COX1 and COX-2 mRNA transcripts in NMBA-induced esophageal tumors in F344 rats [166], PMA-induced expression of both COX-1 and COX-2 in CD-1 mouse skin remained unaffected by resveratrol pretreatment [167]. A significant inhibitory effect of resveratrol on COX-2 expression was observed in inflamed rat colon caused by trinitrobenzenesulfonic acid [168] and in mouse peritoneal macrophages stimulated with LPS, PMA or H2 O2 [164]. The latter study also demonstrated that resveratrol prevented mobilization of arachidonic acid and decreased PGE2 production. In addition, resveratrol attenuated iNOS expression in LPS-activated macrophages without altering COX-2 expression [169]. However, Murakami et al. [165] reported that the expression of both iNOS and COX-2 in LPS- plus interferon-␥-treated Raw 264.7 macrophages was strongly inhibited by resveratrol. Moreover, topically applied resveratrol resulted in the inhibition of PMA-induced COX-2 expression in female ICR mouse skin [153]. Resveratrol inhibited PMA-induced IL-8 gene expression in U937 cells [170] and IL-1␤ production in OCIM2 cells [155]. The modulation of MAPK by resveratrol partly constitutes to the molecular basis of anti-inflammatory and anti-tumor promoting activities exhibited by this dietary phytochemical. Resveratrol pretreatment blocked UVC- and PMA-induced activation of ERK2, JNK1 and p38 MAPK and subsequently transcription of AP-1 reporter gene in HeLa cells [171]. Resveratrol also inhibited PMA-induced activation of ERK and p38 MAPK in mouse skin in vivo [153]. Besides MAPKs, the activation of other upstream signaling kinases such as protein tyrosine kinase and PKC was also inhibited by resveratrol [158,159]. More recently, Stroz et al. [172] demonstrated that resveratrol inhibited H2 O2 -induced NF-␬B activation in HeLa cells partly by blocking activation of PKC␮, which is currently known as protein kinase D. Resveratrol downregulated ␤-catenin and cyclin D1 expression in human colon cancer (SW480) cells thereby inducing apoptosis and growth arrest [173].

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4.4. [6]-Gingerol [6]-Gingerol, the major pungent principle of ginger (Zingiber officinale Roscoe, Zingiberaceae), has been found to inhibit epidermal growth factor-induced AP1 activation and neoplastic transformation in mouse epidermal JB6 cells as revealed by reduced anchorageindependent formation of colonies on soft agar [174]. The compound inhibited tumor promotion and PMAinduced ODC activity and TNF-␣ production in mouse skin [175]. More recently, topical application of [6]-gingerol inhibited PMA-induced COX-2 expression in mouse skin by suppressing NF-␬B activation [176]. Furthermore, [6]-gingerol inhibited PMAinduced degradation of I␬B␣ and nuclear translocation of p65 in mouse skin by blocking the phosphorylation of the upstream kinase p38 MAPK. The transcriptional activity of NF-␬B was also down-regulated by [6]-gingerol which was attributable to reduced interaction of phosphorylated p65 with the coactivator cyclic AMP response element binding protein-binding protein (CBP/p300) [80]. 4.5. Capsaicin Capsaicin is the principal pungent ingredient of hot chili pepper (Capsicum annuum L., Solanaceae). Despite the initial dispute regarding tumor promoting potential of capsaicin, topical application of this compound alone did not promote, but rather inhibited mouse skin carcinogenesis induced by DMBA plus PMA [177–180]. Topical application of capsaicin in female ICR mouse skin inhibited PMA-induced activation of NF-␬B, which was mediated via blockade of I␬B␣ degradation [181]. Moreover, capsaicin inhibited constitutive activation of NF-␬B in malignant melanoma cells, leading to the induction of apoptosis [182]. PMA- or TNF-␣-induced AP-1 activation in mouse skin and cultured human leukemia HL-60 cells was also blocked by capsaicin [183]. Duvoix et al. [184] reported that capsaicin significantly inhibited reporter gene expression as well as TNF-␣- and PMAinduced DNA binding of AP-1 and NF-␬B in K562 and U937 leukemia cells. Moreover, capsaicin inhibited LPS- and IFN-␥-mediated NO production and iNOS expression in Raw 264.7 cells [185]. According to this study, capsaicin also transcriptionally inhibited LPS- and PMA-induced COX-2 expression and PGE2

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production as well as LPS-induced NF-␬B and AP-1 activation. Similarly, capsaicin treatment reduced I␬B␣ degradation and subsequent NF-␬B activation in LPSstimulated peritoneal macrophages [186]. In this study, capsaicin failed to inhibit COX-2 expression at either the protein or the mRNA level, but blocked the iNOS expression. A decrease in NF-␬B activation by capsaicin was accompanied by the growth arrest of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia (ATL) cells [187]. Recently, Park et al. [188] demonstrated that capsaicin inhibited LPSinduced TNF-␣ production in Raw 264.7 cells. 4.6. CAPE CAPE, an active component of honey bee propolis, exhibits diverse biological activities including antioxidant [189], anti-inflammatory [190], immunomodulatory [191] and anticancer effects [192]. Borrelli et al. [193] reported that intraperitoneal administration of CAPE reduced AOM-induced formation of aberrant crypt foci and tumors in rat colon in vivo. Administration of CAPE to male Wistar rats subjected to a modified promotion protocol dramatically reduced nuclear localization of the p65 subunit of NF-␬B without affecting I␬B␣ [194]. A similar report was presented by Marquez et al. [195], who demonstrated that CAPE specifically inhibited both gene transcription and synthesis of IL-2 in stimulated T-cells by suppressing the NF-␬B-dependent transcriptional activity without affecting the degradation of I␬B␣. The compound also significantly decreased the LPS-induced NF-␬B transcriptional activity in Raw 264.7 cells [196]. Treatment of Raw 264.7 cells with CAPE markedly lowered NO production and iNOS expression induced by LPS plus IFN-␥. The anti-inflammatory effect of CAPE was suggested to be mediated through suppression of NF-␬B activation and by direct inhibition of the catalytic activity as well as expression of iNOS [197]. Similarly, CAPE was found to inhibit NO production in LPSactivated murine macrophage-like J774.1 cells [198]. Moreover, CAPE suppressed PMA-induced MMP-9 expression by inhibiting the function of NF-␬B, but not AP-1, in HepG2 cells [199]. A significant decrease in COX-2 activity, as measured by the PGE2 level, in LPS-treated J774.1 cells [200] as well as in rat pulmonary tissue was also reported [201]. In a recent study by Shigeoka et al. [202], CAPE suppressed trans-

