Review Article Implications of Green Tea and Its ...downloads.hindawi.com/journals/bmri/2015/925640.pdfReview Article Implications of Green Tea and Its Constituents in the Prevention

Review ArticleImplications of Green Tea and Its Constituentsin the Prevention of Cancer via the Modulation of CellSignalling Pathway

Arshad H Rahmani1 Fahad M Al shabrmi1 Khaled S Allemailem1

Salah M Aly12 and Masood A Khan3

1Department of Medical Laboratories College of Applied Medical Sciences Qassim University Buraidah 6699 Saudi Arabia2Department of Pathology Faculty of Veterinary Medicine Suez Canal University Ismailia Egypt3Department of Basic Health Science College of Applied Medical Sciences Qassim University Buraidah 6699 Saudi Arabia

Correspondence should be addressed to Arshad H Rahmani rehmaniarshadgmailcom

Received 15 December 2014 Revised 11 March 2015 Accepted 5 April 2015

Academic Editor Muneyuki Masuda

Copyright copy 2015 Arshad H Rahmani 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

Green tea is commonly used as a beverage worldwide especially in China Japan Morocco and Saudi Arabia Green tea andits constituents have been considered very effective in the prevention and treatment of various diseases It contains a variety ofcatechins which show a pivotal role in themodulation of biological activities and also act as chemopreventive agents Earlier studieshave confirmed that green tea and its chief constituent epigallocatechin gallate (EGCG) have a potential role in the management ofcancer through the modulation of cell signaling pathways In this review we focused on the beneficial effects of green tea and itsconstituents in the cancer prevention and treatment and its impact on modulation of molecular pathways

1 Introduction

Natural products mainly plants and their constituents havebeen used in the diseases cure from the ancient time andits role in the health management is very popular in IndiaChina and other parts of the world In Arab world natu-ral productplants seeds and fruits are commonly used indiseases treatment and Prophet Mohammad (PBUH) alsosuggested various plants such as dates fruits olive fruitsand black seed in the treatment of diseases [1] Earlier studyrevealed that medicinal plants and their ingredients suchas olive fruitsoil dates fruits and Nigella sativa have roleas anticancer via modulation of various biological activities[2ndash5] However green tea is a product made from theCamellia sinensis plant and is commonly used as beverageworldwide From the ancient time green tea and its con-stituents show role in health management via modulationof biological process including molecular and biochemicalpathways Green tea shows health promoting effects mainly

due to the polyphenol content [6] especially flavonols whichconstitutes 30 of fresh leaf dry weight [7] The chiefconstituents of green tea are catechins where (minus)-epigallocat-echin gallate is one of the most effective types of catechinsThe anticancer effects of (minus)-epigallocatechin gallate havebeen reported via modulation of signaling pathways andalso play a role in the downregulation of proteins expressioninvolved in the invasiveness of cancer cells [8] Anotherfinding has shown that EGCG inhibited growth of the mouseviral mammary epithelial carcinogenesis model inducedapoptosis and finding suggest the clinical relevance of EGCGas a chemopreventive agent [9] An important study revealedthat EGCG a chief constituent of green tea significantlyreduced tumor volume in xenograft mouse model breastcancer cells [10] and a study summarized the role of thegreen tea constituents EGCG in chemoprevention [11] Inthis review we focused on the therapeutic role of green teaand its constituents in the management of cancer throughmodulation of various cell signalling pathways

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 925640 12 pageshttpdxdoiorg1011552015925640

2 BioMed Research International

HO

HO HO

HO

OH

OH

OH OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

O

O

O O

O

OO

O

Epicatechin Epigallocatechin

Epicatechin-3-gallate Epigallocatechin-3-gallate

Figure 1 Active constituents of green tea

2 Chemical Structure of Active Constituentsof Green Tea

Green tea is a complex mixture of precious compoundsincluding polyphenols flavonoids flavonols and other con-stituents such as amino acids organic acids lipids vita-mins polysaccharides and thiamine Catechins are a type ofpolyphenol and are themain astringency component in greentea and modulate the various genes involved in the devel-opment and progression of cancer The chief catechins are(minus)-epicatechin (EC) (minus)-epicatechin-3-gallate (ECG) (minus)-epigallocatechin (EGC) and (minus)-epigallocatechin-3-gallate(EGCG) [12ndash15] Approximately 30ndash42 of the dry weight ofgreen tea contains phenolic compounds [12 16] and EGCGis one of the most abundant catechins that contains around50ndash80 of the total catechins [16] The chemical structure ofchief constituents of green tea is presented in Figure 1

3 Mechanism of Action of Green Tea inCancer Prevention

Green tea is a product made from the Camellia sinensis plantand is commonly used as beverage worldwide Althoughgreen tea shows vital role in diseases control exact mech-anism of action is still under investigation The possible

mechanisms of action of green tea in cancer prevention andprogression are as follows

(i) Green tea act as inhibitor of cyclooxygenase lipoxy-genases tumour necrosis factor and interleukin path-ways and ultimately controls the development andprogression of tumour

(ii) Green tea shows chemopreventive effect via activationof tumour suppressor genes such as p53 and PTENp21 regulation of apoptosis (bcl2Bax) and inhibi-tion of angiogenesis and other transcription factorsinvolved in the cancer development and progression

(iii) It shows role in neutralization of free radical anddamage of macromolecules due to high antioxidantcapacity and finally prevents the pathogenesis oftumour

(iv) Another possible mechanism of green tea in can-cer prevention is through the modulation of genesinvolved in initiations promotion and progression oftumour (Figure 2)

4 Anticancer Effect of Green Tea throughModulation of Cell Signalling Pathways

Cancer is multifactorial disease including genetic and met-abolic alterations The current mode of treatment based

BioMed Research International 3

Normalcell

InitiationInitiated

cells

ProgressionPreneoplastic

cells

PromotionNeoplastic

cells

Green tea

Constituents

Catechins

Chemopreventiveeffect

(i) GST uarr

(ii) P53 PTEN uarr

(iii) CYP450 darr

(v)

(i) VEGF darr

(ii) COX2 darr

(iv) BCL2 darr

(iii) NF-120581B darr

Bax uarr

Figure 2 Role of green tea in cancer prevention through the modulation of genes involved in initiations promotion and progression ofcancer

Catechin

Activation of tumor suppressorgene (P53 and PTEN)

Regulation of apoptosispathway bcl2 and bax

Inhibition of TNFNF-120581B Akt and

oncogene

Inhibition of VEGF

Inhibition of COXand LOX

Green tea

Inhibition oftelomerase AP-1 and

IGFIR

Activation of PPAR

Prev

entio

n of

canc

er fo

rmat

ion

Figure 3 Green tea modulates the various cell signalling pathways in cancer

on allopath is expensive and also alter the various cellsignalling pathways The diseases management based onnatural products especially plants sources is inexpensive andshows fewer side effects In this view various medicinalplantsnatural products have shown effect as anticancer viamodulation of cell signalling pathways and other biologicalactivities [17ndash21] Earlier finding based on clinical trialsand animal model has confirmed that green tea and itsconstituents play an important role in cancer prevention viaactivationinactivation of genetic pathwaysThe role of green

tea in cancer prevention and treatment based on modulationof cell signalling pathways is discussed in detail below(Figure 3)

41 Effect of Green Tea on Tumour Suppressor Gene Tumoursuppressor gene p53 is the guardian of all genes andregulates the various other molecular pathways Alteredexpressioninactivation of tumour suppressor gene has beenobserved in various types of tumours In this view green tea


and its constituents show a significant role in the activationof p53 gene (Figure 3)

A study demonstrated that GTP and EGCG increase p53transcriptional activity and acetylation by suppressing class Ihistone deacetylases [22] and other studies showed EGCG-induced p53-dependent apoptosis in cancer cells [23]

EGCG a chief constituent of green tea induced theexpression of p53 and its targets p21 and Bax in prostatecancer cells with wild-type but not inactive p53 [24] andother findings demonstrate that EGCG also illustrate role inthe activation of p53 and Bax in breast cancer cells [25] Treat-ment of cultured MCF-7 cells with green tea constituentssuch as EGCG increased the ratio of hypo- to hyperphos-phorylated Rb and this treatment also increased the levelsof other proteins such as p53 p21 (waf1CIP1) and p27[26] Other investigators have confirmed that EGCG at 10to 40 120583molL induces p53-dependent apoptosis of JB6 cellsthrough mitochondrial death pathway [27]

