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Increased Concentration of CatechinsFollowing Black Tea Consumption

Plasma Levels(nmol/L)

Urinary Excretion(nmol/h)

Fecal Excretion(mol)

Epigallocatechin

Epicatechin

Epigallocatechin

Gallate

Epicatechin Gallate

Warden BA, et al. J Nutr 2001;131:1731-1737

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Epidemiological Studies ofTea and Cancer

Ecologic, case-control and cohort studieshave been performed.

Many performed as secondary analyses.

Little information on precision of tea intake.

Several cancer sites investigated: bladder andurinary tract, breast, colon and rectum,esophagus, kidney, liver, lung, nasopharynx,pancreas, stomach and uterus (with mixedresults).

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Recent Epidemiological Studies of TeaAnd Gastric/Stomach Cancer

Country (Tea type) Study Type Risk/Association Reference

China(green tea)

India(unknown)

Japan(green tea)

Japan(green tea)

Japan(green tea)

China(unknown**)

Japan(green tea)

Japan(green tea)

Case-control

Case-control

Prospectivecohort

Prospectivecohort

Prospectivecohort

Nested case-control

Prospectivecohort

Nested case-control

Decrease

Decrease

No association

No association*

No association

Decrease

Decrease***

Setiawan2001

Rao 2002

Tsubono

2001

Hoshiyama 2002

Fujino 2002

Sun 2002

Sasazuki 2004

Hoshiyama 2004

* Deaths **Urinary polyphenols/metabolites ***distal gastric, women only

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Effects of Tea on Human Oral Precancerous

Lesions

A double-blind intervention trial of 59 patients withoral mucosa leukoplakia

Twenty-nine patients received tea administeredorally and topically; 30 patients received placebotreatment

After 6 months, the size of oral lesion decreased in38% of the treated group and in 10% of the placebogroup; the lesion increased in 3.4% of the treatedgroup and in 6.7% of the placebo group

The incidence of micronucleated exfoliated oralmucosa cells in the treated group (0.54%) was lowerthan the control group (1.13%)

Li et al. Proc. Soc. Expr. Biol. Med. 220: 218-224, 1999.

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Effect of Increased Tea Consumption on

Oxidative DNA Damage Among Smokers

A phase II randomized controlled tea intervention trial (4 cups/d) ofdecaffeinated green or black tea among smokers over a 4-mo period.

143 heavy smokers, aged 18-79 y, were randomized to drink eithergreen or black tea or water.

Plasma and urinary levels of catechins rose significantly in the greentea group compared with the other two groups.

Significant decrease in urinary 8-OHdG (-31%) after 4 mo of drinkingdecaffeinated green tea (P = 0.002).

No change in urinary 8-OHdG was seen among smokers assigned to theblack tea group.

Hakim IA, et al. J Nutr. 2003; 133:3303S-3309S.

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Tea and Cancer Prevention

Camellia Sinensis

Yang, CS. Personal Communication

SkinLiver

Colon

Oral

Esophagus

LungStomach

ProstateMammary

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Results of Animal Studies With Tea

110Lung

36Breast

01Prostate

01Bladder

07Liver

310Intestine/Colon

05(Fore)stomach

13Esophagus

02Oral

513Skin

Not ProtectiveProtectiveOrgan Site

Number of Studies

Yang CS. Personal Communication

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The TRAMP MouseTransgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model

that express the oncogene SV40 T antigen specifically in the epithelium ofthe prostate.

Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion ofgreen tea polyphenols. Gupta et al. PNAS 2001;98:10350-10355.

