Review Article Multiple Molecular and Cellular Mechanisms of Action … · 2019. 7. 31. · the mechanisms underlying its antineoplastic activity. 1. Introduction Cancer is a disease

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 705121 17 pageshttpdxdoiorg1011552013705121

Review ArticleMultiple Molecular and Cellular Mechanisms of Action ofLycopene in Cancer Inhibition

Cristina Trejo-Soliacutes1 Jose Pedraza-Chaverriacute23 Moacutenica Torres-Ramos4

Dolores Jimeacutenez-Farfaacuten5 Arturo Cruz Salgado5 Norma Serrano-Garciacutea23

Laura Osorio-Rico6 and Julio Sotelo1

1 Departamentos de Neuroinmunologıa Instituto Nacional de Neurologıa y Neurocirugıa (INNN) CP 14269 Mexico City DF Mexico2Neurobiologıa Molecular y Celular INNN-UNAM Instituto Nacional de Neurologıa y Neurocirugıa (INNN)CP 14269 Mexico City DF Mexico

3 Facultad de Quımica Universidad Nacional Autonoma de Mexico (UNAM) CP 04510 Mexico City DF Mexico4Unidad Periferica de NeuroCiencias INNN-UNAM Instituto Nacional de Neurologıa y Neurocirugıa (INNN)CP 14269 Mexico City DF Mexico

5 Facultad de Odontologıa Universidad Nacional Autonoma de Mexico (UNAM) CP 04510 Mexico City DF Mexico6Neuroquimica Instituto Nacional de Neurologıa y Neurocirugıa (INNN) CP 14269 Mexico City DF Mexico

Correspondence should be addressed to Cristina Trejo-Solıs trejosolisyahoocommx

Received 25 March 2013 Revised 5 June 2013 Accepted 19 June 2013

Academic Editor Yew-Min Tzeng

Copyright copy 2013 Cristina Trejo-Solıs et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Epidemiological studies suggest that including fruits vegetables and whole grains in regular dietary intake might preventand reverse cellular carcinogenesis reducing the incidence of primary tumours Bioactive components present in food cansimultaneously modulate more than one carcinogenic process including cancer metabolism hormonal balance transcriptionalactivity cell-cycle control apoptosis inflammation angiogenesis and metastasis Some studies have shown an inverse correlationbetween a diet rich in fruits vegetables and carotenoids and a low incidence of different types of cancer Lycopene the predominantcarotenoid found in tomatoes exhibits a high antioxidant capacity and has been shown to prevent cancer as evidenced by clinicaltrials and studies in cell culture and animal models In vitro studies have shown that lycopene treatment can selectively arrest cellgrowth and induce apoptosis in cancer cells without affecting normal cells In vivo studies have revealed that lycopene treatmentinhibits tumour growth in the liver lung prostate breast and colon Clinical studies have shown that lycopene protects againstprostate cancer One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practiceThus the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding ofthe mechanisms underlying its antineoplastic activity

1 Introduction

Cancer is a disease that is initiated by a series of cumulativegenetic and epigenetic changes that occur in a normal cellCancer development is characterised by three stages initia-tion promotion and progression [1] Initiation is defined asa rapid and irreversible process that begins with genotoxicDNA damage resulting from exposure to endogenous orexogenous carcinogens The initiation of chemically inducedtumourigenesis involves carcinogenic metabolic activationand the subsequent covalent modification of the genomic

DNA allowing the activation of oncogenes or the inactiva-tion of tumour suppressor genes Tumour promotion is areversible process characterised by the transformation of aninitiated preneoplastic cell due to an epigenetic alterationresulting from chronic exposure to tumour promoters (iegrowth factors hormones and UV radiation) The finalstage of the neoplastic transformation progression involvestumour growthwith the potential for invasion andmetastasis

Four possible strategies have been described for thereduction of cancer incidence and cancer-related mortal-ity (I) prevention (II) early diagnosis (III) improvements

2 Evidence-Based Complementary and Alternative Medicine

on treatment and (IV) improved detection of nondiag-nosed cancers [2] Of these options prevention is the mostfavourable Between 30 to 40 of cases are reportedlypreventable through diet modification adequate body weightmanagement and physical activity [3]

Chemoprevention aims to stop or to reduce cancer de-velopment by intervening in the carcinogenesis process viathe administration of natural or synthetic agents [4] Chemo-preventive compounds have been classified into two groupsblocker and suppressor agents The first group blocks cancerinitiation whereas the second stops or delays the promotionand progression of preneoplastic or malignant cells [5]

Chemopreventive compounds intended for human usemust not elicit significant secondary effects They mustbe efficient against multiple molecular targets and theirmechanism(s) of action should be well defined They alsoshould be inexpensive and accessible In addition chemo-preventive compounds should ideally take the form of anoral agent appropriate for widespread application in thegeneral population These characteristics contrast with thoseof chemotherapeutic agents which are usually very expensiveand toxic and are generally applied when the disease hasalready disseminated so they are less efficient [6]

Epidemiological studies have suggested that the inclusionof fruits vegetables and whole grains in dietary intake mightprevent and even reverse the cellular changes associated withcarcinogenesis at the initial stages thus reducing tumourincidence [4] These encouraging results have been docu-mented in vitro and in vivo as well as in clinical trials [7]These beneficial data are attributed to bioactive compoundsincluding both essential nutrients (ie selenium calciumzinc and vitamins C D and E) and nonessential components(carotenoids flavonoids allyl sulfide indole compoundsconjugated acids and n3 fatty compounds) Bioactive com-pounds have been reported to modify specific carcinogenicprocesses including cancer metabolism hormonal balancetranscription factors cell-cycle control apoptosis inflam-mation angiogenesis and metastasis Furthermore naturalcompounds might modulate cellular processes by acting onmolecular targets such as AP-1 (activator protein-1) STATs(signal transducers and activator of transcription) NF-120581B(nuclear factor-kappa B) HIF (hypoxia inducible factor)Nrf2 (nuclear factor-erythroid 2- related factor 2) MAPKs(mitogen activated protein kinases) PI3KAKT (phospho-inositide 3-kinaseAKT) and VEGF (vascular endothelialgrowth factor) thereby favouring the inhibition of car-cinogenesis Here we review the antineoplastic effects andthe mechanism of action of lycopene a carotenoid that isabundant in fruits and vegetables

2 Lycopene and Cancer

Lycopene is a natural pigment synthesised by photosyntheticplants and microorganisms [8] It is a highly unsaturatedacyclic isomer of 120573-carotene its hydrocarbon chain contains11 conjugated and 2 nonconjugated bonds [9] Lycopene isthe most abundant carotenoid in tomatoes and is present inconcentrations ranging from 09 to 927mg100 g dependingon the variety [10 11] Tomato paste is a more concentrated

source of lycopene (51ndash597mg100 g) than nonprocessedtomatoes [11] Other sources of lycopene are found inred fruits such as rosehips watermelons red grapefruitspapayas apricots and pink guavas [12]

Epidemiological studies support the possibility that ly-copene can reduce cancer risk In a meta-analysis of 72studies 57 reported an inverse association between lycopeneingestion and the risk of diverse cancer types (includingprostate breast lung and colon) and 35 studies reportedstatistically significant associations None of these studiesreported any adverse effects of increased tomato intake orincreased circulating lycopene levels [13] In another studylycopene was found to be the only micronutrient present inthe human serum associated with a decreased risk for breastcancer [14]

In a randomised clinical trial lycopene was applied asa therapeutic agent for prostate cancer [15] In that studypatients received 30mg of lycopene daily over a periodof three weeks prior to undergoing radical prostatectomyEighty percent of the patients supplemented with lycopenepresented with smaller tumours compared with the controlpatients Moreover the plasma levels of the specific prostaticantigen decreased by 18 in the supplemented patientswhereas they increased by 14 in the control group Theseresults indicate that lycopene supplementation might repre-sent an adjuvant treatment for this disease

In addition to the correlation between lycopene andprostate cancer increasing evidence suggests that lycopeneplays an important role in cancer prevention in other organssuch as the breast lung gastrointestinal tract pancreasuterine cervix and the ovaries [13] Although the antioxidantproperties of lycopene were thought to be primarily responsi-ble for its biological effects other mechanisms have also beenidentifiedThe following review is an abbreviated overview ofin vitro and in vivo evidence supporting the contribution oflycopene to cancer prevention

3 Potential Mechanisms ofActions of Lycopene

31 Antioxidant Activity Oxidative stress is caused by theincreased production of reactive oxygen (ROS) and nitrogen(RNS) species including superoxide (O

2

∙minus) hydroxyl (OH∙)

peroxyl (ROO∙) alkoxyl (RO∙) and peroxynitrite (ONOO∙)as well as nonradical species such as singlet oxygen (1O

2)

ozone (O3) and hydrogen peroxide (H

2O2) [16] These

chemical species are generated by a wide variety of processesincluding mitochondrial respiration ischemiareperfusioninflammation and the metabolism of exogenous compounds[17] The excessive generation of ROS might oxidise cellu-lar biomolecules including carbohydrates proteins lipidsand DNA The oxidation of these molecules can facilitatecarcinogenesis-related processes such as cellular transfor-mation proliferation apoptosis resistance angiogenesis andmetastasis via genetic alterations including DNA damagemutation epigenetic changes and genetic instability [18]

Because they contain many double-conjugated bondsnatural carotenoids display strong antioxidant capacity [19]Lycopene possesses robust antioxidant activity that is exerted

Evidence-Based Complementary and Alternative Medicine 3

via different mechanisms For example lycopene can trap1O2 Moreover lycopene has been shown to be twice as

effective as 120573-carotene and 10 times more efficient than 120572-tocopherol in its ability to trap 1O

2[20] Another mechanism

that accounts for the antioxidant activity of lycopene is itsreaction with free radicals [21] Lycopene has also beensuggested to act as an antioxidant in vivo by repairingradicals derived from vitamins E and C [22] Matos et al[23] reported that lycopene protects mammalian cells againstlipid peroxidation and oxidative DNA damage induced invitro by an iron chelant In addition in vivo studies haveshown that mitochondrial DNA damage caused by ROSgeneration through UV radiation is partially blocked bytomato sauces rich in lycopene [24] Muzandu et al [25]reported that in Chinese hamster lung fibroblasts lycopenecan inhibit the DNA damage and protein nitration causedby peroxynitrite generated by 3-morpholinosydnoniminesuggesting that lycopene might quench or bind to eitherperoxynitrite or its intermediates Liu et al [26] showed thatin lycopene-treated prostate cancer cells lycopene localisedpredominantly within the nuclearmembrane consistent withits protective effect

311 Regulation of Antioxidant Response Element (ARE)A previous study proposed that the effects of lycopenemay be attributed to the induction of antioxidant enzymesand phase II detoxifying enzymes [27] The administrationof lycopene (25mgkg) can significantly suppress gastriccancer in vivo by reducing lipid peroxidation increasingthe levels of the antioxidants vitamin C vitamin E andreduced glutathione (GSH) and increasing the activity ofcirculating GSH-dependent enzymes such as the glutathioneperoxidase (GPx) glutathione reductase and glutathione-S-transferase (GST) [28] Lycopene also blocks experimentalbuccal carcinogenesis by inhibiting oxidative stress via theupregulation of detoxification pathways [29]

The transcriptional upregulation of the genes encodingthe antioxidant and phase II detoxifying enzyme is mediatedby cis-acting DNA sequences located within their promoterregions that are known as antioxidant response elements(AREs) The major ARE transcription factor is Nrf2 (nuclearfactor E

2-related factor 2) which plays an important role

in the detoxification of carcinogenic agents and in themodulation of the antioxidant cellular defence system asit promotes the upregulation of stress-induced cytoprotec-tive enzymes including NAD(P)Hquinone oxidoreductase-1 (NQO1) superoxide dismutase (SOD) GST GPx hemeoxygenase-1 (HO-1) glutamate cysteine ligase (GCL) cata-lase and thioredoxin (Tx1) In addition Nrf2 also elicits anti-inflammatory effects [27]

Under normal conditions Nrf2 is localised in the cyto-plasm forming a complex with the inhibitory protein Keap1(Kelch-like ECH-associated protein 1) [30] However oxida-tive stress promotes the dissociation of Nrf2 from Keap1rescuing Nrf2 from proteasomal degradation and inducingits nuclear translocation allowing it to bind to AREs togetherwith other transcription factors to regulate the expression ofthe target genes [31]

