Curcumin a Potential Cancer Chemopreventive Agent through Suppressing NF-κB Signaling

Review Article

2008 MedUnion Press − http://www.mupnet.com 11

Curcumin: a Potential Cancer Chemopreventive Agentthrough Suppressing NF-κB SignalingChih-Li Lin and Jen-Kun Lin1

Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

Curcumin, a naturally occurring compound derived from turmeric, has long beensuggested with strong therapeutic or preventive potential to against several majorhuman diseases because of its anti-oxidative, anti-inflammatory, and anti-cancerouseffects. Although inflammation is a protective effect, persistent inflammation has beenbelieved to involve in the multistage of cancer development. As a result, the aberrantlyincreased activity of NF-κB, a master factor playing a key role in inflammation, isimplicated in a variety of human cancers. Curcumin is known to exert anti-inflammatory effects significantly by interrupting NF-κB signaling at multiple levels.Many observations indicate that curcumin indeed shows valuable potential in thecancer treatment through inhibiting the activity of I-κB kinase, IKK. In this review, theanticancer effects of curcumin and the underlying mechanisms are discussed. We alsoprovide a summary of the recent literatures focusing on NF-κB signaling pathways andtheir potential involvement in the development of anticancer strategies.

Journal of Cancer Molecules 4(1): 11-16, 2008.

Keywords:

curcumin

NF-κB

I-κB

cancer prevention

inflammation

Introduction

Curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is an orange-yellow active compo-nent from the herb Curcuma longa (usually known asturmeric) commonly used in the Indian and Eastern Asia. Itis an orange-yellow crystalline powder with melting point of183°C, molecular formula of C21H20O6, and molecular weightof 368.37 g/mol. The essential structure of this moleculeconsists of feruloylmethane skeleton. Curcumin is a botani-cal pigment derived from the ground rhizome named Cur-cuma species or Zingiberaceae. It is now clear that there arefour major curcuminoids namely curcumin, demethoxycur-cumin, bis-demethoxycurcumin, and a new identified cy-clocurcumin occurring naturally in Curcuma species[1](Figure 1). Traditionally, curcumin has been employed asa spice, cosmetic and medicine. Extensive research hasproven that most of its bioactivities are associated with thecurcuminoid's content [2]. As a medicine, curcumin isshown to exhibit antioxidant, anti-inflammatory, antiviral,antibacterial, antifungal, and anticancer activities, and thushas a potential to against various diseases including diabe-tes, asthma, allergies, arthritis, atherosclerosis, neurode-generative diseases, and other chronic illnesses like cancers[3]. Furthermore, it is widely accepted of curcumin's phar-macological safety, as usually used at doses up to 100mg/day in folk medicine for centuries [4]. In India, curcumin

Received 1/27/08; Revised 2/10/08; Accepted 2/12/08.1Correspondence: Prof. Jen-Kun Lin, Institute of Biochemistry andMolecular Biology, National Taiwan University College of Medicine,Room 947, No. 1, Jen-Ai Road Section 1, Taipei 100, Taiwan. Phone:886-2-23123456 ext. 2213. Fax: 886-2-23918944. E-mail:[email protected]: NF-κB, nuclear factor kappa B; I-κB, inhibitor of NF-κB; IKK, I-κB kinase; ROS, reactive oxygen species; MMP, matrixmetalloproteinase; TRAIL, TNF-related apoptosis inducing ligand;MAPK, mitogen-activated protein kinase; COX-2, cyclooxygenase-2;ERK, extracellular signal-regulated kinase.

has been taken orally for the treatment of sore throat,exhibiting its anti-inflammatory activity significantly.Although the inflammation is a protective effect fundamen-tally, the harmful residuals underline various chronic dis-eases. To date, persistent inflammation has been known tocontribute to multistage carcinogenesis [5]. Therefore, thereare extensive reports suggesting that curcumin has potentialin the treatment of a variety of cancers.

