tea and tea polyphenols in cancer prevention
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Tea and Tea Polyphenols in Cancer Prevention
Sharon Ross, PhD, [email protected]
Nutritional Science Research Group,Division of Cancer Prevention
Tea (Camellia sinensis)
Green Tea Black 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 polyphenolsper 6 ounces
Dried
Tea Leaves
Crushed tea leaves
Polyphenol oxidase
Oxidation,Polymerization
O
OR 2
HO
OH
OH
R1
HO
Yang, CS. Personal Communication
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
Epidemiological Studies ofTea 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 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
Prospective cohort
Nested case-control
Decrease
Decrease
No association
No association*
No association
Decrease
Decrease***
No association
Setiawan2001
Rao 2002
Tsubono2001
Hoshiyama 2002
Fujino 2002
Sun 2002
Sasazuki 2004
Hoshiyama 2004
* Deaths **Urinary polyphenols/metabolites ***distal gastric, women only
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
• 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
Camellia Sinensis
Yang, CS. Personal Communication
SkinLiver
Colon
Oral
Esophagus
LungStomach
ProstateMammary
Results of Animal Studies With Tea
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
Number of Studies
Yang CS. Personal Communication
Lung Tumorigenesis Model in A/J Mice
Yang CS. Personal Communication
Tea given during the initiation stage
-2 0 16 weekstea water
1
NNK
Tea given during the post-initiation stage
water tea0 16 weeks1
NNK
Tea given after lung adenoma formation
water tea0 16 weeks 52 weeks
NNK
-2
Tumors
Tumors
Tumors
The TRAMP MouseTransgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal modelthat 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
030 Weeks2418126
metastasis
neoplasia
hyperplasia
puberty
TRAMP: A Model for Prostate Cancer Progression
Greenberg et al. (Found on TRAMP webpage)
Reactive Oxygen Species
EndoplasmicReticulum
Mitochondrion
O2 H202 OH
Damage DNA, RNA Oxidize Proteins (enzymes, histones) Oxidize Lipids Activate Cell Suicide
TEAX
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
NF-B
Metastasis(MMPs, cell adhesion
molecules, 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
IB
IB
Activation and Roles of NF-Activation and Roles of NF-B in OncogenesisB in Oncogenesis
Altered cytokine production
NF-B
nfkb gene amplif., rearrangement
Survival(Bcl-xL, A1/Bfl-1,
IEX-1L, IAP1, IAP2)Mutations in IB genes
Co-acting factors(AP-1, AhR, c/EBP, p300)
Modifications (phosphorylation,
acetylation)
EGCG
[Proteasome]
DEX
Sonenshein GE. Personal Communication
Tea Polyphenol Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase Activity
Cancer Res. 63(22): 2003
• 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
Microarray Analysis to Identify Genes Responding to EGCG Treatment in Breast
Cancer Cells
Sonenshein GE. Personal Communication
1 2 3 4 1 2 3 40.37 0.36 0.42 0.61 0.17 0.25 0.39 0.30.91 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 0.30.57 0.91 0.51 0.46 0.27 0.58 0.48 0.450.70 0.90 1.01 0.85 0.41 0.93 0.52 0.480.74 0.93 0.46 0.64 0.31 0.56 0.44 0.370.95 1.37 0.56 0.69 0.2 0.55 0.26 0.230.65 0.77 0.73 0.72 0.4 0.67 0.62 0.490.57 0.67 1.51 0.01 0.09 0.46 0.13 0.111.05 0.84 0.93 1.09 1.04 0.95 0.61 0.690.70 1.02 0.36 0.59 0.17 0.6 0.25 0.210.92 0.80 1.00 0.31 0.46 0.74 0.47 0.420.85 0.95 0.57 0.53 0.5 0.84 0.52 0.450.97 1.13 0.49 0.43 0.43 0.85 0.45 0.370.87 1.08 0.49 0.84 0.55 0.91 0.65 0.50.89 1.00 0.35 0.37 0.43 0.82 0.52 0.460.87 1.06 0.51 0.49 0.36 0.81 0.66 0.470.92 0.85 0.57 0.59 0.43 0.72 0.52 0.430.87 0.87 0.34 0.53 0.48 0.75 0.47 0.440.79 0.91 1.42 2.03 0.39 0.84 0.56 0.52.31 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 2.361.25 1.43 1.62 1.43 2.08 1.88 2.17 2.221.26 1.44 1.37 2.14 1.88 2.01 2.02 2.61.21 1.24 1.08 1.45 1.93 1.53 1.6 1.561.32 1.75 0.94 1.22 1.5 2.3 0.71 0.78
2 hours 7 hours1 2 3 4
0.14 0.36 0.31 0.5 0.003
0.17 0.55 0.37 0.44 0.005
0.32 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 0.148
1.7 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 value24 hoursUNIQID AND GENE NAME
AI003699 LIM and SH3 protein 1 AA099134 Hypoxia up-regulated 1 AA181307 aryl hydrocarbon receptorAA520985 rab3 GTPase-activating proteinAA488674 myeloid cell leukemia sequence 1 H50344 tight junction protein 1 AA464532 thrombospondin 1a2AA053886 SREBP 2AA995560 protein tyrosine phosphataseAA872383 metallothionein 1E (functional)AI031571 epithelial cell transforming sequenceR45056 Human clone 23721 mRNA sequenceAA151214 Ras-GTPase activating protein N69204 chromosome segregation 1 W69399 H1 histone family, member 0AI865149 karyopherin alpha 6 R59621 LanC (bacterial lantibiotic synthetase cH92201 nucleosome assembly protein 1-like 4AA773461 chord domain-containing protein 1W46972 solute carrier family 20AA598794 connective tissue growth factorAA916325 aldo-keto reductase family 1,C3AI924357 aldo-keto reductase family 1,C2R93124 aldo-keto reductase family 1,C1AI023541 carbonic anhydrase IXT54298 PPAR(gamma) angiopoietin related
Identification of Genes Affected by EGCG Treatment in D3-1 Identification of Genes Affected by EGCG Treatment in D3-1 Breast Cancer CellsBreast Cancer Cells
24 h samples
Sonenshein GE. Personal Communication
AhR (AA181307)*
CSE-1 (N69204 )*
CTGF (AA598794)*
Heat shock protein 10kD (AA448396)
Prefoldin (AI682392)
ECTS (AI031571)*
DMSO
EGCG 24 h
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 EGCGBMP6 AhRWISP-1 CTGFPPAR ECTSGST HSP10
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 action