InMCF-7 andHepG2 cells lycopene increases themRNAandprotein levels ofNQO1GCL andGSHby activatingNrf2[27] In addition the ethanolic extracts of lycopene activateARE-regulated reporter genes with a potency similar to thatobserved for pure lycopene These findings suggest that oxi-dised metabolites might be responsible for the induction ofphase II enzymes through the modulation of ARE sequences[27] In epithelial bronchial cells (BEAS-2B) the enzymaticmetabolite of lycopene apo-101015840-lycopenoic acid induces thenuclear accumulation of Nrf2 which associates with phase IIdetoxifying enzymes and antioxidant enzymes includingHO-1 NQO1 GST and GCL [32] Moreover apo-101015840-lycopenoicacid increases intracellular levels of GSH suppresses ROSproduction and reduces the oxidative damage induced byH2O2in BEAS-2B cells These data suggest that lycopene-

derived metabolites might mediate the activation of Nrf2-ARE signalling and the subsequent induction of gene expres-sion [32]

Although the molecular mechanism by which lycopeneinduces the nuclear translocation of Nrf2 is unknown Lianand Wang [32] have proposed that highly reactive aldehydegroups present in lycopene-derived metabolites form Schiffbases with the N-terminal group of proteins For examplethese reactions may directly modify cysteine residues inKeap1 and thereby abrogate the ubiquitination and subse-quent Keap1-mediated degradation of Nrf2 The thiol groupsbelonging to the seven cysteine residues of Keap1 are oxidisedor covalently modified allowing the dissociation of the Nrf2-Keap1 complex [33] It is also possible that these lycopenoidsaffect upstream signalling pathways For example lycopenemight targetMAPKs PI3K epidermal growth factor receptor(EGFR) and protein kinase C (PKC) proteins that play animportant role in the regulation of Nrf2-ARE signalling inlung epithelial cells [34 35] (Figure 1)

32 Growth Factors and Signalling Pathways Growth factorsare proteins steroids or any other biochemical substance thatmight bind to cognate receptors that are present on the cellsurface to activate cell signalling cascades that regulate a largevariety of cellular processes Several growth factors includinginsulin-like growth factor 1 (IGF-1) vascular endothelialgrowth factor (VEGF) epidermal growth factor (EGF) andplatelet-derived growth factor (PDGF) play important rolesin carcinogenesis and metastasis The abnormal activation ofsignalling pathways by growth factors leads to increased pro-liferation differentiation maturation apoptosis suppressioninvasion and metastasis [36]

321 Effects of Lycopene on IGF Signalling PathwaysLycopene affects multiple IGF-1-activated signalling path-waysThe IGF family of growth factors (IGF-1 and IGF-2) aremitogens that play important roles in the regulation of pro-liferation differentiation and apoptosis Binding of IGF-1 toits cognate membrane receptor activates the PI3KAKTPKBand RasRafMAP kinase signalling pathways which in turnregulate several biological processes including cell-cycleprogression cell survival and transformation [37] The IGFsare sequestered in the circulation by a family of IGF-binding


ROS

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Figure 1 A possible mechanism of Nrf2 regulation by lycopene Under homeostatic conditions Nrf2 is retained within the cytoplasm by theKeap1 protein Upon activation of upstream protein kinases (MAPKs PI3K PKC and ERK) andor direct effects on Keap1 Nrf2 is releasedfromKeap1 and translocated into the nucleus whereNrf2 associates with smallMaf proteins and binds to AREs Lycopene induces the nucleartranslocation of Nrf2 One possible mechanism involves the direct interaction of lycopene with the cysteine residues of Keap1 which triggersthe release of Nrf2 from the complex Lycopene-generatedmetabolites can activate a wide variety of kinases which can also induce the releaseand nuclear translocation of Nrf2

proteins (IGFBP-1-IGFBP6) that regulate the binding of IGFsto their receptors [38] Any alteration of normal physiologicalIGF-1 signalling leads to increased proliferation and activa-tion of the survival signalling [39] In breast cancer (MCF-7) and lung cells (NCI-H226) lycopene has been reportedto reduce IGF-1 levels and to increase IGFBPs [40 41]Lycopene supplementation increases the circulating levels ofIGFBP-1 and IGFBP-2 in high-risk populations of colorectalcancer patients suggesting that lycopene might reduce therisk of colorectal cancer and potentially the risk of othercancers such as prostate and breast cancer [42] Moreoverin humans exposed to tobacco smoke lycopene treatmentinhibits lung metaplasia by upregulating IGFBP3 and bydecreasing the phosphorylation of BAD thereby promotingapoptosis and inhibiting cell proliferation This study sug-gested that IGFBP3 might inhibit both the PI3KAKTPKBand the RasRafMAP kinase signalling pathways in lungcancer cells as PI3K mediates the phosphorylation of BADon serine136 and MAPK mediates the phosphorylation ofBAD on serine112 [43] Recently in vitro and in vivo prostate

cancermodels have demonstrated that lycopene increases theantineoplastic effects of docetaxel by inhibiting the activationof IGF-1R through the inhibition of IGF-1 stimulation andincreased IGFBP3 expression Furthermore lycopene mightinhibit not only the IGF-1-induced phorylation of IGF-1R butalso the downstream activation of AKT and the expression ofthe antiapoptotic protein survivin in DU145 cells [44]

322 Effects of Lycopene on PDGF Signalling PathwaysPDGF another growth factor that is inhibited by lycopenes isa potent stimulator of the growth and motility of connectivetissue cells such as fibroblasts and smooth muscle cells(SMCs) The biologically active form of PDGF is a dimerformed by two polypeptidic chains that are linked by disulfidebonds It can be either a homodimer (PDGF-AA and PDGF-BB) or a heterodimer (PDGF-AB) This factor exerts itseffects on target cells by binding with different specificitiesto its receptors PDGFR120572 and PDGFR120573 Binding of PDGF toPDGFR causes receptor dimerization autophosphorylationand the activation of receptor tyrosine kinase function


resulting in the subsequent activation of the MAPK andPI3KAKT- PLC120574-PKC signalling pathways [45]

Abnormalities in the PDGF-BB-PDGFR120573 signallingpathway contribute to a number of human diseases includ-ing vascular and malignant pathologies [46] In functionalstudies lycopene inhibits PDGF-BB-induced proliferationand migration of SMCs on gelatin and collagen It alsoinhibits the phosphorylation of PLC120574 and ERK12 by directlybinding to PDGF-BB [47] In the same way lycopene inhibitsPDGF-BB-induced signalling in cultured human fibroblastsas well as the phosphorylation of ERK12 (kinase regulatedby extracellular signals) p38 and JNK (c-jun N-terminalkinase) [48] Moreover lycopene inhibits SMC and fibroblastmigration by reducing PDGF-AA and PDGF-AB signallingas measured by PDGFR120572 phosphorylation and the activationof downstream kinases [49] Chiang et al [50] have shownthat lycopene significantly inhibits the fibroblast migrationinduced by melanoma tumour cells indicating that lycopeneinterferes with stroma-tumour cell interactions Further-more lycopene has been suggested to bind to the PDGFsecreted by melanoma cells and it might inhibit PDGF-induced fibroblast migration Thus lycopene might help toprevent melanoma progression

323 Effects of Lycopene on VEGF Signalling PathwaysVEGF which is encoded by the VEGF-A -B -C -D and -E genes is one of the main regulators of vascular endothelialcells and blood vessel formation and it is a member of theVEGF-PDGF super family along with the placental growthfactor (PLGF) Binding of VEGF to its receptors (VEGFR-1 -2 and -3) results in the activation of the MAPK andPI3K-PLC120574-PKC pathways VEGFR-2 activation increasesand activates endothelial nitric oxide synthase (eNOS) whichraises the levels of nitric oxide (NO) playing a crucial role inVEGF-induced endothelial cell proliferation migration tubeformation vascular permeability increase hypotension andangiogenesis [51 52]

Recent studies have shown that lycopene inhibits humanumbilical vascular endothelial cell (HUVEC) migration andtube formation [53] Moreover high doses of lycopene caninhibit tumour growth in nude mice xenotransplanted withthe PC-3 prostate carcinoma and Sk-Hep-1 hepatocellularcarcinoma cell lines In both of these neoplasms high-doselycopene treatment also decreases the circulating levels ofVEGFThese data suggest that lycopene elicits antiangiogeniceffects [54] Lycopene inhibits angiogenesis by inhibitingmatrix metalloproteinase (MMP)-2 and the urokinase plas-minogen activator (uPA) system through the inhibition ofVEGFR2 signalling pathways including ERK12 p38 andPI3K-AKT and by reducing the expression of Rac-1 proteinThese changes reduce the invasion migration and tubeformation capacity of HUVECs [55]

These results suggest that lycopene may inhibit thecarcinogenic process through the inactivation of the growthfactor (PDGF VEGF and IGF) induced PI3KAKTPKB andRasRAFMAPK signalling pathways When active thesepathways activate transcription factors (NF-120581kB AP-1 andSP-1) that regulate the expression of genes that control cellular

processes such as proliferation cell cycle apoptosis inflam-mation angiogenesis invasion and metastasis (Figure 2)

33 Cell-Cycle Arrest Cell-cycle progression is regulatedthrough the interaction between cyclin-dependent kinases(CDK1 -2 -3 -4 and -6) cyclins (cyclin A -B -D and -E) and inhibitor proteins (p21WAF1 and p27KIP1) [56 57]The coordinated participation of cyclin DCDK46 cyclinECDK2 and cyclin ACDK2 complexes is required for theG1S transition and progression through S phase whereas

the cyclin ACDK12 complexes are required for cells toenter mitosis The activation of the cyclin DCDK46 andcyclin ECDK2 complexes is essential for the phosphoryla-tion of retinoblastoma (Rb) Rb is constitutively expressedand dephosphorylated it forms a complex with histonedeacetylase-1 and the transcription factor E2F inhibiting itstranscriptional activity By activating ERK12 growth factorsmight induce an increase in the expression of cyclin D whichbinds to and activates CDK4 and CDK6 Rb is phosphory-lated by these activated CDKs inducing the dissociation ofhistone deacetylase-1 from the complex allowing for histoneacetylation and facilitating the transcription of specific genesThese genes include cyclin E which binds to and activatesCDK2 CDK2 then hyperphosphorylates Rb releasing theE2F transcription factor which in turn induces the geneexpression necessary for the transition to S phase Amongthese genes are DNApolymerase A dihydrofolate reductasesthymidylate synthase and cyclins [58]

The activity of cell cycle kinases is often upregulatedin cancer due to the overexpression of cyclins and CDKsor to the inactivation of CDK inhibitors Specifically thederegulation and accumulation of proteins involved in thecyclin D-Rb signalling axis are quite common in humancancers including cancers of the liver breast lung skin andoesophagus [58]

331 Effects of Lycopene on Cell Cycle Lycopene induces cell-cycle arrest Park and collaborators [59] reported that thegrowth of human hepatoma Hep3B cells was significantlyinhibited by lycopene treatment which induced G

0G1and

S phase arrest Another study showed that the inhibited cellgrowth induced by lycopene in MCF-7 cells was associatedwith a decrease in cyclinD and c-myc expression In this casereduced CDK4 activity and retention of p27 within cyclin E-CDK2 complexes resulted in decreased CDK2 kinase activityleading to reduced Rb phosphorylation and thus inhibitionof the G

1S transition [60] Using MCF-7 breast cancer cells

and ECC-1 endometrial cells Nahum et al [61] found thatlycopene and all-trans retinoic acid (ATRA) inhibited IGF-1 stimulated cell-cycle progression through the G

1and S

phases and also inhibited Rb phosphorylation These eventswere associated with a reduction in cyclin D and p21WAF1Moreover the attenuation of cyclin Dl levels by lycopene andATRA represents an important mechanism for inhibiting themitogenic action of IGF-I Lycopene also interferes indirectlywith cell-cycle progression by inhibiting the IGF-1-inducedphosphorylation of tyrosine residues within the insulin-1 receptor substrate (IRS-1) and by inhibiting the DNAbinding of the AP-1 transcription factor in breast cancer


Lycopene

Angiogenesismetastasisbull VEGFbull MCP-1bull MMP-2 7 9bull uPAbull VCAM-1bull ICAM-1bull CSCR4

Apoptosisbull IAP12bull XIAPbull FLICEbull cFlipbull TRAF-1 2bull Bcl-2bull Bcl-XL