Anticancer effects of curcumin

Cancers, with diverse histological origin, have therapeuticspecific targets as well as common molecular markersinvolved in their initiation and progression. Based upon thisconcept, curcumin has been shown to affect several in-tracellular targets regulating survival or death of cancer cells.To exert its anticancer activity, curcumin was considered tocounteract the altered functionality of proliferative andapoptotic pathways. Interestingly, accumulating evidencesuggests that curcumin shows anticancer effects at lowerdoses compared to other anticancer drugs. These effectsare mediated through the regulation of numerous biochemi-cal cascades, including various transcription factors, growthfactors, inflammatory cytokines, protein kinases, and otherenzymes [6]. Among these molecular targets, particularly,curcumin is apparently a highly effective molecule to interactwith several inflammatory targets. This suggests thatcurcumin's reported beneficial effects might be due in partto its ability in modulating the immune system. Under thisaspect, we have previously suggested the molecular mecha-nisms of curcumin on cancer prevention [7,8]. In 1991, ourlaboratory had demonstrated that curcumin could suppressthe expression of c-jun, a proliferation-stimulating gene inimmune cells [9,10]. This is the first report to illustrate theassociation of naturally occurring compounds with thesuppression of an oncogene. The apoptotic effects ofcurcumin have been demonstrated by Jiang et al. [11] and

Lin & Lin J. Cancer Mol. 4(1): 11-16, 2008

12 Print ISSN 1816-0735; Online ISSN 1817-4256

A

B

C

D

Figure 1: Chemical structures of curcumin (A) and its derivativesdemethoxycurcumin (B), bis-demethoxycurcumin (C), and cy-clocurcumin (D).

Kuo et al. [12]. In addition, the inhibition of protein kinase Cand xanthine oxidase were also described [13,14]. Finally,we further demonstrated that the nuclear factor kappa B (NF-κB2), the master factor playing a key role in the inflammatoryand immune response, was suppressed by curcuminthrough inhibiting the activity of I-κB kinase (IKK)[15]. Inprinciple, curcumin has been widely demonstrated to havepotent antioxidant activities. It is well known that reactiveoxygen species (ROS) play a key role in enhancing inflam-mation through the activation of stress kinases and redox-sensitive transcription factors such as NF-κB. Oxidativestress activates NF-κB-mediated transcription of pro-inflammatory mediators either through the activation of itsactivating inhibitor IKK or the enhanced recruitment oractivation of transcriptional co-activators. Although numer-ous different pathways are activated during the inflammatoryresponse, NF-κB is thought to be of the most importance incancer-related inflammation [16]. However, curcumin actsas ROS scavenger, increases antioxidant glutathione levelsby induction of glutamate cysteine ligase, and acts as ananti-inflammatory agent through inhibition of NF-κB signal-ing [17]. Persistent activation of NF-κB has been observedin many different cancers. Interestingly, recent works haveidentified that the sustained IKK activation is achieved toactivate NF-κB pathway in many types of human cancer,indicating the activation of NF-κB is likely to result fromalterations in its upstream signaling components [18]. Inaddition, cytotoxic studies in different cell lines have indi-cated that the toxicity of curcumin was significantly higher intumor cells if compared to the normal cells [19]. Consider-ing these recent discoveries, therefore, curcumin can beconsidered as an ideal lead compound for anticancer drugdevelopment [20].

Molecular basis of NF-κB inhibition by curcuminin cancer treatments

NF-κB was initially reported in 1980s as a regulator ofimmunoglobulin gene transcription in B lymphocytes [21].Currently, five mammalian NF-κB family members have beendiscovered, including p50, p52, p65 (RelA), c-Rel and RelB.

To activate specific downstream gene expression, NF-κBmolecules form dimers, dissociate with I-κB inhibitor pro-teins, enter the nucleus upon activation and bind DNA(Figure 2). Aberrantly increased NF-κB activity has beenimplicated in a variety of human cancers. Interruption of NF-κB signaling by curcumin in tumor cells can be achieved assummarized in Table 1. Curcumin inhibits inducible NF-κBactivation and suppresses cancer cell proliferation in breastcancer [22], ovarian cancer [23], pancreatic cancer [24],leukemia and multiple myeloma [25], oral cancer [26],bladder cancer [27], and prostate cancer [28]. Most biologi-cal effects of curcumin are through NF-κB-regulated geneproducts, including apoptosis-related proteins (Bcl-2, Bcl-XL,TRAF), cell cycle regulators (cyclin D1, cyclin D2), growthfactors (interleukin, TNF-α, VEGF), receptors (CD40, CD44,CD86, CCR7, CXCL) and matrix metalloproteinases (MMP-2,MMP-9)(Table 1). Curcumin sensitizes human cancer cells tocell-killing agents through NF-κB pathway. In humanpancreatic cancer, the curcumin combination therapy withTNF-related apoptosis inducing ligand (TRAIL) suggests thatinhibition of NF-κB stimulates TRAIL-induced apoptosis [29].Moreover, Notch-1, Hes-1, and Bcl-XL expression levels canbe concomitantly down-regulated by curcumin treatment,which is correlated with the inactivation of NF-κB activity inincreasing apoptosis [30]. In human prostate cancer,curcumin induces apoptosis through Bax translocation tomitochondria [31] and caspase activation [32], which en-hances the therapeutic efficacy when combined with TRAIL.Similarly, it has also been reported that curcumin inducessensitization to TRAIL by inhibiting Akt-regulated NF-κB andNF-κB-dependent antiapoptotic targets Bcl-2, Bcl-XL, andXIAP in LNCaP and PC3 prostate cancer cells [33](Table 1).Thus, curcumin may play an adjuvant role in treating induci-ble cancer chemoresistance by inhibition of NF-κB signaling.