PTEN (phosphatase and tensin homolog deleted onchromosome TEN) and P16 are other types of tumor sup-pressor gene and altered expression of these genes has beennoticed in tumours An important finding revealed that epi-gallocatechin-3-gallate altered the p16 methylation patternfrom methylated to unmethylated as a result of folic aciddeprivation [28]

Another study has confirmed that EGCG treatmentdemonstrated a significant and dose-dependent inhibitionof PDK1 and PTEN phosphorylation and also proposesthat Akt activation by EGCG in A549 cells occurs neitherthrough PDK1 activation nor through PTEN inactivation[29] Other study findings confirmed that Epigallocatechingallate (EGCG) and sulforaphane (SFN) combinations havetendency to enhance cisplatin-induced apoptosis and G2Mphase arrest via upregulation of p21 thus enhancing theefficacy of cisplatin on both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells [30]

42 Effect of Green Tea on Apoptosis Apoptosis is a pro-cess to keep up the normal and healthy internal milieuAltered ratio of bcl2 and bax has been noticed in differenttypes of cancer Therefore regulation of apoptosis processis critical step in the prevention of cancer In vitro basedstudy has shown that green tea extract especially its majorpolyphenolic component (minus)-epigallocatechin-3-gallate iscapable of inhibiting the growth of a variety of mouse andhuman cancer cells via the induction of apoptosis [31ndash33]Other investigators have reported that (minus)-Epigallocatechin-3-gallate rapidly induced apoptotic cell death in variousmalignant B-cell lines in a dose- and time-dependent man-ner [34] Chemopreventiveantiproliferative potential of (minus)-epigallocatechin gallate (EGCG) was checked in T24 humanbladder cancer cell line and it was observed that EGCGtreatment caused dose- and time-dependent inhibition ofcellular proliferation and cell viability and induced apoptosis[35] A finding showed that green tea and its constituentsselectively induce apoptosis in oral carcinoma cells whileEGCG was able to inhibit the growth and invasion of oralcarcinoma [36] A significant result revealed that green tea

polyphenols induce the transcription of p21waf1 andBax andalso enhance proteasomal degradation of class I HDACs andincrease acetylation of histone H3 that lead to cell cycle arrestand apoptosis in prostate cancer cells [37]

Study was performed to investigate the effect of green teapolyphenols and chief constituent such as epigallocatechin-3-gallate on the induction of apoptosis and regulation ofcell cycle in human and mouse carcinoma cells and studyresults concluded that green tea may protect against cancerby causing cell cycle arrest and inducing apoptosis [38] Avital review presented the available scientific literature aboutthe effects of green tea polyphenols and its chief constituentsEGCG on signaling pathways in prostate cancer [39]

43 Effects of Green Tea on Angiogenesis Angiogenesis playsan important role in the tumour development and progres-sion Inhibition of angiogenesis is the most important step inprevention and treatment of cancer Previous studies showedthat treating nude mice with EGCG constituents of green tearesulted in noticeable inhibition of growth vascularity andproliferation of human colon cancer xenografts [40]

EGCG constituent of green tea significantly shows arole in the inhibition of VEGF expression by suppressing theactivation of HIF-1120572 and NF-120581B pathways thereby inhibitingtumor growth proliferation migration and angiogenesis ofbreast cancer [41]

Earlier investigators reported that that EGCG a majorpolyphenol of green tea inhibited angiogenesis throughblocking Erk-1 and Erk-2 activation and VEGF expression[40]

44 Effects of Green Tea on Phase I and Phase II EnzymesPhase I and phase II genesenzymes play role in modulationof invasion and progression of tumour However enzymessuch as CYP 450 and GST have important role in the cancervia inhibition or activation of initiation promotion and pro-gression process However modulations of CYP450 and GSTenzymesgenes are one of the vital points in managementof cancer development and progression Green tea and itsconstituents show dual role in this phenomena via inhibitionof CYP and activation of GST genes (Figure 3) An experi-mentation was performed to investigate the effect of greentea polyphenols (GTP) on the activities of phase I and phaseII enzymes and results revealed supplementation of GTP byboth simultaneous and posttreatment mode (200mgkg) andthere was a significant increase in the activity of GST andUDP-GT and a significant decrease in the activity of phaseI enzymes [42]

45 Effect of Green Tea on Cyclooxygenase and LipoxygenaseCyclooxygenase (COX) is also known as prostaglandin (PG)H synthase and catalyses the stages of prostanoids synthesis[43] Altered cyclooxygenaselipoxygenase has been noticedin various tumours An important finding has examined theinhibitory effects of EGCG on signaling pathways controllingCOX-2 expression and effect of EGCG on COX-2 expressionnoticed through decreased COX-2 promoter activity via inhi-bition of nuclear factor kappaB (NF-kappaB) activation [44]


The effects of green and black tea polyphenols on cy-clooxygenase (COX) and lipoxygenase (LOX) were stud-ied and revealed that at a concentration of 30microgmL(minus)-epigallocatechin-3-gallate (EGCG) (minus)-epigallocatechin(EGC) and (minus)-epicatechin-3-gallate (ECG) from green teaand theaflavins from black tea inhibited LOX-dependentactivity by 30ndash75 [45] An experimentation was designedto evaluate the effects of green tea and a high-fat diet onarachidonic acid metabolism and aberrant crypt foci forma-tion in an azoxymethane- (AOM-) induced colon carcino-genesis mouse model and results revealed that consump-tion of green tea and dietary fat modulates 5-lipoxygenase-dependent pathway of arachidonic acid metabolism duringAOM-induced colon carcinogenesis [46]

Another important study has demonstrated that pre-treatment of the green tea extract enriched with catechinand epigallocatechin gallate showed inhibition of COX-2expression induced through the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin [47]

46 Effect of Green Tea on Akt Pathways AktPIP3 pathwaysshow an important role in the development and progressionof tumour EGCG a key component of green tea inhibitedthe basal activation of phospho-Akt and Akt kinase activityafter 30min of treatment the inhibition of Akt kinase activityby EGCG preceded the suppression of surviving after 1-hour treatment and followed the increased caspase-9 activityafter 6 h treatment [48] T24 human bladder cancer cellline based test was performed to evaluate the chemopreven-tiveantiproliferative potential of EGCG and results showedthat EGCG inhibits phosphatidylinositol 31015840-kinaseAkt acti-vation that in turn shows role in the modulation of Bcl-2 family proteins leading to enhanced apoptosis of T24cells [49] Experiment was performed to examine the effectsof EGCG on vascular endothelial growth factor (VEGF)production by YCU-H891 HNSCC and MDA-MB-231 breastcarcinoma cell lines and found that treatment with EGCGinhibited the constitutive activation of the EGFR Stat3 andAkt in both cell lines [50]

47 Effect of Green Tea on HER2HER3 and EGFR PathwayAn oncogene is a mutated gene that shows an impor-tant role in the pathogenesis of diseases including cancerActivation or overexpression of ErbB such as ErbB2 (HER2)and ErbB3 (HER3) and EGFR has been observed in var-ious types of tumours Green tea inhibits the growth ofcancer cells by inhibiting the activation of HER2 andHER3 An important study was carried out to observe theeffects of epigallocatechin-3 gallate (EGCG) on HER2neu-overexpressing breast cancer cells and results demonstratedthat EGCG reduced signaling through the phosphatidylinos-itol 3-kinase Akt kinase to NF-kappaB pathway because ofinhibition of basal HER2neu receptor tyrosine phosphory-lation [51] Another study was performed to examine theeffects of EGCGon activation of theHER2 receptor in humanHNSCCandbreast carcinoma cell lines and results confirmedthat treatment of human HNSCC and breast carcinoma celllines with 10 or 30 120583g of EGCG causes 50 inhibition of

growth noticeably inhibiting the phosphorylation of HER2in both cell lines [52] An experiment was performed toevaluate the effects of EGCG a chief constituent of greentea on the HER3 RTK and on COX-2 expression in theSW837 human colon cancer cell line and results showedthat treatment of SW837 colon cancer cells with 20120583gmLof EGCG caused decrease in the phosphorylated forms ofEGFR HER2 and HER3 within 6 hours of treatment [53]