Cyclin DE

c-fos

IGF-1R VEGFR

PDGF-AAPDGF-BBPDGF-AB

IGBP1

IGBP2

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JNK p38

IGF

PI3K

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IKK

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Raf

MAPK

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Cell cycle bull Cyclin DEbull CDK2 4 6bull c-mycbull PCNA

Inflammationbull TNF120572bull Cox-2bull IL-1 6 8

NF120581B

NF120581B

NF120581B

AP-1

AP-1

SP-1

SP-1

darr VEGF

Figure 2 PDGFR- IGF-IR- and VEGFR-mediated signal transduction pathways are possible targets for lycopene PDGFR IGF-IR andVEGFR are activated at the cell surface during tumourigenesis Activation of these receptors induces several downstream signalling pathwaysAmong these pathways the Ras-MAPK (including ERK JNK and p38) and PI3K-AKT pathways transduce signals into the nucleus to activatetranscription factors that regulate the expression of genes that are important for proliferation cell-cycle progression apoptosis inflammationangiogenesis invasion and metastasis Lycopene has been shown to inhibit the IGF-induced activation of IGFR by increasing the expressionof IGFBPs Similarly lycopene directly binds to PDGF to reduce the autophosphorylation of PDGFR and VEGFR


cells [62] Recent studies have demonstrated that lycopeneblocks cells at the G

1S phase transition by decreasing

cyclin D and increasing p21 p27 and p53 levels in LNCaPprostate carcinoma cells Lycopene elicits these changes byinactivating Ras via the inhibition of the mevalonate path-way and decreased expression of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA) Lycopene treatmentalso reduces the farnesylation of Ras which promotes thecytoplasmic accumulation of Ras and its consequent inactiva-tion Furthermore lycopene reduces the Ras-dependent acti-vation of the NF-120581B transcription factor which regulates thetranscription of prosurvival genes including cyclin D Bcl-2 Bcl-XL cIAP and c-myb [63] In addition lycopene wasshown to inhibit the growth of MDA-MB-231 cells by block-ing cell-cycle progression inhibiting Skp2 and increasingp27 levels [64] Skp2 is an E3 ligase involved in cell-cycle pro-gression by targeting various cell-cycle regulators includingp27 p21 and FOXO1 for degradation Skp2 is overexpressedin a variety of human cancers including cancers of the breastcolon and prostate as well as lymphoma andmelanoma [65]In A549 nonsmall lung carcinoma cells lycopene-derivedmetabolites such as apo-101015840-lycopenic acid can induce cell-cycle arrest at the G

1S transition This cell-cycle arrest is

associated with a decrease in cyclin E an increase in thecyclin-dependent kinase inhibitors p21 and p27 and thetranscriptional induction of the RAR120573 tumour suppressorgene which is associated with the increased expression ofp21 and p27 [66] In the androgen-independent prostate cellline DU145 other lycopene-derived products such as apo-81015840-lycopenal and apo-121015840-lycopenal might significantly reducecell proliferation by altering the cell cycle [67]

These results suggest that lycopene blocks cell-cycleprogression from G

1to S phase predominantly by reducing

the levels of cyc D and E and subsequently by inactivatingCDK2 and 4 and decreasing the hyperphosphorylation ofRb Furthermore lycopene increases the expression of CDKinhibitors including p21 and p27 as well as the tumoursuppressor gene p53 and decreases the expression of Skp2(Figure 3) Lycopene can also block growth-factor-mediatedantiapoptotic signals by inhibiting the binding of growth-factors to their receptors or by inhibiting downstream com-ponents of the PI3K-AKT pathway AKT phosphorylatesand inactivates glycogen synthase kinase 3120573 (GSK3120573) Thusby inhibiting GSK3120573 a growth factor might promote thedephosphorylation and stabilisation of cyc D and c-mycCyc D facilitates S-phase entry and c-myc stimulates cellproliferation and survival AKT phosphorylates and inac-tivates the cyclin-dependent kinase inhibitors p21 and p27An increase in the expression of these inhibitors couldin turn inhibit the activity of the CDK 46cyclin D andCDK2cyclin E complexes and reduce the phosphorylation ofRb Reduced phosphorylation or hypophosphorylation of Rbleads to the inactivation of the E2F transcription factor andthe suppression of the S-phase cyclin A An additional targetof AKT is Mdm2 which mediates the ubiquitination anddegradation of p53 which plays a key role in the induction ofcell-cycle arrest in response to a variety of genotoxic stressesand to the activation of oncogenes such as c-myc therebypreventing the propagation of abnormal cells (Figure 3)

34 Apoptosis There is a link between the regulation ofthe cell-cycle and apoptosis cell cycle deregulation is oneof the most potent triggers for apoptosis Specifically thederegulation ofmost components of the cell-cyclemachineryincluding Rb E2F p21 p27 cyclin D or CDK1 might beinvolved in the apoptotic process [68] Apoptosis is regulatedby a complex network of pro- and antiapoptotic proteins itcan be induced by either intrinsic or extrinsic pathways

Extrinsic pathway is initiated by the interaction of ligandswith death receptors such as tumour-necrosis-factor- (TNF-)related apoptosis inducing ligand receptor (TRAILR) andFASCD95APO-1 [69] All of the death receptors containintracellular death domains (DDs) that facilitate the trans-mission of apoptotic signals [70]Themostwell-characterisedpathway is mediated by the death receptor Fas Fas ligand(Fas-L) binds to its receptor inducing the aggregation andactivation of other receptors Once activated they recruit theadaptor protein FADD which also contains DDs in additionto a death effector domain (DED) which is required to recruitthe initiators of apoptosis caspases 8 and 10 The assemblyof these proteins form the death-induced signalling complex(DISC) which leads to the autoactivation of caspases 8 or10 which in turn promote the catalytic activation of theeffector caspases 3 andor 7 [71] Another target of caspase8 is the proapoptotic protein Bid which is hydrolysed totBid inducing Bax oligomerization and depolarization ofthe mitochondrial with release of cyt c Together with theactivation of caspase 9 these events amplify the apoptoticsignal [71]

The intrinsic pathway involves the permeabilisationof the mitochondrial external membrane which facili-tates the cytosolic release of proapoptotic proteins such asSMACDiablo and cytochrome c (cyt c) which are otherwiseconfined within the intermembrane space Cyt c binds to theApaf-1 protein which in turn binds to and activates capsase-9 which is responsible for the activation of the executionersof apoptosis caspases 3 -6 and -7 [68]

Both effector pathways of apoptosis are associated withcaspase activation Caspase activation is tightly regulated byinhibitors of apoptosis proteins (IAPs) such as NAIP cIAP1cIAP2 XIAP and survivin IAPs bind caspases antagonisingtheir activity Specifically XIAP cIAP1 and cIAP2 inhibitcaspase 3 caspase 7 and caspase 9 Survivin inhibits theSMACDiablo protein which binds to and neutralises IAPs[72] The apoptosis is regulates also by members of the Bcl-2family that regulate the mitochondrial release of cyt c Anti-apoptotic Bcl-2 family proteins (Bcl-XL and Bcl-2) remainwithin the external mitochondrial membrane inhibiting therelease of cyt c whereas proapoptotic Bcl-2 family proteins(Bax Bim and Bid) are translocated to the mitochondria toinduce apoptosis Other protein involved in the regulation ofapoptosis is the tumour suppressor p53 that transcriptionallyactivates the proapoptotic genes Bax Noxa PUMA and Bidand transcriptionally represses Bcl-2 and IAPs [73]

341 Effects of Lycopene on Apoptosis Lycopene mediatesapoptosis via death receptors (Figure 3) Tang et al [74]reported that lycopene and EPA (eicosapentaenoic acid)synergistically inhibit the activation of AKT and mammalian


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E2F

CDK46

Figure 3 Lycopene induces cell-cycle arrest and apoptosis Growth factors such as PDGF and IGF enhance cell survival by protectingcells from apoptosis Lycopene blocks cell-cycle progression from G1 to S phase predominantly by reducing the levels of cyc D and E andsubsequently inactivating CDK4 and 2 and reducing the phosphorylation of Rb Furthermore lycopene increases the levels of the CDKinhibitors p21 and p27 and the tumour suppressor p53 and reduces levels of SKP2 (leaf panel) Lycopene promotes apoptosis by decreasingBcl-2 BclXL and survivin expression increasing the levels of the proapoptotic proteins Bax Bad Bim and Fas ligand and activating caspases8 9 and 3 (right panel) Lycopene can also block growth factor-mediated antiapoptotic signals by directly inhibiting the binding of growthfactors to their receptors or by inhibiting the downstreamPI3K-AKTpathway Lycopene can elicit AKT-induced cell-cycle arrest and apoptosisthrough the phosphorylation and inactivation of GSK3120573 p21 p27 Bad and caspase 9 as well as the inactivation of p53 via Mdm2

target of rapamycin (mTOR) enhancing the accumulation ofBax and Fas ligand and blocking the survival ofHT-29 humancolon cancer cells Moreover in combination with S-allyl cys-teine lycopene significantly blocks the in vivo development ofgastric cancer by inducing apoptosis via reduced expressionof Bcl-2 increased expression of Bax and Bim and increasedactivation of caspases 8 and 3 [75]Themetabolite (E E E)-4-methyl-8-oxo-2 4 6-nonatrienal (MON) which is obtainedfrom the autooxidation of lycopene induces apoptosis inHL-60 human promyelocytic leukaemia cells as evidencedbymorphological changes including chromatin condensationand DNA fragmentation both of which are associated withdecreased Bcl-2 and Bcl-XL expression and the activation ofcaspases 8 and 9 MON was suggested to induce apoptosisvia the mitochondrial and death receptor pathways as itmight induce the cytosolic release of cyt c by decreasing theexpression of Bcl-2 and Bcl-XL The enhanced activation ofcaspase 8 induced by MON might be mediated by death

receptors either by direct binding or by induction of Fasligand expression [76]Moreover lycopene induces apoptosisvia themitochondrial pathway by increasing the expression oftBid and by decreasing the phosphorylation of AKT in canineosteosarcoma cells [77]

A number of studies have shown that lycopene inducesapoptotic death via the intrinsic pathway (Figure 3) In theLNCaP cell line lycopene induces mitochondrial apoptosisin a dose-dependent manner by reducing mitochondrialmembrane potential and inducing cyt c release into thecytosol [78] Recently combination treatment with lycopeneand genistein has been demonstrated to significantly reducethe development of a chemically induced breast cancer invivo This suppression was associated with decreased Bcl-2expression increased Bax expression and the activation ofcaspases 3 and 9 [79] Furthermore Wang and Zhang [80]reported that lycopene can induce apoptosis in PC-3 cells byaltering the cell-cycle distribution decreasing cyclin D and


Bcl-2 expression and increasing Bax expression SimilarlyPalozza et al [81] demonstrated that tomato products thatcontain lycopene can inhibit the growth of colon adenocar-cinoma cells by decreasing the expression of cyclin D and theantiapoptotic proteins Bcl-2 and Bcl-XL They also showedthat lycopene induces apoptosis in immortalised fibroblastsby promoting cell-cycle arrest via decreased cyclin D levelsand reduced AKT and Bad phosphorylation [82] Combininglycopene with docetaxel has been shown to induce p53 inLNCaP cells [63] and might synergistically decrease survivinexpression levels in vitro and in vivo [83]

These studies have suggested that lycopene inhibits apop-tosis by decreasing the expression of Bcl-2 BclXL andsurvivin by increasing the expression of the proapoptoticproteins Bax Bad and Bim and Fas ligand and by increasingthe activation of caspases 8 9 and 3 Lycopene can also blockgrowth factor-mediated antiapoptotic signals by directlyinhibiting growth factor-receptor binding or by inhibit-ing downstream components of the PI3K-AKT pathway(Figure 3) AKT can inhibit apoptosis by phosphorylatingand inactivating caspase 9 and Bad a member of the Bcl-2 family of proteins that binds to BclXL and Bcl-2 andinhibits apoptosis by inactivating p53 which regulates thetranscription of Bax and FAS ligand (Figure 3)

35 Cellular Invasion and Metastasis Metastasis is the trans-ference of tumour cells from one organ to another Itrepresents the most severe complication of cancer and isthe main cause of death in most cancer patients [84]Angiogenesis is the initial step in metastasis and is essen-tial for tumour growth and the initial progression of thepremalignant tumour towards becoming an invasive cancerThe subsequent steps involve the loss of cellular adhesion intumour cells alterations in the basal membrane infiltrationand invasion of the surrounding tissues and subsequentpenetration (intravasation) of the tumour cells into bloodor lymphatic vessels which transport these neoplastic cellsinto the circulation The metastatic process proceeds withcell survival in the bloodstream passage into the capillaryterminals of distant organs and escape from these vessels(extravasation) the colonisation of distal sites and the devel-opment of secondary tumours [85]