Curcumin has also been shown to interfere with the func-tions of Akt and mitogen-activated protein kinases (MAPKs),two key molecules for survival signaling. Because NF-κB isa downstream target of Akt and MAPK, the inhibition of Aktand MAPK by curcumin is implicated in mediating thebeneficial effects in anticancer therapy. Curcumin has beenshown to decrease expression and activation of EGFR, HER-2, HER-3 and IGF-1R as well as their downstream effectorsAkt and cyclooxygenase-2 (COX-2) in HCT-116 and HT-29colon cancer cells [34]. The observation that curcumininhibits EGFR and Akt can account for reduced NF-κBactivity and cancer cell apoptosis induced by curcumin atlow concentrations [35]. Curcumin also interrupts extracel-lular signal-regulated kinase (ERK) signaling, reduces NF-κBactivity and results in suppression of connective tissuegrowth factor (CTGF) expression in activated hepatic stellatecells [36]. Likewise, TNF-α stimulates activation of Aktcascade and the recruitment and assembling of NF-κB p65 toinduce MMP-9 expression [37]. In consequence, curcumintreatments block Akt nuclear translocation and thus inhibitMMP-9 expression. Curcumin has also been reported toinhibit histone deacetylase (HDAC) and p300/Notch 1 sig-naling by preventing the degradation of I-κBα in leukemia[38](Table 1). Moreover, in C6 glioma cells, curcumin-reduced cell survival is correlated with the inhibition of NF-κB signaling pathways via prevention of constitutive JNKand Akt activation [39]. It is conceivable that the activatedNF-κB may mediate tumor cell invasion and metastasis aswell, such that suppression of NF-κB by curcumin mayactually increase chemotherapeutic effects. In MDA-MB-231breast cancer cells, curcumin decreases the metastaticactivity and two inflammatory cytokines CXCL1 and CXCL2by down-regulating NF-κB activation [40]. In colon cancercells, curcumin suppresses neurotensin-stimulated IL-8expression and secretion, and blocked neurotensin-stimu-

Cancer Prevention of Curcumin through NF-κB Signaling


Figure 2: Schematic representation of the molecular mechanisms for the anti-inflammatory activity of curcumin. Curcumin is known to exertanti-inflammatory effects significantly by interrupting NF-κB signaling at multiple levels. For example, ROS mediate inflammation through theactivation of stress kinases and redox-sensitive transcription factors such as NF-κB, however, curcumin is a ROS scavenger and thus preventsthe inflammatory signaling. In addition, curcumin can interfere with the functions of Akt and MAPKs, and in turn down-regulate the downstreammolecule, NF-κB.

lated migration [41]. In epithelial cells, curcumin inhibits theTPA-induced up-regulation of COX-2 and MMP-9 throughsuppressing ERK1/2 phosphorylation and NF-κB trans-activation [42]. Furthermore, curcumin exerts anti-inflammatory and growth-inhibitory effects through inhibi-tion of NF-κB and MAPK pathways [43]. By inhibition of NF-κB DNA binding ability, curcumin treatments lead to a down-regulation of UV-enhanced IL-18 expression in NCTC 2544skin cell [44]. In addition, curcumin inhibits the extracellularstimulation of upstream protein kinase Akt, which is corre-lated with down-regulation of the NF-κB targets includingCOX-2 and MMP-9 [45]. Besides, the neutralization of tumor-induced oxidative stress and restoration of NF-κB activityalong with the re-education of the TNF-α signaling pathwaycan be the mechanism. Some results suggest that unlikeother anticancer agents, curcumin is not only devoid ofimmunosuppressive effects but also acts as immunorestorerin tumor-bearing subjects [46]. Overall, all of these observa-tions provide evidence of curcumin's potent anti-inflammatory and anti-carcinogenic effects.

