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Tea and Tea Polyphenols in Cancer Prevention - PowerPoint PPT Presentation

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Tea and Tea Polyphenols in Cancer Prevention

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  1. Tea and Tea Polyphenols in Cancer Prevention Sharon Ross, PhD, MPH rosssha@mail.nih.gov Nutritional Science Research Group, Division of Cancer Prevention

  2. 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

  3. 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

  4. 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).

  5. 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

  6. 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.

  7. 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.

  8. Tea and Cancer Prevention Skin Liver Camellia Sinensis Colon Oral Esophagus Prostate Mammary Stomach Lung Yang, CS. Personal Communication

  9. Results of Animal Studies With Tea Number of Studies Yang CS. Personal Communication

  10. 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

  11. 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.

  12. Reactive Oxygen Species O2 OH H202 X TEA Damage DNA, RNA Oxidize Proteins (enzymes, histones) Oxidize Lipids Activate Cell Suicide Endoplasmic Reticulum Mitochondrion

  13. 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

  14. 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

  15. Tea Polyphenol Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase Activity Cancer Res. 63(22): 2003

  16. 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

  17. 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

  18. 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

  19. 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