351 Wnt120573-Catenin Signalling in Cancer Some reports havesuggested that the Wnt pathway might lead to cellularderegulation by inducing the expression of several oncogenesWnt is a determinant factor in cancer its activation promotesmetastasis [86] Nuclear 120573-catenin is an indicator of thecanonical activity of the Wnt pathway which participatesin the initiation development and progression of severaltumour types [86] 120573-catenin is associated with cytoplasmiccadherin domains and it is linked via 120572-catenin to cell-to-cell junctions within the cytoplasm120573-catenin can be releasedfrom 120572-cadherin into the cytoplasm where it integrates intoa multiprotein complex containing axin APC (adenomatouspolyposis coli) and GSK3120573 In a nonstimulated cellular stateGSK3120573 is activated and phosphorylates 120573-catenin promotingits ubiquitination and proteasomal degradation Phospho-rylation restricts 120573-catenin to the cytoplasm promoting its

degradation and preventing its translocation to the nucleusand therefore its action as a transcription factor The mecha-nisms described previously maintain low amounts of free 120573-catenin within the cytoplasm [87] Various stimuli includingWnt signalling prevent 120573-catenin degradation Wnt proteinsare modified by lipids and intervene in several develop-ment processes through their interaction with the Frizzledand lipoprotein receptor-ligated protein 5 and 6 (LRP-56) receptor molecules The activation of Wnt signallinginactivatesGSK3120573by phosphorylationUnphosphorylated120573-catenin accumulates within the cytoplasm and can enter thenucleus where it can bind to lymphoid enhancer factorT-cell factor (LEFTCF) family transcription factors to inducegene expression [88] Some of the transcriptional targets of120573-catenin have been implicated in cell proliferation [89] andcellular adhesion [90] Growth factors also allow for theaccumulation of 120573-catenin within the cytoplasm and increaseits activity as transcription factor One effect of the signallingcascades induced by growth factors is the inactivation ofGSK3120573 usually by AKT-mediated phosphorylation [88]

352 Anti-Invasive and Antimetastatic Effects of Lycopene onColon Liver and Prostate Cancers In vitro and in vivo studieshave suggested promising anti-inflammatory antiangiogenicanti-invasive and antimetastatic effects of lycopene in thedevelopment of colon liver and prostate cancer The in vitroadministration of lycopene reduces inflammatory signallingSimone et al [91] reported that lycopene inhibits the mRNAand protein expression of the proinflammatory cytokine IL-8 through the inactivation of the NF-120581B transcription factorMoreover lycopene treatment was shown to result in reducedERK12 JNK and p38MAPK phosphorylation and increasedexpression of PPAR120574 resulting in increased PTEN activityand the inactivation of AKT Lycopene has been suggested toinduce NF-120581B inactivation by inhibiting the phosphorylationof IKK120572 and IKB120572 and by decreasing the translocation of theNF-120581Bp65 subunit from the cytosol to the nucleus Lycopenealso inhibits TNF120572 cyclooxygenase (COX)-2 inducible nitricoxide synthase (iNOS) and interleukin (IL)-6 secretion [9293]

Lycopene inhibits in the progression of colon cancer invivo by decreasing proliferating cell nuclear antigen (PCNA)increasing p21 and the activation of caspase 3 increasing theE-cadherin adhesion molecule and decreasing nuclear levelsof 120573-catenin Moreover the effects of lycopene are associatedwith the suppression of COX-2 prostaglandin E2 (PGE

2)

and ERK12 phosphorylation which is inversely correlatedwith plasma levels of MMP-9 in tumour-bearing mice [94]Lycopene also decreases MMP-7 expression in colon cancercellsThe increasedMMP-7 expression correlates withmalig-nant progression of human colon cancer The reduction ofMMP-7 expression by lycopene is correlated with reducedstability and increased E-cadherin expression suggesting thatMMP-7 might hydrolyse this adhesion molecule Further-more lycopene decreases MMP-7 and c-myc expression byinhibiting AKT GSK3120573 and ERK12 phosphorylation withsubsequent reduction of the AP-1 and 120573-catenin transcrip-tion factors The effects of lycopene are associated withGSK3120573 activation and 120573-catenin destabilisation lycopene


might induce 120573-catenin degradation through the activationof GSK3120573 [95] Lycopene might inhibit the growth of coloncancer cells by inactivating the AKT signalling pathway andby increasing the accumulation of cytoplasmic phospho-120573-catenin these effects are associated with decreased promoteractivity and protein expression of cyclin D1 The authors ofthis study suggest that lycopene indirectly regulates cyto-plasmic 120573-catenin levels by modulating its phosphorylationand subsequent proteasomal degradation [96] Recent studiesindicate that increased levels of 120573-catenin correlate with thedownregulation of the Wnt120573-catenin pathway due to theproteasomal degradation of 120573-catenin and the subsequentdecrease in cyclin D [97] as the cyclin D1 gene might be atarget of the 120573-cateninLEF-1 complex [54]

Lycopene inhibits the migration and invasion of SK-Hep-1 hepatoma cells in vitro These effects are associatedwith the upregulation of the nm23-H1 gene which is asuppressor of metastasis [98] Hwang and Lee [97] alsodemonstrated that lycopene inhibits the adhesion invasionand migration of SK-Hep-1 cells These actions are asso-ciated with the decreased activity of MMP-2 and MMP-9 Similarly Huang et al [99] demonstrated that lycopeneinhibits metastatic tumour growth in the lungs of nudemice that were xenotransplanted with SK-Hep-1 cells Theseeffects of lycopene were associated with the inhibition oftumour invasion (decreased MMP-9 and upregulated nm23-H1) cell proliferation (decreased PCNA) and angiogenesis(decreased MMP-9 and VEGF but increased IL-2) in thelungs of nude mice In SK-Hep-1 cells apo-81015840-lycopene hasbeen shown to exhibit more robust antimetastatic activitythan lycopene by inhibiting MMP-2 and MMP-9 expressionincreasing the expression of nm23-H1 TIMP-1 and TIMP-2 (MMP tissue inhibitors) suppressing the Monomeric RhoGTPase- and inhibiting the focal adhesion kinase- (FAK-)mediated signalling pathway [100] Conversely lycopene hasbeen demonstrated to significantly inhibit the DNA bindingof NF-120581B and the simulator protein (SP1) and to therebydecrease MMP-9 secretion and reduce the invasive capacityof human hepatoma cells [101]The authors suggest that theselycopene-induced effects might be attributed to its ability todecrease IGF-1R levels as the IGF-1 signalling pathway hasbeen shown to activate SP1 and NF-120581B which can in turnincrease the expression of MMPs [102]

Consistent with this notion lycopene has been shownto inhibit IGF-1-induced prostate cancer growth by reducingAR (retinoic acid) and 120573-catenin inhibiting the effects ofIGF-1 on the phosphorylation of AKT and GSK3120573 [103] andinhibiting angiogenesis by decreasing VEGF and EGF levelsin nude mice that were xenotransplanted with PC-3 cells[104]

These studies suggest that the regulation of metastaticprogression is a target of lycopene for the preventionand therapeutic intervention against cancer (Figure 4) Thepotential mechanisms underlying the antimetastatic effectsof lycopene include the downregulation of the Wnt120573-catenin pathway Lycopene elicits several effects includingthe increased expression of E-cadherin nm23-H1 and tissueinhibitor of metalloproteinases 2 (TIMP2) proteins and thedecreased activity of GSK3120573 MMP-2 MMP-7 MMP-9 uPA

and 120573-catenin protein (Figure 4) Other potential mecha-nisms underlying the action of lycopene include blocking thegrowth factor-mediated activation of the PI3K-AKT pathwayand theAkt-mediated phosphorylation ofGSK3120573 which oth-erwise phosphorylates 120573-catenin to promote its proteasomaldegradation and to inhibit its activity as a transcription factor(Figure 4)

36 Lycopene as Adjuvant for CancerTherapy Antineoplastictherapies such as radiation and chemotherapy are treatmentsgiven in addition to surgery to suppress tumor relapsethrough elimination of any remaining cancer cells Theseadjuvant therapies are designed to kill actively proliferatingcancer cells but are often ineffective for tumor metastasizedAdditionally their effectiveness is often further hamperedby associated side effects and the development of treatmentresistance Studies have provided some encouraging datademonstrating that lycopene might revert multidrug resis-tance (MDR) inducing apoptosis in tumors cells [105] andcan either be used alone or combined with additional anti-neoplastic agents to inhibit tumor invasion and angiogenesisas well as amelioration of adverse side effects that result fromtreatment with antineoplastic agents [75 79 83]

361 Synergistic Effects of Lycopene with Natural AnticancerCompounds Chemoprevention by diet-derived agents thatinduce apoptosis is a promising strategy to control can-cer due to its potential efficacy and minimal toxicity125-dihydroxyvitamin D

3induces HL-60 cell differentia-

tion [106] However it was shown that the use of 125-dihydroxyvitamin D

3for the treatment of psoriasis leads

to clinical remission however this remission is not alwaysdurable due to clinical resistance to these agents developedafter prolonged treatment frequently associated with toxicside effects [107] To overcome these toxic effects lowerdoses of the differentiation-inducing agents have been testedAmir et al [108] showed that the combination of lowconcentrations of lycopene with 125-dihydroxyvitamin D

3

in HL-60 cells produced a synergistic inhibitory effect oncell proliferation and cell differentiation associated withadditive effect on the accumulation of cells in the GoG1phase compared with the same concentration of lycopene or125-dihydroxyvitamin D

3alone Tang et al [109] reported

that lycopene and fish oil combined at physiological con-centration induced a synergistic inhibitory effect on tumorgrowth in a mouse xenograft model of colon cancer Thechemopreventive effects of both compounds were associatedwith increased expression of cell-cycle inhibitors such asp21CIP1WAF1 and p27Kip1 as well as suppression of prolif-erating cell nuclear antigen 120573-catenin cyclin D1 and c-Myc proteins Furthermore lycopene and fish oil inhibitedtumor progression and inflammation through suppressionof MMP-7 MMP-9 COX-2 and PGE2 Similar synergis-tic inhibitory effects on the proliferation of colon cancercells by lycopene and eicosapentaenoic acid (EPA) a majorcomponent in fish oil even at low concentration werereported by Tang et al [74] The inhibitory mechanism wasassociated with suppression of PI3KAktmTOR signalingpathway and upregulation of apoptotic proteins such as Bax


IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin

120573-catenin120573-catenin

120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B

Figure 4 Lycopene inhibits theWnt120573-catenin pathway In the absence of Wnt a multiprotein complex that includes axin APC and GSK3120573destabilises 120573-catenin 120573-catenin is phosphorylated by GSK3120573 and is subsequently degraded by the proteasome Binding of Wnt to its cellsurface receptors Fzd and Lrp 56 inhibits the phosphorylation of 120573-catenin by GSK3120573 allowing 120573-catenin to accumulate within the cytosol120573-catenin then translocates into the nucleus where it binds and activates LEFTCF and induces gene expression Lycopene increases theexpression of E-cadherin nm23-H1 and TIMP2 as well as the activity of GSK3120573 Furthermore it decreases the levels of MMPs 2 7 and 9uPA and 120573-catenin Lycopene also induces its antimetastatic effects through the inactivation of transcription factors (NF-120581B AP-1 SP-1 andLEFTCF)

and Fas ligand Velmurugan et al [75] demonstrated that thecombination of S-allylcysteine an organosulfur constituentof garlic and lycopene was more effective in suppressing thedevelopment of N-methyl-N1015840-nitro-N1015840-nitroso-guanidine-(MNNG-) induced gastric cancer through diminution ofBcl-2 expression and increase of Bax Bim and caspase 8expression that either agent alone furthermore the induc-tion of apoptosis was achieved at half the dose reportedby previous studies [110] Similarly the combination oflycopene and genistein the most bioactive isoflavones of soy-beans decreased 712-dimethylbenz(a)anthracene- (DMBA-)induced breast cancer in rats modulating the expression ofapoptosis-associated proteins again and the combinationwasmore effective than the administration of either compoundaloneThe authors suggested that apoptosis-inducing effect ofgenistein and lycopene combination may be attributed to theantioxidant and pharmacological properties of the individualagents [79]

