Tea and Tea Polyphenols in

Cancer Prevention

Sharon Ross, PhD, MPH

rosssha@mail.nih.gov
Nutritional Science Research Group,
Division of Cancer Prevention
   
 Tea (Camellia sinensis)
Crushed tea leaves

Polyphenol oxidase

Oxidation,
r i ed es Polymerization
D av
L e
a
Te
HO

Green Tea OH
Black Tea
30-40% Catechins HO O
R1
3-10% Catechins
3-6% Caffeine 2-6% Theaflavins
~310 mg polyphenols OR 2 > 20% Thearubigens
per 6 ounces 3-6% Caffeine
OH
    ~340 mg polyphenols
Yang, CS. Personal Communication per 6 ounces
 Increased Concentration of Catechins
Following Black Tea Consumption

Plasma Levels Urinary Excretion Fecal Excretion

(nmol/L) (nmol/h) (mol)

Epigallocatechin

Epicatechin

Epigallocatechin
Gallate

Epicatechin Gallate

   
Warden BA, et al. J Nutr 2001;131:1731-1737
 Epidemiological Studies of
Tea and Cancer
Ecologic, case-control and cohort studies
have been performed.
Many performed as secondary analyses.
Little information on precision of tea intake.
Several cancer sites investigated: bladder and
urinary tract, breast, colon and rectum,
esophagus, kidney, liver, lung, nasopharynx,
pancreas, stomach and uterus (with mixed
results).
   
 Recent Epidemiological Studies of Tea
And Gastric/Stomach Cancer
Country (Tea type) Study Type Risk/Association Reference

China Case- Decrease Setiawan

(green tea) control 2001
India Case- Decrease Rao 2002
(unknown) control
Tsubono
Japan Prospective No association 2001
(green tea) cohort
Japan Prospective
(green tea) cohort No association* Hoshiyama 2002
Japan Prospective No association Fujino 2002
(green tea) cohort

China Nested case-

control Decrease Sun 2002
(unknown**)

Japan Prospective
(green tea) cohort Decrease*** Sasazuki 2004

Japan Nested case- Hoshiyama 2004

(green tea) control
   
* Deaths **Urinary polyphenols/metabolites ***distal gastric, women only
Effects of Tea on Human Oral Precancerous 
Lesions
• A double­blind intervention trial of 59 patients with 
oral mucosa leukoplakia
• Twenty­nine patients received tea administered 
orally and topically; 30 patients received placebo 
treatment
• After 6 months, the size of oral lesion decreased in 
38% of the treated group and in 10% of the placebo 
group;  the lesion increased in 3.4% of the treated 
group and in 6.7% of the placebo group
• The incidence of micronucleated exfoliated oral 
mucosa cells in the treated group (0.54%) was lower 
than the control group (1.13%)
Li et al. Proc. Soc. Expr. Biol. Med. 220: 218-224, 1999.
   
Effect of Increased Tea Consumption on 
Oxidative DNA Damage Among Smokers 
• A phase II randomized controlled tea intervention trial (4 cups/d) of 
decaffeinated green or black tea among smokers over a 4­mo period. 
• 143 heavy smokers, aged 18­79 y, were randomized to drink either 
green or black tea or water. 
• Plasma and urinary levels of catechins rose significantly in the green 
tea group compared with the other two groups.
• Significant decrease in urinary 8­OHdG (­31%) after 4 mo of drinking 
decaffeinated green tea (P = 0.002). 
• No change in urinary 8­OHdG was seen among smokers assigned to the 
black tea group. 

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

   
 Tea and Cancer Prevention

Liver Skin

Colon Camellia Sinensis

Oral
Esophagus
Prostate
Mammary
Stomach Lung
   
Yang, CS. Personal Communication
 Results of Animal Studies With Tea
Number of Studies
Organ Site Protective Not Protective
Skin 13 5
Oral 2 0
Esophagus 3 1
(Fore)stomach 5 0
Intestine/Colon 10 3
Liver 7 0
Bladder  1 0
Prostate 1 0
Breast 6 3

 
Lung 10
 
1
Yang CS. Personal Communication
Lung Tumorigenesis Model in A/J Mice

NNK Tea given during the initiation stage

↓ Tumors
tea water
-2 0 1 16 weeks

NNK Tea given during the post-initiation stage

↓ Tumors
water tea
-2 0 1 16 weeks
NNK
Tea given after lung adenoma formation
↓ Tumors
water tea
0 16 weeks 52 weeks

   
Yang CS. Personal Communication
 The TRAMP Mouse
Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model
that express the oncogene SV40 T antigen specifically in the epithelium of
the prostate.