100

50

0

30 Weeks2418126

metastasis

neoplasia

hyperplasia

puberty

TRAMP: A Model for Prostate Cancer Progression

Greenberg et al. (Found on TRAMP webpage)

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Reactive Oxygen Species

EndoplasmicReticulum

Mitochondrion

O2 H202 OH

Damage DNA,RNA

Oxidize Proteins

(enzymes, histones)

Oxidize LipidsActivate Cell

Suicide

TEAX

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Biological Activities of TeaPolyphenols

Induce Phase I and Phase II enzymes

Inhibit cell proliferation and induce apoptosis

Several effects on cell signaling pathways (e.g.,cyclooxygenase)

Inhibit angiogenesis and invasion

Inhibit DNA methyltransferase activity

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NF-B Metastasis(MMPs, cell adhesionmolecules,

cell surface proteases)

Angiogenesis

(Cox-2, NOS, VEGF)

Proliferation

(c-myc, cyclin D1, gro

cytokines [IL-2, -6])

Oncoproteins (Her-2/neu, Ras)

IKK activation

CK2 induction

IBIB

Activation and Roles of NF-Activation and Roles of NF-B in OncogenesisB in OncogenesisAltered cytokine production

NF-B

nfkb gene amplif.,

rearrangement

Survival(Bcl-xL, A1/Bfl-1,

IEX-1L, IAP1, IAP2)Mutations in IB genesCo-acting factors

(AP-1, AhR,

c/EBP, p300)

Modifications(phosphorylation,

acetylation)

EGCG

[Proteasome]

DEX

Sonenshein GE.Personal Communication

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Tea Polyphenol Epigallocatechin-3-Gallate

Inhibits DNA Methyltransferase Activity

Cancer Res. 63 22 : 2003

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D3-1 cells, DMBA-transformed MCF-10F mammary

epithelial cells

Human chip microarray (7,500 genes developed by

GenomicTree, Inc, Korea)