In addition to these studies additional reports have anal-ysed the antioxidant or chemopreventive effects of lycopenein combination with other cellular antioxidants Al-Malki

et al [111] investigated the chemopreventive potentialof lycopene and tocopherol on mammary tumorigenesisinduced by DMBA in female rats they found that tocopherolenhanced the ability of lycopene to decrease the levels ofbothmalondialdehyde amarker of lipid oxidation andnitricoxide in serum and breast tissue of DMBA-injected ratsSimilar results were reported with combination of lycopeneand melatonin the treatment inhibited lipid-peroxidationand significantly increased the activities of SOD CAT andGPx [112] In another study lycopene and tocopherol co-treatment contribute to the reduction of prostate cancer byinterfering with internal autocrine or paracrine loops of sexsteroid hormone and growth factor activation and synthesisin the prostate Furthermore it has been reported that acooperative decrease in oxidative stress by the combinationof the two antioxidants can explain a significant reduction inJNK signaling [113]

362 Effects of Lycopene Administration on ChemotherapyLycopene sensitizes cancer cells to some chemotherapeuticdrugs Tang et al [83] showed that lycopene treatment


uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell

ROSAntioxidant enzymes

Growth factorsApoptosisCell-cycle arrest

AngiogenesisInvasionMetastasis

Figure 5 Phases of lycopene intervention in the carcinogenic process Cancer development is a multistep process that includes initiationpromotion and progression The initiation step is started by the addition of a carcinogen or irradiation in normal cells Lycopene and itsmetabolites can block this step by inactivating ROS and inducing the detoxification and antioxidant enzyme systems that protect cells fromthe damage caused by carcinogenic initiators Lycopene can also block or impede tumour promotion and progression by modulating keysignalling pathways induced by tumour promoters inflammatory cytokines and growth factors

enhanced the growth-inhibitory effect of docetaxel in PCain vitro in DU145 cells and in vivo in a xenograftmodel bothmodels with IGF-IR high expression Lycopene inhibitedIGF-IR activation through inhibition of IGF-I and by increas-ing the expression and secretion of IGF-BP Downstreameffects include inhibition of AKT kinase activity and survivinexpression followed by apoptosis Lycopene supplementa-tion also enhances the antitumor activity of cisplatin andameliorate cisplatin-induced renal oxidative stress in rats[114] The chemosensitization effect of lycopene has beendemonstrated in breast cancer cells Lycopene increasedquinacrine activity and inhibitedWnt-TCF signaling throughAPC in cancer cells without affecting MCF-10A in normalbreast cell line [115] Similarly Yang et al [116] demon-strated that lycopene enhances the antiproliferative effect ofLXR120572 agonist T0901317 in DU145 cells and increases theprotein expression of PPAR

120574-LXR120572-ABCA1 leading to high

cholesterol efflux Palozza et al [117] demonstrated that theinhibition of HMG-CoA reductase by lycopene was alsoaccompanied by a reduction in intracellular cholesterol levelsIn addition Yang et al [118] showed that lycopene increasedABCA1 and apo1 expression and decreased total intracellularcholesterol levels in LNCaP cells suggesting that lycopeneis involved in the PPAR-LXR-ABCA1 pathway mediatingthe cholesterol efflux in LNCaP cells It has been shownthat ABCA1 antitumor activity requires efflux function andappears to bemediated by reduction ofmitochondrial choles-terol combinedwith the increased release frommitochondriaof cell death promoting molecules such as cyt c [119]

363 Effects of Lycopene Administration on RadiotherapyRadiation therapy is one of the most widely used anticancer

therapies it is often associatedwith acute side effects thatmaydecrease tolerance to the treatment reduction of the optimaldose and volumen of radiation or interruption of plannedtreatment Andic et al [120] demonstrated that lycopenemay decrease the severity of radiation-induced acute toxicityin the gastrointestinal tract weight loss and diarrhea inrats Interestingly pretreatment with lycopene protects thelymphocytes from 120574-radiation-induced damage by inhibitingthe peroxidation of membrane lipids the accumulation offree radicals and DNA strand break formation [121] Like-wise lycopene has shown protective effects against ultravioletradiation [122]

Intriguingly lycopene appears to protect from side effectswhereas at the same time sensitizes the tumor cells towardsradiation-induced cell death Camacho-Alonso et al [123]demonstrated that lycopene increases cytotoxic activity ofradiotherapy in oral squamous cell carcinoma cells andreduces its invasiveness [123] Similarly Tabassum et al[124] reported that lycopene exerts a synergic effect whencombined with radiation in certain types of tumors suchas HNSCC and prostate cancer These studies suggest thatlycopene might participate simultaneously as a radioprotec-tor for normal cells and radiosensitizer for cancer cells

4 Conclusion

The gradual increase in understanding of cancer biologyduring recent years has resulted in the elucidation ofseveral approaches for intervention in carcinogenesis Theantioxidant anti-inflammatory and proapoptotic activitiesof lycopene and its metabolites might contribute to theprevention of and therapy for cancer by modulating diverse


biochemical processes involved in carcinogenesis (Figure 5)The potentially beneficial effects of lycopene include theinhibition of carcinogenic activation proliferation angiogen-esis invasion and metastasis the blocking of tumour cell-cycle progression and the induction of apoptosis throughalterations in various signalling pathways

More large-scale clinical trials are required to fully evalu-ate the potential value of lycopene and its metabolites in theprevention and treatment of cancer to determine the optimaldosing and route of administration and to identify cancertargets and potential interactions with other drugs

Conflict of Interests

The authors do not have any conflict of interests with thecontent of the paper In addition they do not have directfinancial relation with the commercial identity mentioned inthe paper

Acknowledgments

This review was written at the Unidad de NeuroinmunologıaInstituto Nacional de Neurologıa y Neurocirugıa Mexico Itwas supported by CONACyT Grant U41997-MA1

References

[1] H C Pitot ldquoThe molecular biology of carcinogenesisrdquo Cancervol 72 supplement 3 pp 962ndash970 1993

[2] H Mukhtar and N Ahmad ldquoCancer chemoprevention futureholds inmultiple agentsrdquoToxicology andApplied Pharmacologyvol 158 no 3 pp 207ndash210 1999

[3] M M Manson ldquoCancer preventionmdashthe potential for diet tomodulate molecular signallingrdquo Trends in Molecular Medicinevol 9 no 1 pp 11ndash18 2003

[4] N Ahmad S K Katiyard and H Mukhtar ldquoCancer chemopre-vention by tea polyphenolsrdquo inNutrition and Chemical ToxicityC loannides Ed pp 301ndash344 John Wiley amp Sons ChichesterUK 1998

[5] Y-J Surh ldquoCancer chemoprevention with dietary phytochemi-calsrdquo Nature Reviews Cancer vol 3 no 10 pp 768ndash780 2003

[6] A Challa N Ahmad and H Mukhtar ldquoCancer preventionthrough sensible nutrition (commentary)rdquo International Jour-nal of Oncology vol 11 no 6 pp 1387ndash1392 1997

[7] M B Sporn andK T Liby ldquoCancer chemoprevention scientificpromise clinical uncertaintyrdquo Nature Clinical Practice Oncol-ogy vol 2 no 10 pp 518ndash525 2005

[8] J Chen Z Pu Y Xiao et al ldquoLycopene synthesis via tri-cistronicexpression of LeGGPS2 LePSY1 and crtI in Escherichia colirdquoShengWuGong Cheng Xue Bao vol 28 no 7 pp 823ndash833 2012

[9] J A Olson and N I Krinsky ldquoIntroduction the colorfulfascinating world of the carotenoids important physiologicmodulatorsrdquoThe Journal of the Federation of American Societiesfor Experimental Biology vol 9 no 15 pp 1547ndash1550 1995

[10] S K Clinton ldquoLycopene chemistry biology and implicationsfor human health and diseaserdquoNutrition Reviews vol 56 no 2part 1 pp 35ndash51 1998

[11] L H Tonucci J M Holden G R Beecher F Khachik CS Davis and G Mulokozi ldquoCarotenoid content of thermally

processed tomato-based food productsrdquo Journal of Agriculturaland Food Chemistry vol 43 no 3 pp 579ndash586 1995

[12] A R Mangels J M Holden G R Beecher M R Formanand E Lanza ldquoCarotenoid content of fruits and vegetables anevaluation of analytic datardquo Journal of the American DieteticAssociation vol 93 no 3 pp 284ndash296 1993

[13] E Giovannucci ldquoTomatoes tomato-based products lycopeneand cancer review of the epidemiologic literaturerdquo Journal ofthe National Cancer Institute vol 91 no 4 pp 317ndash331 1999

[14] J F Dorgan A Sowell C A Swanson et al ldquoRelationshipsof serum carotenoids retinol 120572-tocopherol and selenium withbreast cancer risk results from a prospective study inColumbiaMissouri (United States)rdquoCancer Causes and Control vol 9 no1 pp 89ndash97 1998

[15] V A Kirsh S T Mayne U Peters et al ldquoA prospective study oflycopene and tomato product intake and risk of prostate cancerrdquoCancer Epidemiology Biomarkers amp Prevention vol 15 no 1 pp92ndash98 2006

[16] A Hausladen and J S Stamler ldquoNitrosative stressrdquo Methods inEnzymology vol 300 pp 389ndash395 1999

[17] B Halliwell and O I Aruoma ldquoDNA damage by oxygen-derived species Its mechanism and measurement in mam-malian systemsrdquo Federation of European Biochemical SocietiesLetter vol 281 no 1-2 pp 9ndash19 1991

[18] B N Ames ldquoDietary carcinogens and anticarcinogens Oxygenradicals and degenerative diseasesrdquo Science vol 221 no 4617pp 1256ndash1264 1983

[19] N I Krinsky ldquoMechanism of action of biological antioxi-dantsrdquo Proceedings of the Society for Experimental Biology andMedicine vol 200 no 2 pp 248ndash254 1992

[20] P di Mascio S Kaiser and H Sies ldquoLycopene as the most effi-cient biological carotenoid singlet oxygen quencherrdquoArchives ofBiochemistry and Biophysics vol 274 no 2 pp 532ndash538 1989

[21] N I Krinsky ldquoThe antioxidant and biological properties of thecarotenoidsrdquo Annals of the New York Academy of Sciences vol854 pp 443ndash447 1998

[22] A Bast G R M M Haenen R van den Berg and H van denBerg ldquoAntioxidant effects of carotenoidsrdquo International Journalfor Vitamin and Nutrition Research vol 68 no 6 pp 399ndash4031998

[23] H R Matos P di Mascio and M H G Medeiros ldquoProtectiveeffect of lycopene on lipid peroxidation and oxidative DNAdamage in cell culturerdquoArchives of Biochemistry and Biophysicsvol 383 no 1 pp 56ndash59 2000

[24] M Rizwan I Rodriguez-Blanco A Harbottle M A Birch-Machin R E B Watson and L E Rhodes ldquoTomato pasterich in lycopene protects against cutaneous photodamage inhumans in vivo a randomized controlled trialrdquo British Journalof Dermatology vol 164 no 1 pp 154ndash162 2011

[25] K Muzandu M Ishizuka K Q Sakamoto et al ldquoEffect oflycopene and 120573-carotene on peroxynitrite-mediated cellularmodificationsrdquo Toxicology and Applied Pharmacology vol 215no 3 pp 330ndash340 2006

[26] A Liu N Pajkovic Y Pang et al ldquoAbsorption and subcellularlocalization of lycopene in human prostate cancer cellsrdquoMolec-ular Cancer Therapeutics vol 5 no 11 pp 2879ndash2885 2006

[27] A Ben-Dor M Steiner L Gheber et al ldquoCarotenoids activatethe antioxidant response element transcription systemrdquoMolec-ular Cancer Therapeutics vol 4 no 1 pp 177ndash186 2005


[28] B Velmurugan V Bhuvaneswari and S Nagini ldquoAntiperoxida-tive effects of lycopene during N-methyl-N1015840-nitro-N-nitroso-guanidine-induced gastric carcinogenesisrdquo Fitoterapia vol 73no 7-8 pp 604ndash611 2002

[29] V Bhuvaneswari B Velmurugan S Balasenthil C RRamachandran and S Nagini ldquoChemopreventive efficacy oflycopene on 712-dimethylbenz[a]anthracene-induced hamsterbuccal pouch carcinogenesisrdquo Fitoterapia vol 72 no 8 pp865ndash874 2001