Elevated levels of the epidermal growth factor receptor(EGFR) have been noticed in several of tumour Variousmedicinal plants have confirmed the inhibitory effect oncancer progression via inhibiting the activities of EGFRA test was made to investigate the effects of EGCG onthe proliferation of human epidermoid carcinoma cell lineA431 and results revealed that EGCG strongly inhibited theprotein tyrosine kinase (PTK) activities of EGF-R PDGF-R and FGF-R [54] Another experiment was performed toexamine the effects of EGCG on cellular localization of theEGFR in cells such as SW480 cells and results of the studydemonstrated that treatment of the cells for 30min with1 120583gmL of EGCG caused a decrease in cell surface-associatedEGFRs and this was associated with internalization of EGFRsinto endosomal vesicles [55] Experiment was carried outto evaluate the effects of EGCG (10ndash100 120583gmL) treatmenton growth and invasion in a breast carcinoma cell lineresistant to tamoxifen (MCF-7Tam) and parental MCF-7 andthe results revealed that dose-dependent downregulation ofEGFR mRNA expression and protein level occurred after50 120583gmL EGCG treatments of MCF-7Tam cells [56]

48 Effect of Green Tea on c-Met and PDGFR Activationof the other member of receptor tyrosine kinases (RTKs)including c-Met and PDGFR is also suppressed by greentea catechins and this is associated with cancer preven-tion An important study results confirmed that EGCG achief tea polyphenol inhibited cell proliferation in erlotinib-sensitive and -resistant cell lines including those with c-Met overexpression and acquired resistance to erlotinib andfurthermore also completely inhibited ligand-induced c-Metphosphorylation and partially inhibited EGFR phosphoryla-tion [57]

Overactivity of PDGF has been associated with cancerdevelopment and progression and also shows role in thepathogenesis of various diseases An important result demon-strated that PDGF-induced mRNA expression of c-fos andegr-1 was totally inhibited in EGCG-treated vascular SMCs[58]

49 Effect of Green Tea on MAPKRAS Pathways Alteredactivity of MAPKRAS pathways is the one of the culprits inthe cancer development and progression Natural inhibitorsshow important therapeutic role in the regulation of theactivity of MAPKRAS pathways and finally prevent thecarcinogenesis Green tea and its constituents have shownrole as inhibitor of the activity of mitogen-activated proteinkinases (MAPKs) key factor for survival signalling

Prior investigation has reported that tea polyphenolsEGCG and TFs were shown to decrease the activity of AP-1 a transcription factor via inhibition of MAPK mainly the


JNK in JB6 cells [59] Other important findings revealed thatpolyphenols of tea such as EGCGwith 10ndash20120583gmL inhibitedMAPK pathway as well as activator protein-1 (AP-1) activityin human colon cancer cells [60] A study concluded thatreduction of the AR and growth factor IGF-1 modulationof inflammation biomarkers and decrease in the MAPKsignalingmay contribute to the reduction in cell proliferationand apoptosis induction and therefore provide a biochemicalbasis of EGCG suppressing prostate cancer without toxicity[61]

Other finding results have shown that lung tissue ofthe mice treated with tobacco-specific nitrosamine 4-(meth-ylnitrosamine)-1-(3-pyridyl)-1-butanone NNK showed a sig-nificantly high level of expression in c-myc c-raf and c-H-rasoncogenes after 4 or 8 weeks and they were all inhibited by2 tea drinking with inhibitory rates of 50 20 and 50respectively [62]

410 Effect of Green Tea on Androgen Receptor Overex-pression of androgen and its receptor has been noticed invarious tumors Natural products and its constituents showrole in the cancer prevention via downregulation of variousgenes including degradation of androgen Earlier resultshave shown that EGCG chief constituents of green tea wasobserved subsequently to inhibit nuclear translocation andprotein expression of AR in a tumor xenograft model [63]

Another study revealed that EGCG suppressed cell pro-liferation prostate specific antigen (PSA) expression andAR transcriptional activity in the different LNCaP sublines[64] and an important result has shown that tea polyphenolEGCG inhibited LNCaP cell growth and the expression ofandrogen regulated PSA and hK2 genes [65]

411 Effect of Green Tea on Nuclear Transcription Factor NF-120581B Overexpressionaltered nuclear transcription shows rolein the development and progression of tumour and alsoshows alterations of other genetic pathways Therefore inhi-bition of nuclear transcription factor is a vital step in theman-agement of tumour A vital study results showed that EGCGa chief green tea polyphenol decreased lipopolysaccharide(LPS)-induced TNF120572 production in a dose-dependent fash-ion in themacrophage cell line RAW2647 and also inhibitedLPS-induced TNF120572mRNA expression as well as nuclear NF-120581Bndashbinding activity [66]

Another significant finding showed that EGCG the chiefpolyphenol of green tea attenuated the excessive expressionof CTGF induced by abdominal aortic constriction (AAC)or AngII and also showed role in the reduction of nucleartranslocation of NF-120581B p65 subunit and degradation ofI120581B-120572 [67] Previous finding reported significant inhibitionsof tumor growth and tumor angiogenesis through EGCGin addition to that a major green tea catechin inhibitedthe activation of HIF-1120572 and NF-120581B and decreased VEGFexpression in breast carcinoma cells [68]

412 Effect of Green Tea on AP-1 Transcription Factor AP-1 is a transcription factor that includes Jun and Fos pro-tein families and play role in the cancer development and

progression Altered expression of AP-1 or Jun and Fos hasbeen noticed in various tumours Green tea ingredients playa role in cancer prevention through the inhibition of AP-1 transcription factor Theaflavins and EGCG chief con-stituents of green tea inhibitedUVB-inducedAP-1 activationin a concentration-dependent manner [69] A study wasperformed to investigate the antitumor promotion effectsof EGCG and theaflavins and results showed that doserange of 5ndash20120583M inhibited cell transformation EGCG andtheaflavins also inhibited AP-1-dependent transcriptionalactivity and DNA binding activity [59] Another findingalso showed that all of polyphenols of green tea and blacktea except (minus)-epicatechin showed strong inhibition of cellgrowth and AP-1 activity [70]

413 Effect of Green Tea on Signal Transducer and Activator ofTranscription3 (Stat3) Molecular effects of EGCGon humanHNSCC cell lines such as YCU-N861 and YCU-H891 wereexamined and results of this study showed that treatmentwith EGCG inhibited phosphorylation of the EGFR signaltransducer activator of transcription3 (Stat3) and extracel-lular regulated kinase (ERK) proteins [71]

Another study was performed to examine the effectsof EGCG on vascular endothelial growth factor (VEGF)production by YCU-H891 HNSCC and MDA-MB-231 breastcarcinoma cell lines and results confirm the constitutive acti-vation of the EGFR Stat3 and Akt inhibited by the treatmentwith a major biologically active component of green teaEGCG [50]

414 Effect of Green Tea on Peroxisome Proliferator-ActivatedReceptors Peroxisome proliferator-activated receptors(PPARs) belong to the superfamily of nuclear receptors[72] It contains three genes that give PPAR-120572 PPAR-120575and PPAR-gamma different subtypes Role of PPARs hasbeen noticed in various tumors but the exact mechanism isnot fully understood In this vista several natural productsshow a pivotal role in the activation of PPARs through themodulation of other genetic pathways and finally exhibitrole in cancer prevention Green tea and its constituentsconfirmed the diseases preventive role in various types ofdiseases An important study results showed that moderategreen tea extract concentration supplemented to the car-diomyocyte medium from initial seeding selectively acti-vated the PPAR-betadelta isoform [73] and other resultsconfirmed that PPAR120572 is a direct negative regulator of hemeoxygenase (HO-1) activation by EGCG and confers cellsusceptibility to EGCG [74]

415 Effect of Green Tea on Telomerase Telomeres are struc-tures present at the ends of human chromosomes and showrole in the protection and DNA damage Upregulation oftelomerase has been observed in several types of tumoursIn this vista green tea shows a significant role in the man-agement of telomerase activity and consequently inhibits thetumour development and progression