TRAMP: A Model for Prostate Cancer Progression

metastasis
100
neoplasia

hyperplasia 50

puberty
0
6 12 18 24 30 Weeks
Greenberg et al. (Found on TRAMP webpage)

Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of

green tea polyphenols. Gupta et al. PNAS 2001;98:10350-10355.
   
 Reactive Oxygen Species

O2 H 20 2 OH
X TEA

Damage DNA,
RNA
Oxidize Proteins
(enzymes, histones)
Endoplasmic Oxidize Lipids
Reticulum Activate Cell
Mitochondrion Suicide

   
 Biological Activities of Tea
Polyphenols

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

   
Activation and Roles of NF-κ B in Oncogenesis
Oncoproteins (Her-2/neu, Ras) Altered cytokine production
EGCG

nfkb gene amplif., IKK activation Proliferation

rearrangement CK2 induction (c-myc, cyclin D1, gro
cytokines [IL-2, -6])

NF-κB Survival
IκB (Bcl-xL, A1/Bfl-1,
Mutations in IκB genes [Proteasome] IEX-1L, IAP1, IAP2)
IκB
Angiogenesis
(Cox-2, NOS, VEGF)
Co-acting factors
(AP-1, AhR, Metastasis
c/EBP, p300) NF-κB (MMPs, cell adhesion
molecules,
cell surface proteases)

Modifications DEX
 
(phosphorylation,  
acetylation) Sonenshein GE. Personal Communication
Tea Polyphenol Epigallocatechin­3­Gallate 
Inhibits DNA Methyltransferase Activity

   
Cancer Res. 63(22): 2003
 Microarray Analysis to Identify Genes
Responding to EGCG Treatment in Breast
Cancer Cells

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

epithelial cells
• Human chip microarray (7,500 genes developed by
GenomicTree, Inc, Korea)
• Dose: 60 µg/ml EGCG (dissolved in DMSO) or
equivalent volume of DMSO, as control
• Time points: 2, 7, and 24 hrs
• Experiment performed twice, each time in duplicate