[30] S B Cullinan J D Gordan J Jin J W Harper and J A DiehlldquoThe Keap1-BTB protein is an adaptor that bridges Nrf2 to aCul3-based E3 ligase oxidative stress sensing by a Cul3-Keap1ligaserdquoMolecular and Cellular Biology vol 24 no 19 pp 8477ndash8486 2004

[31] T W Kensler N Wakabayashi and S Biswal ldquoCell survivalresponses to environmental stresses via the Keap1-Nrf2-AREpathwayrdquo Annual Review of Pharmacology and Toxicology vol47 pp 89ndash116 2007

[32] F Lian and X-D Wang ldquoEnzymatic metabolites of lycope-ne induce Nrf2-mediated expression of phase II detoxify-ingantioxidant enzymes in human bronchial epithelial cellsrdquoInternational Journal of Cancer vol 123 no 6 pp 1262ndash12682008

[33] K Itoh K I Tong and M Yamamoto ldquoMolecular mecha-nism activating Nrf2-Keap1 pathway in regulation of adaptiveresponse to electrophilesrdquo Free Radical Biology and Medicinevol 36 no 10 pp 1208ndash1213 2004

[34] H Zhang andH J Forman ldquoAcrolein induces heme oxygenase-1 through PKC-120575 and PI3K in human bronchial epithelial cellsrdquoAmerican Journal of Respiratory Cell andMolecular Biology vol38 no 4 pp 483ndash490 2008

[35] S Papaiahgari Q Zhang S R Kleeberger H-Y Cho and SP Reddy ldquoHyperoxia stimulates an Nrf2-ARE transcriptionalresponse via ROS-EGFR-P13K-AktERKMAP kinase signalingin pulmonary epithelial cellsrdquoAntioxidants andRedox Signalingvol 8 no 1-2 pp 43ndash52 2006

[36] B Alberts A Johnson J Lewis M Raff K Roberts and PWalter Molecular Biology of the Cell Garland Science NewYork NY USA 4th edition 2002

[37] F Folli L Bonfanti E Renard C R Kahn and A MerighildquoInsulin receptor substrate-1 (IRS-1) distribution in the ratcentral nervous systemrdquo Journal of Neuroscience vol 14 no 11part 1 pp 6412ndash6422 1994

[38] J I Jones andD R Clemmons ldquoInsulin-like growth factors andtheir binding proteins biological actionsrdquo Endocrine Reviewsvol 16 no 1 pp 3ndash34 1995

[39] J DiGiovanni K Kiguchi A Frijhoff et al ldquoDeregulated ex-pression of insulin-like growth factor 1 in prostate epitheliumleads to neoplasia in transgenic micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 97 no 7 pp 3455ndash3460 2000

[40] E Giovannucci ldquoInsulin-like growth factor-1 (IGF-1) and IGFbinding protein-3 (IGFBP-3) and risk of cancerrdquo HormoneResearch vol 51 pp 34ndash41 1999

[41] J Levy E Bosin B Feldman et al ldquoLycopene is a more potentinhibitor of human cancer cell proliferation than either 120572-carotene or 120573-carotenerdquoNutrition and Cancer vol 24 no 3 pp257ndash266 1995

[42] A Vrieling D W Voskuil J M Bonfrer et al ldquoLycopenesupplementation elevates circulating insulin-like growth factor-binding protein-1 and -2 concentrations in persons at greater

risk of colorectal cancerrdquo The American Journal of ClinicalNutrition vol 86 no 5 pp 1456ndash1462 2007

[43] C Liu F Lian D E Smith R M Russell and X-D WangldquoLycopene supplementation inhibits lung squamous metaplasiaand induces apoptosis via up-regulating insulin-like growthfactor-binding protein 3 in cigarette smoke-exposed ferretsrdquoCancer Research vol 63 no 12 pp 3138ndash3144 2003

[44] Y Tang B Parmakhtiar A R Simoneau et al ldquoLycopeneenhances docetaxelrsquos effect in castration-resistant prostate can-cer associated with insulin-like growth factor I receptor levelsrdquoNeoplasia vol 13 no 2 pp 108ndash119 2011

[45] C-H Heldin U Eriksson and A Ostman ldquoNew members ofthe platelet-derived growth factor family of mitogensrdquo Archivesof Biochemistry and Biophysics vol 398 no 2 pp 284ndash2902002

[46] R V Hoch and P Soriano ldquoRoles of PDGF in animal develop-mentrdquo Development vol 130 no 20 pp 4769ndash4784 2003

[47] H-M Lo C-F Hung Y-L Tseng B-H Chen J-S Jian andW-B Wu ldquoLycopene binds PDGF-BB and inhibits PDGF-BB-induced intracellular signaling transduction pathway in ratsmooth muscle cellsrdquo Biochemical Pharmacology vol 74 no 1pp 54ndash63 2007

[48] W Li J Fan M Chen et al ldquoMechanism of human dermalfibroblast migration driven by type I collagen and platelet-derived growth factor-BBrdquoMolecular Biology of the Cell vol 15no 1 pp 294ndash309 2004

[49] C-P Chen C-F Hung S-C Lee H-M Lo P-H Wu andW-B Wu ldquoLycopene binding compromised PDGF-AA-ABsignaling and migration in smooth muscle cells and fibroblastsprediction of the possible lycopene binding site within PDGFrdquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 381 no5 pp 401ndash414 2010

[50] H-S Chiang W-B Wu J-Y Fang et al ldquoLycopene inhibitsPDGF-BB-induced signaling and migration in human dermalfibroblasts through interaction with PDGF-BBrdquo Life Sciencesvol 81 no 21-22 pp 1509ndash1517 2007

[51] M Shibuya ldquoStructure and function of VEGFVEGF-receptorsystem involved in angiogenesisrdquo Cell Structure and Functionvol 26 no 1 pp 25ndash35 2001

[52] W Risau ldquoMechanisms of angiogenesisrdquo Nature vol 386 no6626 pp 671ndash674 1997

[53] M Sahin E Sahin and S Gumuslu ldquoEffects of lycopene andapigenin on human umbilical vein endothelial cells in vitrounder angiogenic stimulationrdquo Acta Histochemica vol 114 no2 pp 94ndash100 2012

[54] C-M Yang Y-T Yen C-S Huang and M-L Hu ldquoGrowthinhibitory efficacy of lycopene and 120573-carotene againstandrogen-independent prostate tumor cells xenografted innude micerdquo Molecular Nutrition amp Food Research vol 55 no4 pp 606ndash612 2011

[55] M L Chen Y H Lin C M Yang and M L Hu ldquoLycopeneinhibis angiogenesis both in vitro and in vivo by inhibitingMMP-2uPA system through VEGFR2-mediated PI3K-AKTand ERKp38 signaling pathwaysrdquoMolecular Nutrition amp FoodResearch vol 56 no 5 pp 889ndash899 2012

[56] A W Murray ldquoRecycling the cell cycle cyclins revisitedrdquo Cellvol 116 no 2 pp 221ndash234 2004

[57] J P Alao ldquoThe regulation of cyclin D1 degradation roles in can-cer development and the potential for therapeutic inventionrdquoMolecular Cancer vol 6 article 24 2007

[58] C J Sherr ldquoThe pezcoller lecture cancer cell cycles revisitedrdquoCancer Research vol 60 no 14 pp 3689ndash3695 2000


[59] YO Park E-SHwang andTWMoon ldquoThe effect of lycopeneon cell growth and oxidative DNA damage of Hep3B humanhepatoma cellsrdquo BioFactors vol 23 no 3 pp 129ndash139 2005

[60] A Nahum K HirschM Danilenko et al ldquoLycopene inhibitionof cell cycle progression in breast and endometrial cancer cellsis associated with reduction in cyclin D levels and retention ofp27Kip1 in the cyclin E-cdk2 complexesrdquo Oncogene vol 20 no26 pp 3428ndash3436 2001

[61] A Nahum L Zeller M Danilenko et al ldquoLycopene inhibitionof IGF-induced cancer cell growth depends on the level of cyclinD1rdquo European Journal of Nutrition vol 45 no 5 pp 275ndash2822006

[62] M Karas H Amir D Fishman et al ldquoLycopene interferes withcell cycle progression and insulin-like growth factor I signalingin mammary cancer cellsrdquo Nutrition and Cancer vol 36 no 1pp 101ndash111 2000

[63] P Palozza M Colangelo R Simone et al ldquoLycopene inducescell growth inhibition by altering mevalonate pathway and Rassignaling in cancer cell linesrdquo Carcinogenesis vol 31 no 10 pp1813ndash1821 2010

[64] C-C Chang W-C Chen T-F Ho H-S Wu and Y-H WeildquoDevelopment of natural anti-tumor drugs bymicroorganismsrdquoJournal of Bioscience and Bioengineering vol 111 no 5 pp 501ndash511 2011

[65] Z Wang H Fukushima H Inuzuka et al ldquoSkp2 is a promisingtherapeutic target in breast cancerrdquo Frontiers in Oncology vol 1no 57 pii 18702 2012

[66] F Lian D E Smith H Ernst R M Russell and X-D WangldquoApo-101015840-lycopenoic acid inhibits lung cancer cell growth invitro and suppresses lung tumorigenesis in the AJ mousemodel in vivordquoCarcinogenesis vol 28 no 7 pp 1567ndash1574 2007

[67] N A Ford A C Elsen K Zuniga B L Lindshield and JW Erdman Jr ldquoLycopene and apo-121015840-lycopenal reduce cellproliferation and alter cell cycle progression in human prostatecancer cellsrdquo Nutrition and Cancer vol 63 no 2 pp 256ndash2632011

[68] D R Green and G Kroemer ldquoThe pathophysiology of mito-chondrial cell deathrdquo Science vol 305 no 5684 pp 626ndash6292004

[69] C Sandu E Gavathiotis T Huang I Wegorzewska and MH Werner ldquoA mechanism for death receptor discrimination bydeath adaptorsrdquo The Journal of Biological Chemistry vol 280no 36 pp 31974ndash31980 2005

[70] S Luschen M Falk G Scherer S Ussat M Paulsen and SAdam-Klages ldquoThe Fas-associated death domain proteincas-pase-8c-FLIP signaling pathway is involved in TNF-inducedactivation of ERKrdquo Experimental Cell Research vol 310 no 1pp 33ndash42 2005

[71] M MacFarlane and A C Williams ldquoApoptosis and disease alife or death decisionrdquo EuropeanMolecular Biology OrganitationReports vol 5 no 7 pp 674ndash678 2004

[72] A M Verhagen and D L Vaux ldquoCell death regulation by themammalian IAP antagonist DiabloSmacrdquo Apoptosis vol 7 no2 pp 163ndash166 2002

[73] S Haupt M Berger Z Goldberg and Y Haupt ldquoApoptosismdashthe p53 networkrdquo Journal of Cell Science vol 116 part 20 pp4077ndash4085 2003

[74] F-Y Tang H-J ChoM-H Pai and Y-H Chen ldquoConcomitantsupplementation of lycopene and eicosapentaenoic acid inhibitsthe proliferation of human colon cancer cellsrdquo The Journal ofNutritional Biochemistry vol 20 no 6 pp 426ndash434 2009

[75] B Velmurugan A Mani and S Nagini ldquoCombination of S-allylcysteine and lycopene induces apoptosis by modulatingBcl-2 Bax Bim and caspases during experimental gastriccarcinogenesisrdquo European Journal of Cancer Prevention vol 14no 4 pp 387ndash393 2005

[76] H Zhang E Kotake-Nara H Ono and A Nagao ldquoA novelcleavage product formed by autoxidation of lycopene inducesapoptosis in HL-60 cellsrdquo Free Radical Biology and Medicinevol 35 no 12 pp 1653ndash1663 2003

[77] J J Wakshlag and C E Balkman ldquoEffects of lycopene onproliferation and death of canine osteosarcoma cellsrdquoAmericanJournal of Veterinary Research vol 71 no 11 pp 1362ndash13702010

[78] H L Hantz L F Young and K R Martin ldquoPhysiologicallyattainable concentrations of lycopene induce mitochondrialapoptosis in LNCaP human prostate cancer cellsrdquo ExperimentalBiology and Medicine vol 230 no 3 pp 171ndash179 2005

[79] K Sahin M Tuzcu N Sahin et al ldquoInhibitory effects ofcombination of lycopene and genistein on 712- Dimethylbenz(a)anthracene-induced breast cancer in ratsrdquoNutrition andCancer vol 63 no 8 pp 1279ndash1286 2011