It is also known that curcumin with its potent antioxidantproperty is anticipated to exert its bioactivities. In K562leukemia cells, curcumin-induced topoisomerase I- and II-DNA complexes are prevented by the antioxidant N-acetylcysteine; this suggests ROS may directly mediate theformation of these complexes [47]. However, the suppres-sion of TNF-α-induced NF-κB activation by curcumin sug-gests a critical role of its structural signature rather than itsROS scavenger ability [48]. Curcumin acts through theinhibition of I-κB phosphorylation and thus prevents I-κBdegradation by the proteosome. The work from Marin et al.[49] indicates that curcumin induces apoptosis and NF-κBinhibition in melanoma cells but not normal cells, which is

correlated with decrease of phospho-I-κBα level. Further-more, the inhibition of I-κB degradation leads to a down-regulation of COX-2 expression [50]. By inhibition of I-κBdegradation, curcumin suppresses the expression of NF-κB,COX-2 and MMP-9, and indeed suppresses the incidence ofbreast cancer metastasis [51]. Other than inhibiting I-κBdegradation, curcumin has also been reported to inhibitligand-independent dimerization such as TLR4 receptorcomplex [52]. In MDA-MB-468 breast cancer cells and HT29colon cancer cells, curcumin treatments inhibit Stat3 phos-phorylation, resulting in reduction of nicotinamide N-methyltransferase (NNMT) level [53]. In human endometrialcancer cells, curcumin down-regulates Ets-1 and Bcl-2expression and induces apoptosis, suggesting a novelmolecular mechanism for the antitumor activity [54](Table 1).Curcumin also inhibits acid sphingomyelinase (ASPMase),and the effect might be involved in its anti-proliferativeproperty against colon cancer cells [55]. Furthermore, it hasalso been reported that curcumin induces apoptosis selec-tively in human papilloma virus (HPV)-associated cervicalcancer cells [50].

Curcumin also participates in non-cancer treat-ments related to NF-κB

The mechanisms of curcumin for treating other diseaseshave also been mentioned for decades. For example, it hasbeen reported of hypolipidemic and hypercholesterolemiceffects by dietary curcumin supplement [56]. Basically,curcumin prevents tissue damage by at least two mecha-nisms: acting as an antioxidant and by inhibiting NF-κBactivation to minimized oxidative stress [57,58]. Interest-



Table 1: Summary of target molecules as yet reported for curcumin actions

Target molecule System involved Reference

c-Jun/AP-1 tumor promotion Huang et al., 1991 [9]; Lin, 2007 [6]protein kinase C tumor promotion Liu et al., 2003 [14]NF-κB tumor growth; inflammation Dhandapani et al., 2007 [39]; Chao et al., 2007 [43]IKK tumor growth Kunnumakkara et al., 2007 [24]TRAIL apoptosis Khanbolooki et al., 2006 [29]Bcl-2, Bcl-XL anti-apoptosis Deeb et al., 2007 [33]EGFR, HER-2, HER-3 tumor growth Patel et al., 2008 [34]MMP-9 tumor growth Lee et al., 2007 [37]HDAC leukemia cell growth Chen et al., 2007 [38]MAPK tumor growth; inflammation Chao et al., 2007 [43]COX-2 inflammation Shakibaei et al., 2007 [45]TLR4 immunity Youn et al., 2006 [52]Ets-1 tumor growth Yu & Shah, 2007 [54]NNMT tumor growth Tomida et al., 2007 [53]ASPMase tumor growth Cheng et al., 2007 [55]