A valuable study was performed to examine the effectsof epigallocatechin-3-gallate (EGCG) on human SCLC cells


and results confirm that drug-sensitive (H69) and drug-resistant (H69VP) small-cell lung carcinoma cells incubationin EGCG at 1 times IC(50) for 24 h resulted in 50ndash60 reducedtelomerase activity [75]

Previous study was carried out to investigate the effect ofthe major tea polyphenol epigallocatechin gallate (EGCG)in cervical carcinogenesis and results showed that inhib-ited telomerase activity in human papillomavirus type 18-(HPV 18-) immortalized endocervical cell (HEN-18) andectocervical cell (HEC-18) as well as serum-adapted HEN-18 (HEN-18S) transformed HEC-18 (HEN-18T) [76] The invitro activitymeasurement on cell lysates fromU937 orHT29cells showed that EGCG is the strongest telomerase inhibitoramong the different catechins tested [77]

416 Effect of Green Tea on Insulin-Like Growth Factor IReceptor (IGFIR) The insulin-like growth factor I receptor(IGFIR) shows a pivotal role in the development and progres-sion of cancer However various medicinal plants or naturalproducts have confirmed the inhibitory effect on insulin-like growth factor I receptor (IGFIR) protein and preventthe cancer development and progression The insulin-likegrowth factor I receptor (IGFIR) is constitutively activated inEwing family tumors (EFTs) and (minus)-epigallocatechin gallate(EGCG) a chief constituents green tea inhibits cell prolif-eration and survival of EFT cells through the inhibition ofIGFIR activity and also EGCG treated EFT cell lines blockedthe autophosphorylation of IGFIR tyrosine residues [78]

The treatment of SW837 colon cancer cell lines with20120583gmL of EGCG caused decrease in the phosphorylatedform of the IGF-1R protein within 6 h and when SW837cells were treated with EGCG for 96 h with concentration10 120583gmL of EGCG it also caused inhibition of activationof IGF-1R and decrease in the IGF-1 protein [79] Effects ofEGCG on activity of IGFIGF-1R axis in HepG2 human hep-atocellular carcinoma cells was determined and results con-firmed that treatment of HepG2 cells with EGCG-inducedapoptosis caused a decrease in the p-IGF-1R protein [80]

5 Safety and Toxicities of Green Tea

Green tea and its constituents play an important role inthe maintenance of health due to their versatile therapeuticapproach Numerous results based on in vivo and in vitrostudy confirmed that green tea and their constituents such asEGCG show health promoting effect at certain dose throughthe modulation of various biological activities On the otherhand green teaEGCG overdose cause adverse complicationsincluding acute liver failurehepatotoxicity via alterations inliver enzymes An experiment based on rat model revealedthat oral dose delivering 2000mg EGCG preparationkg waslethal to rats but dose with 200mg EGCGkg induced notoxicity [81] Other studies based on animal models haveshown that green tea prevent hepatotoxicity induced byhepatotoxicants [82ndash84]

Recent finding results concluded that supplementationof 500mg green tea polyphenols daily to postmenopausalosteopenic women for 24 weeks did not cause any adverse

complications on liver and kidney function and had noinfluence on quality of life [85] Earlier important resultssuggest high concentrations of green tea extract exert acutetoxicity in rat liver cells and (minus)-epigallocatechin-3-gallatea chief constituents of green tea seems to be one of theprincipal constituents responsible for such effect [86] and poadministration of EGCG or polyphenon E with daily dose of800mg (based on the EGCG content) for 4 weeks is safe andwell tolerated in healthy human [87]

Experiment based on rat model showed that green teaextract with dose of 5 in diet for 13 wk induced thyroidenlargement in normal rats [88 89] and other investiga-tors studied the hepatotoxic effects of high dose EGCGtea polyphenols in male CF-1 mice and results indicatedthat higher bolus doses of EGCG are hepatotoxic to mice[90] Numerous previous findings reported that patientsshow hepatotoxicity due to the consumption of supplementscontaining green tea extracts [91ndash95] Latest data suggest thatcatechins are commonly present in several herbal dietarysupplements (HDS) that are implicated in hepatotoxicityeven when not identified on the product label [96] and casesof hepatotoxicity have been linked with consumption of highdoses green tea-containing supplements [97]

6 Bioavailability of Green Tea

The quantity of drugs that are accessible to the target tis-suesor organ is important for biological activityHighly polardrugsfat soluble have low bioavailability due to incompleteabsorption of drugs in the GI tract poor absorption andhigh rate of metabolism Various earlier reports confirmthat green tea constituents were found to be low in plasmathan the actual ingested quantity and therefore it shows lessbiological activities Earlier study proved that EGCG andEGC levels detected in plasma correspond to 02ndash20 of theingested amount [98] Various types of formulation based onnanoparticles micelles and liposome play an important rolein the enhancement of absorption of green tea constituentsand encapsulated form shows better results in modulationof biological activities due to high intestinal absorption Inthis vista an important study exhibited that encapsulationof catechins in chitosan nanoparticles (CS NP) enhancestheir intestinal absorption and is a promising strategy forimproving their bioavailability [99]

Another study on basal cell carcinoma has shown thatnearly no drug molecules were observed when free EGCGwas administrated to BCCs whereas EGCG encapsulated inliposomes with deoxycholic acid (DA) and ethanol increaseddrug deposition by 20-fold as compared to the free form[100] It was previously proved that high efficiency andyield were achieved from the incorporation of catechin orEGCG inside the liposome structure [101] Bioavailability ofgreen tea differs with types of polyphenols EGCG chiefpolyphenols of green tea is found in large proportion inplasma in a free form [102ndash104] and epigallocatechin gallate(EGCG) principal ingredients with dose of 50mg peakplasma concentrations were approximately 015 120583molL [105]An important study reported that at similar concentration


of epigallocatechin and epigallocatechin-3-gallate in a greentea drink plasma concentration of epigallocatechin concen-tration was observed approximately 2-3 times more than theepigallocatechin-3-gallate concentration after tea consump-tion [103]

7 Clinical Trials Based Study on Green Tea

Numerous series of preclinical studies have proven thatgreen tea and their constituents show an important role inprevention and treatment of human cancers A study basedon 49920 men subjects in Japan aged 40ndash69 years whocompleted a questionnaire that included green tea consump-tion habit at baseline and were followed until the end of2004 established that drinking 5 or more cupsday comparedwith less than 1 cupday demonstrated decreased risk ofadvanced prostate cancer (multivariate relative risk was 05295 confidence interval 028 096) [106] Another importantstudy has investigated antineoplastic effects of green teain patients with androgen independent prostate carcinoma42 patients who were asymptomatic and had manifestedprogressive prostate specific antigen elevation with hormonetherapy were checked and study results concluded thatgreen tea carries limited antineoplastic activity as definedby a decline in PSA levels among patients with androgenindependent prostate carcinoma [107] A significant and firststudy confirmed that green tea catechins have potent in vivochemoprevention activity for human prostate cancer and dataof this study suggest that up to 90 of chemopreventionefficacy can be obtained by GTCs administration in menprone to develop prostate cancer [108] and study reportsindicate that human metachronous colorectal adenomaswere significantly prevented by daily green tea consumptionsupplemented with GTE [109]

8 Conclusion

The allopath based anticancer drugs are expensive and alsoshow adverse effect via alteration in molecular pathwaysGreen tea is widely used in traditional medicine sinceancient time due to being inexpensive efficacy and fewerside effect properties The studies based on animal modeland cell lines demonstrated anticancer activity of green teaand its constituents by modulating cell signalling pathwaysincluding angiogenesis apoptosis and transcription factorExtensive study based on animal model may contribute tounderstanding the exact mechanism of action and toxicitylevelside effect without alteration of therapeutic potentialAdditionally the detailed study of green tea and its con-stituents based on clinical trials would be very helpful in thedesigning of novel anticancer drugs

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] M I Al-Bukhari and S Al-BukhariThe Collection of AuthenticSayings of Prophet Mohammad (Peace Be Upon Him) Division71 on Medicine Hilal Yayinlari Ankara Turkey 2nd edition1976

[2] AAhmadAHusainMMujeeb et al ldquoA reviewon therapeuticpotential of Nigella sativa a miracle herbrdquo Asian Pacific Journalof Tropical Biomedicine vol 3 no 5 pp 337ndash352 2013