[80] A Wang and L Zhang ldquoEffect of lycopene on proliferation andcell cycle of hormone refractory prostate cancer PC-3 cell linerdquoWei Sheng Yan Jiu vol 36 no 5 pp 575ndash578 2007

[81] P Palozza S Serini A Boninsegna et al ldquoThe growth-inhibitory effects of tomatoes digested in vitro in colon adeno-carcinoma cells occur through down regulation of cyclin D1Bcl-2 and Bcl-xLrdquo British Journal of Nutrition vol 98 no 4 pp789ndash795 2007

[82] P Palozza A Sheriff S Serini et al ldquoLycopene inducesapoptosis in immortalized fibroblasts exposed to tobacco smokecondensate through arresting cell cycle and down-regulatingcyclin D1 pAKT and pBadrdquo Apoptosis vol 10 no 6 pp 1445ndash1456 2005


[84] KW Hunter N P S Crawford and J Alsarraj ldquoMechanisms ofmetastasisrdquoBreast Cancer Research vol 10 supplement 1 articleS2 2008

[85] M Bacac and I Stamenkovic ldquoMetastatic cancer cellrdquo AnnualReview of Pathology vol 3 pp 221ndash247 2008

[86] S-Y LinW Xia J CWang et al ldquo120573-catenin a novel prognosticmarker for breast cancer its roles in cyclin D1 expression andcancer progressionrdquo Proceedings of the National Academy ofSciences of the United States of America vol 97 no 8 pp 4262ndash4266 2000

[87] W J Nelson and R Nusse ldquoConvergence ofWnt120573-catenin andcadherin pathwaysrdquo Science vol 303 no 5663 pp 1483ndash14872004

[88] H-S Kim C Skurk S R Thomas et al ldquoRegulation ofangiogenesis by glycogen synthase kinase-3120573rdquo The Journal ofBiological Chemistry vol 277 no 44 pp 41888ndash41896 2002

[89] O Tetsu and F McCormick ldquo120573-catenin regulates expression ofcyclin D1 in colon carcinoma cellsrdquo Nature vol 398 no 6726pp 422ndash426 1999

[90] D Gradl M Kuhl and D Wedlich ldquoTheWntWg signal trans-ducer 120573-catenin controls fibronectin expressionrdquoMolecular andCellular Biology vol 19 no 8 pp 5576ndash5587 1999


[91] R E Simone M Russo A Catalano et al ldquoLycopene inhibitsNF-KB-Mediated IL-8 expression and changes redox andPPAR120574 signalling in cigarette smoke-stimulated macrophagesrdquoPLoS ONE vol 6 no 5 article e19652 2011

[92] D Feng W-H Ling and R-D Duan ldquoLycopene suppressesLPS-induced NO and IL-6 production by inhibiting the activa-tion of ERK p38MAPK and NF-120581B in macrophagesrdquo Inflam-mation Research vol 59 no 2 pp 115ndash121 2010

[93] M M Rafi P N Yadav and M Reyes ldquoLycopene inhibitsLPS-induced proinflammatory mediator inducible nitric oxidesynthase in mouse macrophage cellsrdquo Journal of Food Sciencevol 72 no 1 pp S069ndashS074 2007

[94] F-Y Tang M-H Pai and X-D Wang ldquoConsumption oflycopene inhibits the growth and progression of colon cancerin a mouse xenograft modelrdquo Journal of Agricultural and FoodChemistry vol 59 no 16 pp 9011ndash9021 2011

[95] M-C Lin F-Y Wang Y-H Kuo and F-Y Tang ldquoCancerchemopreventive effects of lycopene suppression of MMP-7expression and cell invasion in human colon cancer cellsrdquoJournal of Agricultural and Food Chemistry vol 59 no 20 pp11304ndash11318 2011

[96] F-Y Tang C-J Shih L-H Cheng H-J Ho and H-J ChenldquoLycopene inhibits growth of human colon cancer cells viasuppression of the Akt signaling pathwayrdquoMolecular Nutritionamp Food Research vol 52 no 6 pp 646ndash654 2008

[97] E-S Hwang and H J Lee ldquoInhibitory effects of lycopeneon the adhesion invasion and migration of SK-Hep1 humanhepatoma cellsrdquo Experimental Biology and Medicine vol 231no 3 pp 322ndash327 2006

[98] C-S Huang M-K Shih C-H Chuang and M-L HuldquoLycopene inhibits cell migration and invasion and upregulatesNm23-H1 in a highly invasive hepatocarcinoma SK-Hep-1cellsrdquo Journal of Nutrition vol 135 no 9 pp 2119ndash2123 2005

[99] C-S Huang J-W Liao and M-L Hu ldquoLycopene inhibitsexperimental metastasis of human hepatoma SK-Hep-1 cells inathymic nudemicerdquo Journal of Nutrition vol 138 no 3 pp 538ndash543 2008

[100] C-M Yang T-Y Hu andM-L Hu ldquoAntimetastatic effects andmechanisms of apo-81015840-lycopenal an enzymatic metabolite oflycopene against human hepatocellular carcinoma SK-Hep-1cellsrdquo Nutrition and Cancer vol 64 no 2 pp 274ndash285 2012

[101] C-S Huang Y-E Fan C-Y Lin and M-L Hu ldquoLycopeneinhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B andstimulatory protein-1rdquo The Journal of Nutritional Biochemistryvol 18 no 7 pp 449ndash456 2007

[102] E Mira S Manes R A Lacalle G Marquez and A CMartınez ldquoInsulin-like growth factor I-triggered cell migrationand invasion are mediated by matrix metalloproteinase-9rdquoEndocrinology vol 140 no 4 pp 1657ndash1664 1999

[103] X Liu J D Allen J T Arnold andM R Blackman ldquoLycopeneinhibits IGF-I signal transduction and growth in normalprostate epithelial cells by decreasing DHT-modulated IGF-Iproduction in co-cultured reactive stromal cellsrdquo Carcinogen-esis vol 29 no 4 pp 816ndash823 2008

[104] DAltavilla A Bitto F Polito et al ldquoThe combination of serenoarepens selenium and lycopene is more effective than serenoarepens alone to prevent hormone dependent prostatic growthrdquoJournal of Urology vol 186 no 4 pp 1524ndash1529 2011

[105] JMolnar NGyemant IMucsi et al ldquoModulation ofmultidrugresistance and apoptosis of cancer cells by selected carotenoidsrdquoIn Vivo vol 18 no 2 pp 237ndash244 2004

[106] R P Warrell Jr S R Frankel W H Miller Jr et al ldquoDifferen-tiation therapy of acute promyelocytic leukemia with tretinoin(all-trans-retinoic acid)rdquoThe New England Journal of Medicinevol 324 no 20 pp 1385ndash1393 1991

[107] S Christakos M Raval-Pandya R P Wernyj and W YangldquoGenomic mechanisms involved in the pleiotropic actions of125-dihydroxyvitamin D3rdquo The Biochemical Journal vol 316part 2 pp 361ndash371 1996

[108] H Amir M Karas J Giat et al ldquoLycopene and 125-dihy-droxyvitamin D3 cooperate in the inhibition of cell cycleprogression and induction of differentiation in HL-60 leukemiccellsrdquo Nutrition and Cancer vol 33 no 1 pp 105ndash112 1999

[109] F-Y Tang M-H Pai Y-H Kuo and X-D Wang ldquoConcomi-tant consumption of lycopene and fish oil inhibits tumor growthand progression in a mouse xenograft model of colon cancerrdquoMolecular Nutrition amp Food Research vol 56 no 10 pp 1520ndash1531 2012

[110] B Velmurugan V Bhuvaneswari U K Burra and S NaginildquoPrevention of N-methyl-N1015840-nitro-N-nitrosoguanidine andsaturated sodium chloride-induced gastric carcinogenesis inWistar rats by lycopenerdquoEuropean Journal of Cancer Preventionvol 11 no 1 pp 19ndash26 2002

[111] A L Al-Malki S S Moselhy and M Y Refai ldquoSynergisticeffect of lycopene and tocopherol against oxidative stress andmammary tumorigenesis induced by 712-dimethyl[a]benzan-thracene in female ratsrdquo Toxicology and Industrial Health vol28 no 6 pp 542ndash548 2012

[112] S S Moselhy and M A B Al Mslmani ldquoChemopreventiveeffect of lycopene alone or with melatonin against the genesisof oxidative stress and mammary tumors induced by 712dimethyl(a)benzanthracene in sprague dawely female ratsrdquoMolecular and Cellular Biochemistry vol 319 no 1-2 pp 175ndash180 2008

[113] U Siler L Barella V Spitzer et al ldquoLycopene and vitaminE interfere with autocrineparacrine loops in the Dunningprostate cancer modelrdquo FASEB Journal vol 18 no 9 pp 1019ndash1021 2004

[114] A Dogukan M Tuzcu C A Agca et al ldquoA tomato lycopenecomplex protects the kidney from cisplatin-induced injuryvia affecting oxidative stress as well as Bax Bcl-2 and HSPsexpressionrdquo Nutrition and Cancer vol 63 no 3 pp 427ndash4342011

[115] R Preet P Mohapatra D Das et al ldquoLycopene synergisticallyenhances quinacrine action to inhibit Wnt-TCF signaling inbreast cancer cells through APCrdquo Carcinogenesis vol 34 no 2pp 277ndash286 2013

[116] C-M Yang Y-L Lu H-Y Chen and M-L Hu ldquoLycopeneand the LXR120572 agonist T0901317 synergistically inhibit theproliferation of androgen-independent prostate cancer cells viathe PPAR120574-LXR120572-ABCA1 pathwayrdquo The Journal of NutritionalBiochemistry vol 23 no 9 pp 1155ndash1162 2012

[117] P Palozza A Catalano R E Simone M C Mele and A Cit-tadini ldquoEffect of lycopene and tomato products on cholesterolmetabolismrdquo Annals of Nutrition amp Metabolism vol 61 no 2pp 126ndash134 2012

[118] C-M Yang I-H Lu H-Y Chen and M-L Hu ldquoLycopeneinhibits the proliferation of androgen-dependent humanprostate tumor cells through activation of PPAR120574-LXR120572-ABCA1 pathwayrdquo The Journal of Nutritional Biochemistry vol23 no 1 pp 8ndash17 2012


[119] B Smith and H Land ldquoAnticancer activity of the cholesterolexporter ABCA1 generdquo Cell Reports vol 2 no 3 pp 580ndash5902012

[120] F Andic M Garipagaoglu E Yurdakonar N Tuncel and OKucuk ldquoLycopene in the prevention of gastrointestinal toxicityof radiotherapyrdquo Nutrition and Cancer vol 61 no 6 pp 784ndash788 2009

[121] M Srinivasan N Devipriya K B Kalpana and V P MenonldquoLycopene an antioxidant and radioprotector against 120574-radiation-induced cellular damages in cultured human lympho-cytesrdquo Toxicology vol 262 no 1 pp 43ndash49 2009

[122] Z Fazekas D Gao R N Saladi Y Lu M Lebwohl and HWeildquoProtective effects of lycopene against ultraviolet B-inducedphotodamagerdquo Nutrition and Cancer vol 47 no 2 pp 181ndash1872003

[123] F Camacho-Alonso P Lopez-Jornet and M Tudela-MuleroldquoSynergic effect of curcumin or lycopene with irradiation uponoral squamous cell carcinoma cellsrdquoOral Diseases vol 19 no 5pp 465ndash472 2013

[124] A Tabassum R G Bristow and V Venkateswaran ldquoIngestionof selenium and other antioxidants during prostate cancerradiotherapy a good thingrdquoCancer Treatment Reviews vol 36no 3 pp 230ndash234 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


on treatment and (IV) improved detection of nondiag-nosed cancers [2] Of these options prevention is the mostfavourable Between 30 to 40 of cases are reportedlypreventable through diet modification adequate body weightmanagement and physical activity [3]

Chemoprevention aims to stop or to reduce cancer de-velopment by intervening in the carcinogenesis process viathe administration of natural or synthetic agents [4] Chemo-preventive compounds have been classified into two groupsblocker and suppressor agents The first group blocks cancerinitiation whereas the second stops or delays the promotionand progression of preneoplastic or malignant cells [5]

