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Tea and Tea Polyphenols in Cancer Prevention Sharon Ross, PhD, MPH rosssha@mail.nih.gov Nutritional Science Research Group, Division of Cancer Prevention HO OH O HO R 1 OR 2 OH Tea ( Camellia sinensis ) Crushed tea leaves Polyphenol oxidase Oxidation, Polymerization Dried

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slide1

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

HO

OH

O

HO

R

1

OR

2

OH

Tea (Camellia sinensis)

Crushed tea leaves

Polyphenol oxidase

Oxidation,

Polymerization

Dried

Tea Leaves

Black Tea

Green Tea

30-40% Catechins

3-6% Caffeine

~310 mg polyphenols

per 6 ounces

3-10% Catechins

2-6% Theaflavins

> 20% Thearubigens

3-6%  Caffeine

~340 mg polyphenols

per 6 ounces

Yang, CS. Personal Communication

increased concentration of catechins following black tea consumption
Increased Concentration of Catechins Following 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

slide4

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).
slide5

Recent Epidemiological Studies of Tea

And Gastric/Stomach Cancer

Country (Tea type)

Study Type

Risk/Association

Reference

Setiawan

2001

Rao 2002

Tsubono

2001

Hoshiyama 2002

Fujino 2002

Sun 2002

Sasazuki 2004

Hoshiyama 2004

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

Prospective

cohort

Prospective

cohort

Prospective

cohort

Nested case-

control

Prospective

cohort

Nested case-

control

Decrease

Decrease

No association

No association*

No association

Decrease

Decrease***

No association

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

effects of tea on human oral precancerous lesions
Effects of Tea on Human Oral Precancerous Lesions
  • A double-blind intervention trial of 59 patients with oral mucosa leukoplakia
  • Twenty-nine 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
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 4-mo period.
  • 143 heavy smokers, aged 18-79 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 8-OHdG (-31%) after 4 mo of drinking decaffeinated green tea (P = 0.002).
  • No change in urinary 8-OHdG was seen among smokers assigned to the black tea group.

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

tea and cancer prevention
Tea and Cancer Prevention

Skin

Liver

Camellia Sinensis

Colon

Oral

Esophagus

Prostate

Mammary

Stomach

Lung

Yang, CS. Personal Communication

results of animal studies with tea
Results of Animal Studies With Tea

Number of Studies

Yang CS. Personal Communication

lung tumorigenesis model in a j mice
Lung Tumorigenesis Model in A/J Mice

Tea given during the initiation stage

NNK

 Tumors

tea

water

-2

0

1

16 weeks

Tea given during the post-initiation stage

NNK

 Tumors

tea

water

-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
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

50

hyperplasia

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.

slide12

Reactive Oxygen Species

O2

OH

H202

X

TEA

Damage DNA,

RNA

Oxidize Proteins

(enzymes, histones)

Oxidize Lipids

Activate Cell

Suicide

Endoplasmic

Reticulum

Mitochondrion

slide13

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

slide14

Activation and Roles of NF-kB in Oncogenesis

Oncoproteins (Her-2/neu, Ras)

Altered cytokine production

EGCG

IKK activation

CK2 induction

Proliferation

(c-myc, cyclin D1, gro

cytokines [IL-2, -6])

nfkb gene amplif., rearrangement

Survival

(Bcl-xL, A1/Bfl-1,

IEX-1L, IAP1, IAP2)

NF-kB

IkB

Mutations in IkB genes

[Proteasome]

IkB

Angiogenesis

(Cox-2, NOS, VEGF)

Co-acting factors

(AP-1, AhR,

c/EBP, p300)

Metastasis

(MMPs, cell adhesion molecules,

cell surface proteases)

NF-kB

DEX

Modifications

(phosphorylation, acetylation)

Sonenshein GE.Personal Communication

tea polyphenol epigallocatechin 3 gallate inhibits dna methyltransferase activity
Tea Polyphenol Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase Activity

Cancer Res. 63(22): 2003

slide16

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 g/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

slide17

2 hours

7 hours

24 hours

UNIQID AND GENE NAME

p value

1

2

3

4

1

2

3

4

1

2

3

4

0.37

0.36

0.42

0.61

0.17

0.25

0.39

0.3

0.14

0.36

0.31

0.5

AI003699 LIM and SH3 protein 1

0.003

0.91

1.32

0.46

0.48

0.4

0.94

0.57

0.46

0.17

0.55

0.37

0.44

AA099134 Hypoxia up-regulated 1

0.005

0.79

0.80

0.46

0.48

0.36

0.51

0.36

0.3

0.32

0.64

0.3

0.35

AA181307 aryl hydrocarbon receptor

0.005

0.57

0.91

0.51

0.46

0.27

0.58

0.48

0.45

0.24

0.44

0.49

0.47

AA520985 rab3 GTPase-activating protein

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

0.74

0.93

0.46

0.64

0.31

0.56

0.44

0.37

0.28

0.52

0.48

0.48

H50344 tight junction protein 1

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

0.65

0.77

0.73

0.72

0.4

0.67

0.62

0.49

0.31

0.52

0.47

0.6

AA053886 SREBP 2

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

1.05

0.84

0.93

1.09

1.04

0.95

0.61

0.69

0.65

0.46

0.47

0.45

AA872383 metallothionein 1E (functional)

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

0.92

0.80

1.00

0.31

0.46

0.74

0.47

0.42

0.44

0.76

0.43

0.49

R45056 Human clone 23721 mRNA sequence

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

Identification of Genes Affected by EGCG Treatment in D3-1 Breast Cancer Cells

24 h samples

Sonenshein GE.Personal Communication

slide18

RT-PCR and Northern Blot Analysis Confirms Affects of EGCG

on Expression of Several Genes

EGCG 24 h

DMSO

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))

TGF (R36467)

  • Genes Regulated by 24 h EGCG
    • BMP6AhR
    • WISP-1CTGF
    • PPARECTS
    • GSTHSP10

PTP3 (AA995560)*

Thrombospondin (AA464532)*

GAPDH

Ring finger protein (AA402960)

RT-PCR

Sonenshein GE.Personal Communication

slide19

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 action