[3] A H Rahmani S M Aly H Ali A Y Babiker S Suikarand A A Khan ldquoTherapeutic effects of date fruits (Phoenixdactylifera) in the prevention of diseases viamodulation of anti-inflammatory anti-oxidant and anti-tumour activityrdquo Interna-tional Journal of Clinical and Experimental Medicine vol 7 no3 pp 483ndash491 2014

[4] A H Rahmani A S Albutti and S M Aly ldquoTherapeutics roleof olive fruitsoil in the prevention of diseases via modulationof anti-oxidant anti-tumour and genetic activityrdquo InternationalJournal of Clinical and Experimental Medicine vol 7 no 4 pp799ndash808 2014

[5] M A Khan H-C Chen M Tania and D-Z Zhang ldquoAnti-cancer activities ofNigella sativa (black cumin)rdquoAfrican Journalof Traditional Complementary andAlternativeMedicines vol 8supplement 5 pp 226ndash232 2011

[6] N Khan and H Mukhtar ldquoTea polyphenols for health promo-tionrdquo Life Sciences vol 81 no 7 pp 519ndash533 2007

[7] D L McKay and J B Blumberg ldquoThe role of tea in humanhealth an updaterdquo Journal of the American College of Nutritionvol 21 no 1 pp 1ndash13 2002

[8] N Khan F Afaq M Saleem N Ahmad and H MukhtarldquoTargetingmultiple signaling pathways by green tea polyphenol(minus)-epigallocatechin-3-gallaterdquo Cancer Research vol 66 no 5pp 2500ndash2505 2006

[9] H Yanaga T Fujii T Koga R Araki and K Shirouzu ldquoPre-vention of carcinogenesis of mouse mammary epithelial cellsRIIIMG by epigallocatechin gallaterdquo International Journal ofMolecular Medicine vol 10 no 3 pp 311ndash315 2002

[10] N D Mineva K E Paulson S P Naber A S Yee and GE Sonenshein ldquoEpigallocatechin-3-gallate inhibits stem-likeinflammatory breast cancer cellsrdquoPloSONE vol 8 no 9 ArticleID e73464 2013

[11] L Schramm ldquoGoing green the role of the green tea componentEGCG in chemopreventionrdquo Journal of CarcinogenesisampMuta-genesis vol 4 article 142 2013

[12] D A Balentine S A Wiseman and L C M Bouwens ldquoThechemistry of tea flavonoidsrdquo Critical Reviews in Food Scienceand Nutrition vol 37 no 8 pp 693ndash704 1997

[13] C J Dufresne and E R Farnworth ldquoA review of latest researchfindings on the health promotion properties of teardquo Journal ofNutritional Biochemistry vol 12 no 7 pp 404ndash421 2001

[14] J V Higdon and B Frei ldquoTea catechins and polyphenols healtheffectsmetabolism and antioxidant functionsrdquoCritical Reviewsin Food Science and Nutrition vol 43 no 1 pp 89ndash144 2003

[15] H Mukhtar and N Ahmad ldquoTea polyphenols prevention ofcancer and optimizing healthrdquoTheAmerican Journal of ClinicalNutrition vol 71 no 6 supplement pp 1698Sndash1704S 2000

[16] M E Harbowy D A Balentine A P Davies and Y Cai ldquoTeachemistryrdquo Critical Reviews in Plant Sciences vol 16 pp 415ndash480 1997

[17] A H Rahmani M A Al Zohairy S M Aly and M A KhanldquoCurcumin a potential candidate in prevention of cancer via


modulation of molecular pathwaysrdquo BioMed Research Interna-tional vol 2014 Article ID 761608 15 pages 2014

[18] M A Randhawa and M S Alghamdi ldquoAnticancer activity ofNigella sativa (Black Seed)mdasha reviewrdquoThe American Journal ofChinese Medicine vol 39 no 6 pp 1075ndash1091 2011

[19] A H Rahmani F M Al Shabrmi and S M Aly ldquoActiveingredients of ginger as potential candidates in the preventionand treatment of diseases via modulation of biological activ-itiesrdquo International Journal of Physiology Pathophysiology andPharmacology vol 6 no 2 pp 125ndash136 2014

[20] D A Balentine S A Wiseman and L C Bouwens ldquoThechemistry of tea flavonoidsrdquo Critical Reviews in Food Scienceand Nutrition vol 37 pp 693ndash704 1997

[21] A Bhanot R Sharma and M N Noolvi ldquoNatural sources aspotential anti-cancer agents a reviewrdquo International Journal ofPhytomedicine vol 3 no 1 pp 9ndash26 2011

[22] V S Thakur K Gupta and S Gupta ldquoGreen tea polyphenolsincrease p53 transcriptional activity and acetylation by sup-pressing class I histone deacetylasesrdquo International Journal ofOncology vol 41 no 1 pp 353ndash361 2012

[23] K Hastak S Gupta N Ahmad M K Agarwal M L Agarwaland H Mukhtar ldquoRole of p53 and NF-120581B in epigallocatechin-3-gallate-induced apoptosis of LNCaP cellsrdquo Oncogene vol 22no 31 pp 4851ndash4859 2003

[24] K Hastak M K Agarwal H Mukhtar and M L AgarwalldquoAblation of either p21 or Bax prevents p53-dependent apoptosisinduced by green tea polyphenol epigallocatechin-3-gallaterdquoThe FASEB Journal vol 19 no 7 pp 789ndash791 2005

[25] A M Roy M S Baliga and S K Katiyar ldquoEpigallocatechin-3-gallate induces apoptosis in estrogen receptor-negative humanbreast carcinoma cells via modulation in protein expresssionof p53 and Bax and caspase-3 activationrdquo Molecular CancerTherapeutics vol 4 no 1 pp 81ndash90 2005

[26] Y-C Liang S-Y Lin-Shiau C-F Chen and J-K Lin ldquoInhi-bition of cyclin-dependent kinases 2 and 4 activities as wellas induction of Cdk inhibitors p21 and p27 during growtharrest of human breast carcinoma cells by (minus)-epigallocatechin-3-gallaterdquo Journal of Cellular Biochemistry vol 75 no 1 pp 1ndash121999

[27] J Qin H-G Chen Q Yan et al ldquoProtein phosphatase-2A isa target of epigallocatechin-3-gallate and modulates p53-Bakapoptotic pathwayrdquo Cancer Research vol 68 no 11 pp 4150ndash4162 2008

[28] E Navarro-Peran J Cabezas-Herrera L S D Campo and JN Rodrıguez-Lopez ldquoEffects of folate cycle disruption by thegreen tea polyphenol epigallocatechin-3-gallaterdquo InternationalJournal of Biochemistry andCell Biology vol 39 no 12 pp 2215ndash2225 2007

[29] M J Kim H I Kim J Chung T S Jeong and H R Parkldquo(minus)-Epigallocatechin-3-gallate (EGCG) increases the viabilityof serum-starvedA549 cells through its effect onAktrdquoAmericanJournal of Chinese Medicine vol 37 no 4 pp 723ndash734 2009

[30] H Chen C N Landen Y Li R D Alvarez and T OTollefsbol ldquoEnhancement of cisplatin-mediated apoptosis inovarian cancer cells through potentiating G2M arrest and p21upregulation by combinatorial epigallocatechin gallate andsulforaphanerdquo Journal of Oncology vol 2013 9 pages 2013

[31] C S Yang and Z-Y Wang ldquoTea and cancerrdquo Journal of theNational Cancer Institute vol 85 no 13 pp 1038ndash1049 1993

[32] S Gupta N Ahmad A-L Nieminen andHMukhtar ldquoGrowthinhibition cell-cycle dysregulation and induction of apopto-sis by green tea constituent (-)-epigallocatechin-3-gallate in

androgen-sensitive and androgen-insensitive human prostatecarcinoma cellsrdquoToxicology andApplied Pharmacology vol 164no 1 pp 82ndash90 2000

[33] M Barthelman W B Bair III K K Stickland et al ldquo(minus)-Epigallocatechin-3-gallate inhibition of ultraviolet B-inducedAP-1 activityrdquoCarcinogenesis vol 19 no 12 pp 2201ndash2204 1998