  Sonenshein GE. Personal Communication

 
 Identification of Genes Affected by EGCG Treatment in D3-1
Breast Cancer Cells
UNIQID AND GENE NAME 2 hours 7 hours 24 hours
1 2 3 4 1 2 3 4 1 2 3 4 p value
AI003699 LIM and SH3 protein 1 0.37 0.36 0.42 0.61 0.17 0.25 0.39 0.3 0.14 0.36 0.31 0.5 0.003
AA099134 Hypoxia up-regulated 1 0.91 1.32 0.46 0.48 0.4 0.94 0.57 0.46 0.17 0.55 0.37 0.44 0.005
AA181307 aryl hydrocarbon receptor 0.79 0.80 0.46 0.48 0.36 0.51 0.36 0.3 0.32 0.64 0.3 0.35 0.005
AA520985 rab3 GTPase-activating protein 0.57 0.91 0.51 0.46 0.27 0.58 0.48 0.45 0.24 0.44 0.49 0.47 0.002
AA488674 myeloid cell leukemia sequence 1 0.70 0.90 1.01 0.85 0.41 0.93 0.52 0.48 0.33 0.62 0.32 0.45 0.004
H50344 tight junction protein 1 0.74 0.93 0.46 0.64 0.31 0.56 0.44 0.37 0.28 0.52 0.48 0.48 0.002
AA464532 thrombospondin 1a2 0.95 1.37 0.56 0.69 0.2 0.55 0.26 0.23 0.28 0.73 0.39 0.45 0.011
AA053886 SREBP 2 0.65 0.77 0.73 0.72 0.4 0.67 0.62 0.49 0.31 0.52 0.47 0.6 0.003
AA995560 protein tyrosine phosphatase 0.57 0.67 1.51 0.01 0.09 0.46 0.13 0.11 0.08 0.47 0.4 1 0.075
AA872383 metallothionein 1E (functional) 1.05 0.84 0.93 1.09 1.04 0.95 0.61 0.69 0.65 0.46 0.47 0.45 0.002
AI031571 epithelial cell transforming sequence 0.70 1.02 0.36 0.59 0.17 0.6 0.25 0.21 0.2 0.63 0.28 1 0.082
R45056 Human clone 23721 mRNA sequence 0.92 0.80 1.00 0.31 0.46 0.74 0.47 0.42 0.44 0.76 0.43 0.49 0.009
AA151214 Ras-GTPase activating protein 0.85 0.95 0.57 0.53 0.5 0.84 0.52 0.45 0.4 0.79 0.43 0.52 0.014
N69204 chromosome segregation 1 0.97 1.13 0.49 0.43 0.43 0.85 0.45 0.37 0.37 0.83 0.45 0.5 0.020
W69399 H1 histone family, member 0 0.87 1.08 0.49 0.84 0.55 0.91 0.65 0.5 0.36 1.02 0.38 0.43 0.065
AI865149 karyopherin alpha 6 0.89 1.00 0.35 0.37 0.43 0.82 0.52 0.46 0.4 0.77 0.49 0.57 0.011
R59621 LanC (bacterial lantibiotic synthetase c 0.87 1.06 0.51 0.49 0.36 0.81 0.66 0.47 0.39 0.85 0.51 0.55 0.022
H92201 nucleosome assembly protein 1-like 4 0.92 0.85 0.57 0.59 0.43 0.72 0.52 0.43 0.5 0.73 0.57 0.65 0.004
AA773461 chord domain-containing protein 1 0.87 0.87 0.34 0.53 0.48 0.75 0.47 0.44 0.94 0.75 0.67 0.63 0.035
W46972 solute carrier family 20 0.79 0.91 1.42 2.03 0.39 0.84 0.56 0.5 0.71 0.83 0.72 0.81 0.005
AA598794 connective tissue growth factor 2.31 2.12 0.49 0.53 0.75 0.91 1 0.5 1.03 0.91 0.54 0.6 0.148
AA916325 aldo-keto reductase family 1,C3 1.31 1.51 0.95 1.00 1.9 2.05 2.43 2.36 1.7 1.51 1.39 1.37 0.007
AI924357 aldo-keto reductase family 1,C2 1.25 1.43 1.62 1.43 2.08 1.88 2.17 2.22 1.84 1.53 1.47 1.44 0.008
R93124 aldo-keto reductase family 1,C1 1.26 1.44 1.37 2.14 1.88 2.01 2.02 2.6 1.82 1.56 1.77 1.75 0.001
AI023541 carbonic anhydrase IX 1.21 1.24 1.08 1.45 1.93 1.53 1.6 1.56 2.11 2.69 2.11 2.08 0.003
T54298 PPAR(gamma) angiopoietin related 1.32 1.75 0.94 1.22 1.5 2.3 0.71 0.78 5.27 2.31 2.22 2.96 0.054
24 h samples

   
Sonenshein GE. Personal Communication
RT-PCR and Northern Blot Analysis Confirms Affects of EGCG
on Expression of Several Genes
h
24
SO CG
M
D EG
CSE-1 (N69204 )*
AhR (AA181307)* AhR (AA181307)
CTGF (AA598794)*
Heat shock protein 10kD (AA448396)
28S
Prefoldin (AI682392)
18S
ECTS (AI031571)*
Angiopoietin (T54298)*
Northern
WISP-1 (AI473336)
BMP6 (AA424833)
GST (A4(aa152374))
TGFβ (R36467)
Genes Regulated by 24 h EGCG
PTP3 (AA995560)* BMP6 AhR
Thrombospondin (AA464532)* WISP-1 CTGF
GAPDH PPARγ ECTS
GST HSP10
Ring finger protein (AA402960)
RT-PCR
   
Sonenshein GE. Personal Communication
 Summary
Green, black and oolong teas are differentiated by
tea manufacturing processes
Teas are rich in polyphenols, e.g., catechins,
theaflavins, thearubigens
Epidemiological studies show inconsistent
evidence for the association between tea
consumption and reduced risk of cancer
Preclinically, tea frequently inhibits colon,
esophageal, liver, lung and skin tumorigenesis
Tea and tea polyphenols may have multiple sites of
 
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