forming growth factor (TGF)-␤-induced Akt phosphorylation, resulting in a decreased motility of A549 cells. Although ␥-radiation-induced mRNA expression of different pro-inflammatory cytokines was barely affected by CAPE, it significantly enhanced the mRNA expression of an anti-inflammatory cytokine IL-10 in rats [203]. 4.7. Yakuchinones and structurally related diarylheptanoids Several diarylheptanoids present in Alpinia species elicited antitumor promoting effects partly by blocking signal transduction via the MAPKs-NF-␬B pathway thereby suppressing expression and/or production of various inflammatory mediators [204–206]. According to Chun et al. [204,205], yakuchinone A and yakuchinone B, which are phenolic diarylheptanoids derived from A. oxyphylla, inhibited PMA-induced inflammation and epidermal ODC activity as well as skin tumor promotion in female ICR mice. Moreover, both compounds reduced PMA-induced expression of COX2, iNOS and TNF-␣ as well as TNF-␣ production in mouse skin possibly by down-regulating NF-␬B activation. Recently, Yadav et al. [206] demonstrated that 7-(4 -hydroxy-3 -methoxyphenyl)-1-phenylhept4en-3-one, a diarylheptanoid from A. officinarum, inhibited expression of both protein and mRNA transcripts of COX-2 and iNOS as well as NO production by blocking ERK phosphorylation and NF-␬B DNA binding in Raw 264.7 cells stimulated with LPS. 4.8. Ginsenosides Epidemiological studies have suggested an inverse relationship between intake of ginseng and the risk of certain cancers. The chemopreventive potential of some ginseng saponins has been partly attributed to their anti-inflammatory properties [207–209]. Rg3, a major ginsenoside derived from heat-processed ginseng, suppressed papillomagenesis in a twostage mouse skin carcinogenesis model as well as PMA-induced ODC activity [207]. Molecular mechanisms underlying inhibition of tumor promotion by Rg3 appear to involve the downregulation of COX-2 expression in both PMA-treated mouse skin [207,208] and cultured human breast epithelial cells [209] via blockade of NF-␬B activation.

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Moreover, Rg3 inhibited PMA-induced phosphorylation of ERK and AP-1 DNA binding in mouse skin [207]. Recently, we have reported that pretreatment of female ICR mouse skin with topically applied IH-901 (20-O-beta-d-glucopyranosyl-20(S)protopanaxadiol), a novel intestinal bacterial metabolite derived from protopanaxadiol type saponins of Panax ginseng C.A. Meyer, results in the inhibition of PMA-promoted papillomagenesis and ODC activity as well as expression of COX-2 and production of PGE2 [210]. Further mechanistic study revealed that IH-901 inhibited PMA-induced NF-␬B DNA binding, which was mediated by blocking phosphorylation and subsequent degradation of I␬B␣. In addition, IH-901 attenuated PMA-induced phosphorylation of ERK1/2 and Akt [210].

kinases involved in the pro-inflammatory signal pathways activate one or more of above transcription factors thereby contribute to carcinogenesis. Currently, molecular target-based chemoprevention with anti-inflammatory phytochemicals focuses on targeted silencing of improper transmission of undesired signals. However, extreme complexity of the cellular signaling network, especially various still unidentified cross-talk between signaling molecules, appears to be a major hurdle that hampers simplifying the mechanistic basis of chemoprevention. Nonetheless, unraveling pro-inflammatory signal transduction pathways underlying field cancerization would help substantially find the specific molecular target of each of antiinflammatory phytochemicals in achieving success in chemoprevention.

5. Future perspectives

Acknowledgements

Dysregulation of cellular signaling pathways is considered as common denominator implicated in pathogenesis of various ailments including cancer. One such altered cellular event is deregulated pro-inflammatory signaling, which is amenable to dietary modulation. In the context of molecular management of disease, the term “signal transduction therapy” has been coined by Levitzki who proposed that targeting signal transduction events may be a rational approach for controlling malignant transformation [211]. Numerous antiinflammatory agents, particularly those from edible plants, exert chemopreventive activities by targeting multiple components of the pro-inflammatory signaling cascades. Supplementary to the existing knowledge of mechanistic basis of chemoprevention by anti-inflammatory phytochemicals is the recent breakthrough in uncovering the molecular aspects of longsuspected association between inflammation and cancer. Pro-inflammatory mediators, such as prostanoids, cytokines and leukotrienes, etc. produced after overstimulation of signaling mediated via transcription factors NF-␬B and/or AP-1 transform normal cells into malignant phenotypes. Recent observations that upregulation of signaling through ␤-catenin–Tcf plays a pivotal role in inflammation-associated cancers further proposes ␤-catenin-mediated signaling as an additional prime target for the prevention of cancer by anti-inflammatory therapies. Certain protein

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