[34] T Nakazato K Ito Y Ikeda and M Kizaki ldquoGreen tea com-ponent catechin induces apoptosis of human malignant Bcells via production of reactive oxygen speciesrdquo Clinical CancerResearch vol 11 no 16 pp 6040ndash6049 2005

[35] J Qin L-P Xie X-Y Zheng et al ldquoA component of greentea (minus)-epigallocatechin-3-gallate promotes apoptosis in T24human bladder cancer cells via modulation of the PI3KAktpathway and Bcl-2 family proteinsrdquoBiochemical and BiophysicalResearch Communications vol 354 no 4 pp 852ndash857 2007

[36] S D Hsu B B Singh J B Lewis et al ldquoChemoprevention oforal cancer by green teardquo General dentistry vol 50 no 2 pp140ndash146 2002

[37] V S Thakur K Gupta and S Gupta ldquoGreen tea polyphenolscauses cell cycle arrest and apoptosis in prostate cancer cells bysuppressing class I histone deacetylasesrdquoCarcinogenesis vol 33no 2 pp 377ndash384 2012

[38] N Ahmad D K Feyes A-L Nieminen R Agarwal and HMukhtar ldquoGreen tea constituent epigallocatechin-3-gallate andinduction of apoptosis and cell cycle arrest in human carcinomacellsrdquo Journal of the National Cancer Institute vol 89 no 24 pp1881ndash1886 1997

[39] N Khan and H Mukhtar ldquoModulation of signaling pathwaysin prostate cancer by green tea polyphenolsrdquo BiochemicalPharmacology vol 85 no 5 pp 667ndash672 2013

[40] Y D Jung M S Kim B A Shin et al ldquoEGCG a majorcomponent of green tea inhibits tumour growth by inhibitingVEGF induction in human colon carcinoma cellsrdquo BritishJournal of Cancer vol 84 no 6 pp 844ndash850 2001

[41] J-W Gu K L Makey K B Tucker et al ldquoEGCG a major greentea catechin suppresses breast tumor angiogenesis and growthvia inhibiting the activation of HIF-1120572 and NF120581B and VEGFexpressionrdquo Vascular Cell vol 5 no 1 article 9 2013

[42] P Srinivasan S Suchalatha P V A Babu et al ldquoChemopre-ventive and therapeutic modulation of green tea polyphenolson drug metabolizing enzymes in 4-nitroquinoline 1-oxideinduced oral cancerrdquo Chemico-Biological Interactions vol 172no 3 pp 224ndash234 2008

[43] LMinghetti ldquoCyclooxygenase-2 (COX-2) in inflammatory anddegenerative brain diseasesrdquo Journal of Neuropathology andExperimental Neurology vol 63 no 9 pp 901ndash910 2004

[44] G Peng D A Dixon S J Muga T J Smith and M J War-govich ldquoGreen tea polyphenol (minus)-epigallocatechin-3-gallateinhibits cyclooxygenase-2 expression in colon carcinogenesisrdquoMolecular Carcinogenesis vol 45 no 5 pp 309ndash319 2006

[45] J Hong T J Smith C-T Ho D A August and C SYang ldquoEffects of purified green and black tea polyphenols oncyclooxygenase- and lipoxygenase-dependent metabolism ofarachidonic acid in human colon mucosa and colon tumortissuesrdquo Biochemical Pharmacology vol 62 no 9 pp 1175ndash11832001

[46] J Ju Y Liu J Hong M-T Huang A H Conney and C SYang ldquoEffects of green tea and high-fat diet on arachidonicacid metabolism and aberrant crypt foci formation in anazoxymethane-induced colon carcinogenesis mouse modelrdquoNutrition and Cancer vol 46 no 2 pp 172ndash178 2003


[47] J K Kundu H K Na K S Chun et al ldquoInhibition of phorbolester-induced COX-2 expression by epigallocatechin gallate inmouse skin and cultured human mammary epithelial cellsrdquoJournal of Nutrition vol 133 no 11 supplement 1 pp 3805Sndash3810S 2003

[48] Y Tang D Y Zhao S Elliott et al ldquoEpigallocatechin-3 gallateinduces growth inhibition and apoptosis in human breast can-cer cells through survivin suppressionrdquo International Journal ofOncology vol 31 no 4 pp 705ndash711 2007


[50] M Masuda M Suzui J T E Lim A Deguchi J-W Soh andI B Weinstein ldquoEpigallocatechin-3-gallate decreases VEGFproduction in head and neck and breast carcinoma cells byinhibiting EGFR-related pathways of signal transductionrdquo Jour-nal of ExperimentalTherapeutics and Oncology vol 2 no 6 pp350ndash359 2002

[51] S Pianetti S Guo K T Kavanagh and G E SonensheinldquoGreen tea polyphenol epigallocatechin-3 gallate inhibits Her-2neu signaling proliferation and transformed phenotype ofbreast cancer cellsrdquo Cancer Research vol 62 no 3 pp 652ndash6552002

[52] M Masuda M Suzui J T E Lim and I B WeinsteinldquoEpigallocatechin-3-gallate inhibits activation of HER-2neuand downstream signaling pathways in human head and neckand breast carcinoma cellsrdquo Clinical Cancer Research vol 9 no9 pp 3486ndash3491 2003

[53] M Shimizu A Deguchi A K Joe J F Mckoy H Moriwakiand I B Weinstein ldquoEGCG inhibits activation of HER3 andexpression of cyclooxygenase-2 in human colon cancer cellsrdquoJournal of ExperimentalTherapeutics and Oncology vol 5 no 1pp 69ndash78 2005

[54] Y-C Liang S-Y Lin-shiau C-F Chen and J-K Lin ldquoSuppres-sion of extracellular signals and cell proliferation through EGFreceptor binding by (-)-epigallocatechin gallate in human A431epidermoid carcinoma cellsrdquo Journal of Cellular Biochemistryvol 67 no 1 pp 55ndash65 1997

[55] S Adachi T Nagao S To et al ldquo(minus)-epigallocatechin gallatecauses internalization of the epidermal growth factor receptorin human colon cancer cellsrdquo Carcinogenesis vol 29 no 10 pp1986ndash1993 2008

[56] F Farabegoli A Papi andM Orlandi ldquo(ndash)-Epigallocatechin-3-gallate down-regulates EGFRMMP-2MMP-9 and EMMPRINand inhibits the invasion of MCF-7 tamoxifen-resistant cellsrdquoBioscience Reports vol 31 no 2 pp 99ndash108 2011

[57] S A Milligan P Burke D T Coleman et al ldquoThe green teapolyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cellsrdquo Clinical Cancer Research vol 15no 15 pp 4885ndash4894 2009

[58] H-Y Ahn K R Hadizadeh C Seul Y-P Yun H Vetter and ASachinidis ldquoEpigallocathechin-3 gallate selectively inhibits thePDGF-BB-induced intracellular signaling transduction path-way in vascular smooth muscle cells and inhibits transfor-mation of sis-transfected NIH 3T3 fibroblasts and humanglioblastoma cells (A172)rdquoMolecular Biology of the Cell vol 10no 4 pp 1093ndash1104 1999

[59] Z Dong W-Y Ma C Huang and C S Yang ldquoInhibition oftumor promoter-induced activator protein 1 activation and cell

transformation by tea polyphenols (minus)-epigallocatechin gallateand theaflavinsrdquo Cancer Research vol 57 no 19 pp 4414ndash44191997

[60] M Shimizu A Deguchi J T E Lim H Moriwaki LKopelovich and I B Weinstein ldquo(-)-Epigallocatechin gallateand polyphenon E inhibit growth and activation of the epider-mal growth factor receptor and human epidermal growth factorreceptor-2 signaling pathways in human colon cancer cellsrdquoClinical Cancer Research vol 11 no 7 pp 2735ndash2746 2005

[61] C E Harper B B Patel JWang I A Eltoum and C A Lamar-tiniere ldquoEpigallocatechin-3-gallate suppresses early stage butnot late stage prostate cancer inTRAMP mice mechanisms ofactionrdquo Prostate vol 67 no 14 pp 1576ndash1589 2007

[62] G Hu C Han and J Chen ldquoInhibition of oncogene expressionby green tea and (-)-epigallocatechin gallate in micerdquo Nutritionand Cancer vol 24 no 2 pp 203ndash209 1995