Chemopreventive compounds intended for human usemust not elicit significant secondary effects They mustbe efficient against multiple molecular targets and theirmechanism(s) of action should be well defined They alsoshould be inexpensive and accessible In addition chemo-preventive compounds should ideally take the form of anoral agent appropriate for widespread application in thegeneral population These characteristics contrast with thoseof chemotherapeutic agents which are usually very expensiveand toxic and are generally applied when the disease hasalready disseminated so they are less efficient [6]

Epidemiological studies have suggested that the inclusionof fruits vegetables and whole grains in dietary intake mightprevent and even reverse the cellular changes associated withcarcinogenesis at the initial stages thus reducing tumourincidence [4] These encouraging results have been docu-mented in vitro and in vivo as well as in clinical trials [7]These beneficial data are attributed to bioactive compoundsincluding both essential nutrients (ie selenium calciumzinc and vitamins C D and E) and nonessential components(carotenoids flavonoids allyl sulfide indole compoundsconjugated acids and n3 fatty compounds) Bioactive com-pounds have been reported to modify specific carcinogenicprocesses including cancer metabolism hormonal balancetranscription factors cell-cycle control apoptosis inflam-mation angiogenesis and metastasis Furthermore naturalcompounds might modulate cellular processes by acting onmolecular targets such as AP-1 (activator protein-1) STATs(signal transducers and activator of transcription) NF-120581B(nuclear factor-kappa B) HIF (hypoxia inducible factor)Nrf2 (nuclear factor-erythroid 2- related factor 2) MAPKs(mitogen activated protein kinases) PI3KAKT (phospho-inositide 3-kinaseAKT) and VEGF (vascular endothelialgrowth factor) thereby favouring the inhibition of car-cinogenesis Here we review the antineoplastic effects andthe mechanism of action of lycopene a carotenoid that isabundant in fruits and vegetables

2 Lycopene and Cancer

Lycopene is a natural pigment synthesised by photosyntheticplants and microorganisms [8] It is a highly unsaturatedacyclic isomer of 120573-carotene its hydrocarbon chain contains11 conjugated and 2 nonconjugated bonds [9] Lycopene isthe most abundant carotenoid in tomatoes and is present inconcentrations ranging from 09 to 927mg100 g dependingon the variety [10 11] Tomato paste is a more concentrated

source of lycopene (51ndash597mg100 g) than nonprocessedtomatoes [11] Other sources of lycopene are found inred fruits such as rosehips watermelons red grapefruitspapayas apricots and pink guavas [12]

Epidemiological studies support the possibility that ly-copene can reduce cancer risk In a meta-analysis of 72studies 57 reported an inverse association between lycopeneingestion and the risk of diverse cancer types (includingprostate breast lung and colon) and 35 studies reportedstatistically significant associations None of these studiesreported any adverse effects of increased tomato intake orincreased circulating lycopene levels [13] In another studylycopene was found to be the only micronutrient present inthe human serum associated with a decreased risk for breastcancer [14]

In a randomised clinical trial lycopene was applied asa therapeutic agent for prostate cancer [15] In that studypatients received 30mg of lycopene daily over a periodof three weeks prior to undergoing radical prostatectomyEighty percent of the patients supplemented with lycopenepresented with smaller tumours compared with the controlpatients Moreover the plasma levels of the specific prostaticantigen decreased by 18 in the supplemented patientswhereas they increased by 14 in the control group Theseresults indicate that lycopene supplementation might repre-sent an adjuvant treatment for this disease

In addition to the correlation between lycopene andprostate cancer increasing evidence suggests that lycopeneplays an important role in cancer prevention in other organssuch as the breast lung gastrointestinal tract pancreasuterine cervix and the ovaries [13] Although the antioxidantproperties of lycopene were thought to be primarily responsi-ble for its biological effects other mechanisms have also beenidentifiedThe following review is an abbreviated overview ofin vitro and in vivo evidence supporting the contribution oflycopene to cancer prevention

3 Potential Mechanisms ofActions of Lycopene

31 Antioxidant Activity Oxidative stress is caused by theincreased production of reactive oxygen (ROS) and nitrogen(RNS) species including superoxide (O

2

∙minus) hydroxyl (OH∙)

peroxyl (ROO∙) alkoxyl (RO∙) and peroxynitrite (ONOO∙)as well as nonradical species such as singlet oxygen (1O

2)

ozone (O3) and hydrogen peroxide (H

2O2) [16] These

chemical species are generated by a wide variety of processesincluding mitochondrial respiration ischemiareperfusioninflammation and the metabolism of exogenous compounds[17] The excessive generation of ROS might oxidise cellu-lar biomolecules including carbohydrates proteins lipidsand DNA The oxidation of these molecules can facilitatecarcinogenesis-related processes such as cellular transfor-mation proliferation apoptosis resistance angiogenesis andmetastasis via genetic alterations including DNA damagemutation epigenetic changes and genetic instability [18]

Because they contain many double-conjugated bondsnatural carotenoids display strong antioxidant capacity [19]Lycopene possesses robust antioxidant activity that is exerted

















ROS

LycopeneROS

Keap1

Keap1

HS SH

OH

HS SH

AREEpRE

Nrf2

Nrf2

Nrf2

Maf

P



JNKERKp38PKC

Lycopene
















0G1and




1and S



Lycopene



Cyclin DE

c-fos

IGF-1R VEGFR


IGBP1

IGBP2

IGBP3

PDGFR

IRS-1

IkB

c-jun

JNK p38

IGF

PI3K

p-AKT

IKK

Ras

Raf

MAPK

ERK

MEKK4

Proteasome



NF120581B

NF120581B

NF120581B

AP-1

AP-1

SP-1

SP-1

darr VEGF

















Skp2

IGF-1R FASR

IGF

p-AKT

IRS-1

PI3KBIDCaspase 3

Caspase 8

p53

FasL

Caspase 9

Badmdm2

Bax


S

M

Cyc D

Cyc ECDK2

Cyc ACDK2

Cyc ACDK1

Cyc BCDK1

p21

Survivin

p27

4

SmacDiablo

IAPs

Lycopene

IGBP1IGBP2IGBP3

G1

G2

pRBE2FGSK3120573

tBIDpRBp

Bcl-2

Bcl-2

Bcl-XL

E2F

CDK46













2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































ROS

LycopeneROS

Keap1

Keap1

HS SH

OH

HS SH

AREEpRE

Nrf2

Nrf2

Nrf2

Maf

P



JNKERKp38PKC

Lycopene
















0G1and




1and S



Lycopene



Cyclin DE

c-fos

IGF-1R VEGFR


IGBP1

IGBP2

IGBP3

PDGFR

IRS-1

IkB

c-jun

JNK p38

IGF

PI3K

p-AKT

IKK

Ras

Raf

MAPK

ERK

MEKK4

Proteasome



NF120581B

NF120581B

NF120581B

AP-1

AP-1

SP-1

SP-1

darr VEGF

















Skp2

IGF-1R FASR

IGF

p-AKT

IRS-1

PI3KBIDCaspase 3

Caspase 8

p53

FasL

Caspase 9

Badmdm2

Bax


S

M

Cyc D

Cyc ECDK2

Cyc ACDK2

Cyc ACDK1

Cyc BCDK1

p21

Survivin

p27

4

SmacDiablo

IAPs

Lycopene

IGBP1IGBP2IGBP3

G1

G2

pRBE2FGSK3120573

tBIDpRBp

Bcl-2

Bcl-2

Bcl-XL

E2F

CDK46













2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ROS

LycopeneROS

Keap1

Keap1

HS SH

OH

HS SH

AREEpRE

Nrf2

Nrf2

Nrf2

Maf

P



JNKERKp38PKC

Lycopene
















0G1and




1and S



Lycopene



Cyclin DE

c-fos

IGF-1R VEGFR


IGBP1

IGBP2

IGBP3

PDGFR

IRS-1

IkB

c-jun

JNK p38

IGF

PI3K

p-AKT

IKK

Ras

Raf

MAPK

ERK

MEKK4

Proteasome



NF120581B

NF120581B

NF120581B

AP-1

AP-1

SP-1

SP-1

darr VEGF

















Skp2

IGF-1R FASR

IGF

p-AKT

IRS-1

PI3KBIDCaspase 3

Caspase 8

p53

FasL

Caspase 9

Badmdm2

Bax


S

M

Cyc D

Cyc ECDK2

Cyc ACDK2

Cyc ACDK1

Cyc BCDK1

p21

Survivin

p27

4

SmacDiablo

IAPs

Lycopene

IGBP1IGBP2IGBP3

G1

G2

pRBE2FGSK3120573

tBIDpRBp

Bcl-2

Bcl-2

Bcl-XL

E2F

CDK46













2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























0G1and




1and S



Lycopene



Cyclin DE

c-fos

IGF-1R VEGFR


IGBP1

IGBP2

IGBP3

PDGFR

IRS-1

IkB

c-jun

JNK p38

IGF

PI3K

p-AKT

IKK

Ras

Raf

MAPK

ERK

MEKK4

Proteasome



NF120581B

NF120581B

NF120581B

AP-1

AP-1

SP-1

SP-1

darr VEGF

















Skp2

IGF-1R FASR

IGF

p-AKT

IRS-1

PI3KBIDCaspase 3

Caspase 8

p53

FasL

Caspase 9

Badmdm2

Bax


S

M

Cyc D

Cyc ECDK2

Cyc ACDK2

Cyc ACDK1

Cyc BCDK1

p21

Survivin

p27

4

SmacDiablo

IAPs

Lycopene

IGBP1IGBP2IGBP3

G1

G2

pRBE2FGSK3120573

tBIDpRBp

Bcl-2

Bcl-2

Bcl-XL

E2F

CDK46













2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Lycopene



Cyclin DE

c-fos

IGF-1R VEGFR


IGBP1

IGBP2

IGBP3

PDGFR

IRS-1

IkB

c-jun

JNK p38

IGF

PI3K

p-AKT

IKK

Ras

Raf

MAPK

ERK

MEKK4

Proteasome



NF120581B

NF120581B

NF120581B

AP-1

AP-1

SP-1

SP-1

darr VEGF

















Skp2

IGF-1R FASR

IGF

p-AKT

IRS-1

PI3KBIDCaspase 3

Caspase 8

p53

FasL

Caspase 9

Badmdm2

Bax


S

M

Cyc D

Cyc ECDK2

Cyc ACDK2

Cyc ACDK1

Cyc BCDK1

p21

Survivin

p27

4

SmacDiablo

IAPs

Lycopene

IGBP1IGBP2IGBP3

G1

G2

pRBE2FGSK3120573

tBIDpRBp

Bcl-2

Bcl-2

Bcl-XL

E2F

CDK46













2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































Skp2

IGF-1R FASR

IGF

p-AKT

IRS-1

PI3KBIDCaspase 3

Caspase 8

p53

FasL

Caspase 9

Badmdm2

Bax


S

M

Cyc D

Cyc ECDK2

Cyc ACDK2

Cyc ACDK1

Cyc BCDK1

p21

Survivin

p27

4

SmacDiablo

IAPs

Lycopene

IGBP1IGBP2IGBP3

G1

G2

pRBE2FGSK3120573

tBIDpRBp

Bcl-2

Bcl-2

Bcl-XL

E2F

CDK46













2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Skp2

IGF-1R FASR

IGF

p-AKT

IRS-1

PI3KBIDCaspase 3

Caspase 8

p53

FasL

Caspase 9

Badmdm2

Bax


S

M

Cyc D

Cyc ECDK2

Cyc ACDK2

Cyc ACDK1

Cyc BCDK1

p21

Survivin

p27

4

SmacDiablo

IAPs

Lycopene

IGBP1IGBP2IGBP3

G1

G2

pRBE2FGSK3120573

tBIDpRBp

Bcl-2

Bcl-2

Bcl-XL

E2F

CDK46













2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























2)














3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























3





IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















IGBP1IGBP2IGBP3

IGF

IGF-1R

AKT

DVL

GSK-3120573

LRP

Cadh

erin

Cadh

erin

AP-1SP-1

LEFTCF

Wnt

MMP 2 7 9uPA

TIMP 2nm23-H1

PAI-1

Actin

AP-1 SP-1

MMP 2 7 9uPA

Axin APC

Lycopene

120573-catenin


120573-c

aten

in

120573-catenin

120573-c

aten

in

120572-c

aten

in

NF120581B

NF120581B







uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















uarr

darr

uarr

darr

darr

uarr

uarr

uarr

Initiation

Reversible

Irreversible

Irreversible

Promotion

Prog

ressio

n

Lycopene

Normalcell

Initiatedcell











4 Conclusion







Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Acknowledgments


References








































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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