ingly, feeding curcumin to the diabetic rats controls oxida-tive stress by inhibiting the increase in thiobarbituric acidreactive substances (TBARS) and protein carbonyls byreversing altered antioxidant enzyme activities withoutaltering the hyperglycemic state [59]. By inhibiting ROSgeneration, curcumin also protects pancreatic islets againstβ cell toxins [60]. All evidence shows that curcumin appearsto be beneficial in preventing diabetes-induced oxidativestress, and the inhibition of NF-κB-dependent pathway is atleast in part involved in the anti-diabetic mechanisms [61].Moreover, recent studies also focus on the underlyingmechanisms by which curcumin exerts its neuroprotectiveeffects. Pretreatment with curcumin can reverse oxidativedamage in all major regions of brain. In PC12 cells, curcu-min treatments maintain the mitochondrial redox andrespiratory functions without a marked effect on ROSproduction and cell viability, indicating that the alterations inmitochondrial energy metabolism and redox functions iscritical in determining the switch between neuronal celldeath and survival [62]. Curcumin is as well demonstratedto convert the amyloid form of prion protein (PrP) to oli-gomers and fibrils but not the native form, showing that thepartially unfolded structural intermediate of the PrP can betargeted by curcumin [63]. Epidemiological studies indicatethat the consumption of curcumin significantly reduced therisk of Alzheimer's disease. By modulating β-amyloidprecursor protein metabolism, curcumin and its derivativesdisplay strong neuroprotective activity in the low µM range[64]. These findings suggest curcumin as a possible thera-peutic option to treat neurodegenerative diseases [65].

Clinical relevance with curcumin involved in NF-κB signaling

Curcumin has long been expected to be a therapeutic orpreventive agent for several major human diseases becauseof its anti-oxidative, anti-inflammatory, and anti-cancerouseffects. The absorption, bioavailability and metabolism ofcurcumin have been studied in humans [66]. In 2001, aphase I clinical trial has demonstrated that curcumin is nottoxic to humans up to 8,000 mg/day when taken for 3 months[67]. Besides, the data also suggest a biological effect ofcurcumin in the chemoprevention of cancer. In 1986,Satoskar et al. [68] showed curcumin's anti-inflammatory

response in a preclinical trial. In 2004, Sharma et al. [69]designed a dose-escalation study to explore the pharmacol-ogy of curcumin in humans (n = 50). By measuring in patientblood leukocytes, levels of inducible prostaglandin E2(PGE2) production were reduced after treatments. Becausecurcumin is known to inhibit NF-κB-stimulated inflammatorysignaling by blocking I-κB degradation, the result indicatedthat curcumin down regulated COX-2 transcription, at leastin part, by inhibition of NF-κB signaling [69]. In addition tothe cancer therapy, other effects of curcumin were alsostudied in patients including rheumatoid arthritis, athero-sclerosis, chronic pancreatitis, psoriasis, hyperlipidemia,and neurodegenerative diseases. For example, a short-termhuman study (n = 36) has suggested that curcumin signifi-cantly decreases serum cholesterol concentration [70]. Inaddition, Zhang et al. [71] have demonstrated that curcumintreatments stimulate immune clearance of amyloidosis in ADbrain, suggesting a potential neuropreventive role forcurcumin. Another study has also found that curcuminexerts its inhibition in patients with H. pylori-induced chronicinflammation, suggesting curcumin is therapeutic in humansubjects with inflammation-related diseases [72].

Conclusion

Extensive research for decades has made the clear con-clusion that curcumin appears beneficial therapeutic effectson inflammation-related diseases including cancer. Markedby chronic inflammation modulator, NF-κB is the majormolecular target of curcumin treatments (Figure 2). Sinceblocking of I-κB degradation and its control by IKK areessential steps in down-regulating NF-κB activation, target-ing this point by curcumin for NF-κB-specific blockagewithout safety concern is worth exploring in future. Anotherchallenge is to know how bioactive are curcumin metabolitesunder the physiological processing. The absorption, bio-availability and the metabolism of curcumin have beenstudied in vivo in our laboratory. Curcumin-glucuronoside,dihydrocurcumin-glucuronoside, tetrahydrocurcumin-glucu-ronoside, and tetrahydrocurcumin were found to be themajor metabolites of curcumin. The data shows thatalthough curcumin is poorly absorbed, it is rapidly metabo-lized so that the concentrations detected in free serum arevery low. As in the absence of detail information on the

Cancer Prevention of Curcumin through NF-κB Signaling


biological effects of curcumin metabolites, efforts arenecessary to establish the roles of curcumin metabolites aswell as key elements of the structure-activity relationships.Understanding the molecular mechanisms underlying theanti-inflammatory and anti-cancer actions of curcumin andits derivatives should ultimately prove to be helpful towardthe designing of more effective and safe drugs in the treat-ment of human cancer.

Acknowledgments

This study was supported by the National Science Councilgrants NSC96-2311-B-002-020 and NSC96-2321-B-002-026.The authors also thank their colleagues and researchassociates for their continuous efforts and hard work thatmake this review article possible.

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Curcumin a Potential Cancer Chemopreventive Agent through Suppressing NF-κB Signaling

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