[63] I A Siddiqui M Asim B B Hafeez V M Adhami R STarapore andHMukhtar ldquoGreen tea polyphenol EGCGbluntsandrogen receptor function in prostate cancerrdquo The FASEBJournal vol 25 no 4 pp 1198ndash1207 2011

[64] C-P Chuu R-Y Chen J M Kokontis R A Hiipakka and SLiao ldquoSuppression of androgen receptor signaling and prostatespecific antigen expression by (-)-epigallocatechin-3-gallate indifferent progression stages of LNCaP prostate cancer cellsrdquoCancer Letters vol 275 no 1 pp 86ndash92 2009

[65] F Ren S Zhang S H Mitchell R Butler and C Y F YoungldquoTea polyphenols down-regulate the expression of the androgenreceptor in LNCaP prostate cancer cellsrdquo Oncogene vol 19 no15 pp 1924ndash1932 2000

[66] F Yang W J S De Villiers C J McClain and G W VarilekldquoGreen tea polyphenols block endotoxin-induced tumor necro-sis factor- production and lethality in a murine modelrdquo Journalof Nutrition vol 128 no 12 pp 2334ndash2340 1998

[67] Y Cai S-S Yu T-T Chen et al ldquoEGCG inhibits CTGFexpression via blocking NF-120581B activation in cardiac fibroblastrdquoPhytomedicine vol 20 no 2 pp 106ndash113 2013

[68] J-W Gu K L Makey K B Tucker et al ldquoEGCG a major greentea catechin suppresses breast tumor angiogenesis and growthvia inhibiting the activation of HIF-1120572 and NF120581B and VEGFexpressionrdquo Vascular Cell vol 5 article 9 2013

[69] M NomuraW-YMa C Huang et al ldquoInhibition of ultravioletB-induced AP-1 activation by theaflavins from black teardquoMolecular Carcinogenesis vol 28 no 3 pp 148ndash155 2000

[70] J Y Chung C Huang XMeng Z Dong and C S Yang ldquoInhi-bition of activator protein 1 activity and cell growth by purifiedgreen tea and black tea polyphenols in H-ras-transformedcells structure- activity relationship andmechanisms involvedrdquoCancer Research vol 59 no 18 pp 4610ndash4617 1999

[71] M Masuda M Suzui and I B Weinstein ldquoEffects of epi-gallocatechin-3-gallate on growth epidermal growth factorreceptor signaling pathways gene expression and chemosen-sitivity in human head and neck squamous cell carcinoma celllinesrdquo Clinical Cancer Research vol 7 no 12 pp 4220ndash42292001

[72] S Green and W Wahli ldquoPeroxisome proliferator-activatedreceptors finding the orphan a homerdquo Molecular and CellularEndocrinology vol 100 no 1-2 pp 149ndash153 1994

[73] F Danesi M di Nunzio E Boschetti and A Bordoni ldquoGreentea extract selectively activates peroxisome proliferator-acti-vated receptor betadelta in cultured cardiomyocytesrdquo BritishJournal of Nutrition vol 101 no 12 pp 1736ndash1739 2009


[74] S Zhang X Yang J Luo et al ldquoPPAR120572 activation sensitizescancer cells to epigallocatechin-3- gallate (egcg) treatment viasuppressing heme oxygenase-1rdquo Nutrition and Cancer vol 66no 2 pp 315ndash324 2014

[75] D Sadava EWhitlock and S E Kane ldquoThe green tea polyphe-nol epigallocatechin-3-gallate inhibits telomerase and inducesapoptosis in drug-resistant lung cancer cellsrdquo Biochemical andBiophysical Research Communications vol 360 no 1 pp 233ndash237 2007

[76] M Yokoyama M Noguchi Y Nakao A Pater and T IwasakaldquoThe tea polyphenol (minus)-epigallocatechin gallate effects ongrowth apoptosis and telomerase activity in cervical cell linesrdquoGynecologic Oncology vol 92 no 1 pp 197ndash204 2004

[77] I Naasani H Seimiya and T Tsuruo ldquoTelomerase inhibitiontelomere shortening and senescence of cancer cells by tea cat-echinsrdquo Biochemical and Biophysical Research Communicationsvol 249 no 2 pp 391ndash396 1998

[78] H-G Kang J M Jenabi X F Liu C P Reynolds T J Tricheand P H B Sorensen ldquoInhibition of the insulin-like growthfactor I receptor by epigallocatechin gallate blocks proliferationand induces the death of ewing tumor cellsrdquo Molecular CancerTherapeutics vol 9 no 5 pp 1396ndash1407 2010

[79] M Shimizu A Deguchi Y Hara H Moriwaki and I BWeinstein ldquoEGCG inhibits activation of the insulin-like growthfactor-1 receptor in human colon cancer cellsrdquo Biochemical andBiophysical Research Communications vol 334 no 3 pp 947ndash953 2005

[80] M Shimizu Y Shirakami H Sakai et al ldquoEGCG inhibitsactivation of the insulin-like growth factor (IGF)IGF-1 receptoraxis in human hepatocellular carcinoma cellsrdquo Cancer Lettersvol 262 no 1 pp 10ndash18 2008

[81] R A Isbrucker J A Edwards E Wolz A Davidovich andJ Bausch ldquoSafety studies on epigallocatechin gallate (EGCG)preparations Part 2 dermal acute and short-term toxicitystudiesrdquo Food and Chemical Toxicology vol 44 no 5 pp 636ndash650 2006

[82] K Sai S Kai T Umemura et al ldquoProtective effects of green teaon hepatotoxicity oxidative DNA damage and cell proliferationin the rat liver induced by repeated oral administration of 2-nitropropanerdquo Food and Chemical Toxicology vol 36 no 12 pp1043ndash1051 1998

[83] J-H Chen G L Tipoe E C Liong et al ldquoGreen teapolyphenols prevent toxin-induced hepatotoxicity in mice bydown-regulating inducible nitric oxide-derived prooxidantsrdquoThe American Journal of Clinical Nutrition vol 80 no 3 pp742ndash751 2004

[84] H S Oz C J McClain H T Nagasawa M B Ray W JS de Villiers and T S Chen ldquoDiverse antioxidants protectagainst acetaminophen hepatotoxicityrdquo Journal of Biochemicaland Molecular Toxicology vol 18 no 6 pp 361ndash368 2004

[85] C-L Shen M-C Chyu B C Pence et al ldquoGreen tea polyphe-nols supplementation and Tai Chi exercise for postmenopausalosteopenic women safety and quality of life reportrdquo BMCComplementary and Alternative Medicine vol 10 article 762010

[86] M SchmidtH-J Schmitz A Baumgart et al ldquoToxicity of greentea extracts and their constituents in rat hepatocytes in primaryculturerdquo Food and Chemical Toxicology vol 43 no 2 pp 307ndash314 2005

[87] H-H S Chow Y Cai I A Hakim et al ldquoPharmacokineticsand safety of green tea polyphenols aftermultiple-dose adminis-tration of epigallocatechin gallate and polyphenon E in healthy

individualsrdquo Clinical Cancer Research vol 9 no 9 pp 3312ndash3319 2003

[88] Y Sakamoto HMikuriya K Tayama et al ldquoGoitrogenic effectsof green tea extract catechins by dietary administration in ratsrdquoArchives of Toxicology vol 75 no 10 pp 591ndash596 2001

[89] K Satoh Y Sakamoto A Ogata et al ldquoInhibition of aromataseactivity by green tea extract catechins and their endocrinolog-ical effects of oral administration in ratsrdquo Food and ChemicalToxicology vol 40 no 7 pp 925ndash933 2002

[90] J D Lambert M J Kennett S Sang K R Reuhl J Ju and CS Yang ldquoHepatotoxicity of high oral dose (minus)-epigallocatechin-3-gallate in micerdquo Food and Chemical Toxicology vol 48 no 1pp 409ndash416 2010

[91] MMolinari K D SWatt T Kruszyna et al ldquoAcute liver failureinduced by green tea extracts case report and review of theliteraturerdquo Liver Transplantation vol 12 no 12 pp 1892ndash18952006