Dose: 60 g/ml EGCG (dissolved in DMSO) orequivalent volume of DMSO, as control

Time points: 2, 7, and 24 hrs Experiment performed twice, each time in duplicate

Microarray Analysis to Identify Genes

Responding to EGCG Treatment in Breast

Cancer Cells

Sonenshein GE.Personal Communication

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1 2 3 4 1 2 3 4

0.37 0.36 0.42 0.61 0.17 0.25 0.39 0.3

0.91 1.32 0.46 0.48 0.4 0.94 0.57 0.460.79 0.80 0.46 0.48 0.36 0.51 0.36 0.3

0.57 0.91 0.51 0.46 0.27 0.58 0.48 0.45

0.70 0.90 1.01 0.85 0.41 0.93 0.52 0.48

0.74 0.93 0.46 0.64 0.31 0.56 0.44 0.37

0.95 1.37 0.56 0.69 0.2 0.55 0.26 0.23

0.65 0.77 0.73 0.72 0.4 0.67 0.62 0.49

0.57 0.67 1.51 0.01 0.09 0.46 0.13 0.11

1.05 0.84 0.93 1.09 1.04 0.95 0.61 0.69

0.70 1.02 0.36 0.59 0.17 0.6 0.25 0.21

0.92 0.80 1.00 0.31 0.46 0.74 0.47 0.42

0.85 0.95 0.57 0.53 0.5 0.84 0.52 0.45

0.97 1.13 0.49 0.43 0.43 0.85 0.45 0.37

0.87 1.08 0.49 0.84 0.55 0.91 0.65 0.5

0.89 1.00 0.35 0.37 0.43 0.82 0.52 0.46

0.87 1.06 0.51 0.49 0.36 0.81 0.66 0.47

0.92 0.85 0.57 0.59 0.43 0.72 0.52 0.43

0.87 0.87 0.34 0.53 0.48 0.75 0.47 0.44

0.79 0.91 1.42 2.03 0.39 0.84 0.56 0.5

2.31 2.12 0.49 0.53 0.75 0.91 1 0.51.31 1.51 0.95 1.00 1.9 2.05 2.43 2.36

1.25 1.43 1.62 1.43 2.08 1.88 2.17 2.22

1.26 1.44 1.37 2.14 1.88 2.01 2.02 2.6

1.21 1.24 1.08 1.45 1.93 1.53 1.6 1.56

1.32 1.75 0.94 1.22 1.5 2.3 0.71 0.78

2 hours 7 hours

1 2 3 4

0.14 0.36 0.31 0.5 0.003

0.17 0.55 0.37 0.44 0.0050.32 0.64 0.3 0.35 0.005

0.24 0.44 0.49 0.47 0.002

0.33 0.62 0.32 0.45 0.004

0.28 0.52 0.48 0.48 0.002

0.28 0.73 0.39 0.45 0.011

0.31 0.52 0.47 0.6 0.003

0.08 0.47 0.4 1 0.075

0.65 0.46 0.47 0.45 0.002

0.2 0.63 0.28 1 0.082

0.44 0.76 0.43 0.49 0.009

0.4 0.79 0.43 0.52 0.014

0.37 0.83 0.45 0.5 0.020

0.36 1.02 0.38 0.43 0.065

0.4 0.77 0.49 0.57 0.011

0.39 0.85 0.51 0.55 0.022

0.5 0.73 0.57 0.65 0.004

0.94 0.75 0.67 0.63 0.035

0.71 0.83 0.72 0.81 0.005

1.03 0.91 0.54 0.6 0.1481.7 1.51 1.39 1.37 0.007

1.84 1.53 1.47 1.44 0.008

1.82 1.56 1.77 1.75 0.001

2.11 2.69 2.11 2.08 0.003

5.27 2.31 2.22 2.96 0.054

p value

24 hoursUNIQID AND GENE NAME

AI003699 LIM and SH3 protein 1

AA099134 Hypoxia up-regulated 1AA181307 aryl hydrocarbon receptor

AA520985 rab3 GTPase-activating protein

AA488674 myeloid cell leukemia sequence 1

H50344 tight junction protein 1

AA464532 thrombospondin 1a2

AA053886 SREBP 2

AA995560 protein tyrosine phosphatase

AA872383 metallothionein 1E (functional)

AI031571 epithelial cell transforming sequence

R45056 Human clone 23721 mRNA sequence

AA151214 Ras-GTPase activating protein

N69204 chromosome segregation 1

W69399 H1 histone family, member 0

AI865149 karyopherin alpha 6

R59621 LanC (bacterial lantibiotic synthetase c

H92201 nucleosome assembly protein 1-like 4

AA773461 chord domain-containing protein 1

W46972 solute carrier family 20

AA598794 connective tissue growth factorAA916325 aldo-keto reductase family 1,C3

AI924357 aldo-keto reductase family 1,C2

R93124 aldo-keto reductase family 1,C1

AI023541 carbonic anhydrase IX

T54298 PPAR(gamma) angiopoietin related

Identification of Genes Affected by EGCG Treatment in D3-1Identification of Genes Affected by EGCG Treatment in D3-1

Breast Cancer CellsBreast Cancer Cells

24 h samples

Sonenshein GE.Personal Communication

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AhR (AA181307)*

CSE-1 (N69204 )*

CTGF (AA598794)*

Heat shock protein 10kD (AA448396)

Prefoldin (AI682392)

ECTS (AI031571)*

DMSO

EGCG

24h

TGF (R36467)BMP6 (AA424833)

GST (A4(aa152374))

Angiopoietin (T54298)*

PTP3 (AA995560)*

Thrombospondin (AA464532)*

WISP-1 (AI473336)

GAPDH

Ring finger protein (AA402960)

AhR (AA181307)

28S

18S

RT-PCR

Northern

RT-PCR and Northern Blot Analysis Confirms Affects of EGCG

on Expression of Several Genes

Genes Regulated by 24 h EGCG

BMP6 AhR

WISP-1 CTGF

PPAR ECTSGST HSP10

Sonenshein GE.Personal Communication

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Summary

Green, black and oolong teas are differentiated bytea manufacturing processes

Teas are rich in polyphenols, e.g., catechins,theaflavins, thearubigens

Epidemiological studies show inconsistentevidence for the association between teaconsumption and reduced risk of cancer

Preclinically, tea frequently inhibits colon,esophageal, liver, lung and skin tumorigenesis

Tea and tea polyphenols may have multiple sites ofaction