[92] T Vial G Bernard B Lewden J Dumortier and J DescotesldquoAcute hepatitis due to Exolise aCamellia sinensis-derived drug[1]rdquo Gastroenterologie Clinique et Biologique vol 27 no 12 pp1166ndash1167 2003

[93] C Pedros G Cereza N Garcıa and J-R Laporte ldquoLivertoxicity of Camellia sinensis dried atanolic extractrdquo MedicinaClinica vol 121 no 15 pp 598ndash599 2003

[94] H L Bonkovsky Md ldquoHepatotoxicity associated with sup-plements containing Chinese green tea (Camellia sinensis)rdquoAnnals of Internal Medicine vol 144 no 1 pp 68ndash71 2006

[95] C Duenas Sadornil S Fabregas Puigtio and R DurandezldquoHepatotoxicity due to Camellia sinensisrdquoMedicina Clinica vol122 no 17 pp 677ndash678 2004

[96] V J Navarro H L Bonkovsky S-I Hwang M Vega HBarnhart and J Serrano ldquoCatechins in dietary supplements andhepatotoxicityrdquoDigestiveDiseases and Sciences vol 58 no 9 pp2682ndash2690 2013

[97] G Mazzanti F Menniti-Ippolito P A Moro et al ldquoHepa-totoxicity from green tea a review of the literature and twounpublished casesrdquo European Journal of Clinical Pharmacologyvol 65 no 4 pp 331ndash341 2009

[98] K Nakagawa S Okuda and T Miyazawa ldquoDose-dependentincorporation of tea catechins (-)-epigallocatechin-3-gallateand (-)-epigallocatechin into human plasmardquo BioscienceBiotechnology and Biochemistry vol 61 no 12 pp 1981ndash19851997

[99] A Dube J A Nicolazzo and I Larson ldquoChitosan nanoparticlesenhance the intestinal absorption of the green tea catechins (+)-catechin and (minus)-epigallocatechin gallaterdquo European Journal ofPharmaceutical Sciences vol 41 no 2 pp 219ndash225 2010

[100] J Y Fang W R Lee S C Shen and Y L Huang ldquoEffect ofliposome encapsulation of tea catechins on their accumulationin basal cell carcinomasrdquo Journal of Dermatological Science vol42 no 2 pp 101ndash109 2006

[101] A Rashidinejad E J Birch D Sun-Waterhouse and D WEverett ldquoDelivery of green tea catechin and epigallocatechingallate in liposomes incorporated into low-fat hard cheeserdquoFood Chemistry vol 156 pp 176ndash183 2014

[102] U Ullmann J Haller J P Decourt et al ldquoA single ascendingdose study of epigallocatechin gallate in healthy volunteersrdquoJournal of International Medical Research vol 31 no 2 pp 88ndash101 2003

[103] X Meng S Sang N Zhu et al ldquoIdentification and charac-terization of methylated and ring-fission metabolites of tea


catechins formed in humans mice and ratsrdquoChemical Researchin Toxicology vol 15 no 8 pp 1042ndash1050 2002

[104] M-J Lee P Maliakal L Chen et al ldquoPharmacokinetics of teacatechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans Formation of different metabolites andindividual variabilityrdquo Cancer Epidemiology Biomarkers andPrevention vol 11 no 10 pp 1025ndash1032 2002

[105] C Manach G Williamson C Morand A Scalbert and CRemesy ldquoBioavailability and bioefficacy of polyphenols inhumans I Review of 97 bioavailability studiesrdquo The AmericanJournal of Clinical Nutrition vol 81 no 1 pp 230Sndash242S 2005

[106] N Kurahashi S Sasazuki M Iwasaki and M Inoue ldquoGreentea consumption and prostate cancer risk in Japanese men aprospective studyrdquo The American Journal of Epidemiology vol167 no 1 pp 71ndash77 2008

[107] A Jatoi N Ellison P A Burch et al ldquoA phase II trial of greentea in the treatment of patients with androgen independentmetastatic prostate carcinomardquo Cancer vol 97 no 6 pp 1442ndash1446 2003

[108] S Bettuzzi M Brausi F Rizzi G Castagnetti G Peracchia andA Corti ldquoChemoprevention of human prostate cancer by oraladministration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia a preliminary reportfrom a one-year proof-of-principle studyrdquo Cancer Research vol66 no 2 pp 1234ndash1240 2006

[109] M Shimizu Y Fukutomi M Ninomiya et al ldquoGreen teaextracts for the prevention of metachronous colorectal ade-nomas a pilot studyrdquo Cancer Epidemiology Biomarkers andPrevention vol 17 no 11 pp 3020ndash3025 2008

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


HO

HO HO

HO

OH

OH

OH OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OHOH

OH

OH

O

O

O O

O

OO

O

Epicatechin Epigallocatechin

Epicatechin-3-gallate Epigallocatechin-3-gallate

Figure 1 Active constituents of green tea

2 Chemical Structure of Active Constituentsof Green Tea

Green tea is a complex mixture of precious compoundsincluding polyphenols flavonoids flavonols and other con-stituents such as amino acids organic acids lipids vita-mins polysaccharides and thiamine Catechins are a type ofpolyphenol and are themain astringency component in greentea and modulate the various genes involved in the devel-opment and progression of cancer The chief catechins are(minus)-epicatechin (EC) (minus)-epicatechin-3-gallate (ECG) (minus)-epigallocatechin (EGC) and (minus)-epigallocatechin-3-gallate(EGCG) [12ndash15] Approximately 30ndash42 of the dry weight ofgreen tea contains phenolic compounds [12 16] and EGCGis one of the most abundant catechins that contains around50ndash80 of the total catechins [16] The chemical structure ofchief constituents of green tea is presented in Figure 1

3 Mechanism of Action of Green Tea inCancer Prevention

Green tea is a product made from the Camellia sinensis plantand is commonly used as beverage worldwide Althoughgreen tea shows vital role in diseases control exact mech-anism of action is still under investigation The possible

mechanisms of action of green tea in cancer prevention andprogression are as follows

(i) Green tea act as inhibitor of cyclooxygenase lipoxy-genases tumour necrosis factor and interleukin path-ways and ultimately controls the development andprogression of tumour

(ii) Green tea shows chemopreventive effect via activationof tumour suppressor genes such as p53 and PTENp21 regulation of apoptosis (bcl2Bax) and inhibi-tion of angiogenesis and other transcription factorsinvolved in the cancer development and progression

(iii) It shows role in neutralization of free radical anddamage of macromolecules due to high antioxidantcapacity and finally prevents the pathogenesis oftumour

(iv) Another possible mechanism of green tea in can-cer prevention is through the modulation of genesinvolved in initiations promotion and progression oftumour (Figure 2)

4 Anticancer Effect of Green Tea throughModulation of Cell Signalling Pathways

Cancer is multifactorial disease including genetic and met-abolic alterations The current mode of treatment based


Normalcell

InitiationInitiated

cells


cells

PromotionNeoplastic

cells

Green tea

Constituents

Catechins


(i) GST uarr

(ii) P53 PTEN uarr

(iii) CYP450 darr

(v)

(i) VEGF darr

(ii) COX2 darr

(iv) BCL2 darr


Bax uarr


Catechin




oncogene

Inhibition of VEGF


Green tea


IGFIR

Activation of PPAR

Prev

entio

n of

canc

er fo

rmat

ion





























































8 Conclusion




References




























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Normalcell

InitiationInitiated

cells


cells

PromotionNeoplastic

cells

Green tea

Constituents

Catechins


(i) GST uarr

(ii) P53 PTEN uarr

(iii) CYP450 darr

(v)

(i) VEGF darr

(ii) COX2 darr

(iv) BCL2 darr


Bax uarr


Catechin




oncogene

Inhibition of VEGF


Green tea


IGFIR

Activation of PPAR

Prev

entio

n of

canc

er fo

rmat

ion





























































8 Conclusion




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8 Conclusion




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of






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OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































8 Conclusion




References




























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































8 Conclusion




References




























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































8 Conclusion




References




























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















8 Conclusion




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






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OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






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OncologyJournal of





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Journal of

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Review Article Implications of Green Tea and Its ...downloads.hindawi.com/journals/bmri/2015/925640.pdfReview Article Implications of Green Tea and Its Constituents in the Prevention