title: Polymeric black tea polyphenols inhibit mouse skin chemical carcinogenesis by decreasing cell proliferation.
abstract: OBJECTIVE
  The aim of this study was to investigate the antitumour promoting effects and possible mechanisms of action of the most abundant polymeric black tea polyphenols (PBPs 1-5) or thearubigins, in vivo.
  
  
  METHODS
  Effect of PBP pre-treatments on 12-O-tetradecanoylphorbol-13-acetate (TPA) promoted skin papillomas was studied in 7,12-dimethylbenz(a)anthracene initiated mice over 40 weeks. Cell proliferation and apoptosis, in epidermis of the skin, were measured using appropriate immunohistochemical staining. Mitogen-activated protein kinase signalling studies were conducted with Western blot analysis at 10, 20, 30 and 40 weeks of promotion.
  
  
  RESULTS
  Pre-treatments with PBP fractions differentially altered latency, multiplicity and incidence of skin papillomas as compared to TPA treatments thereby exhibiting antipromoting effects. Most PBP fractions decreased TPA-induced cell proliferation by decreasing activation of signalling kinases (c-Jun N-terminal protein kinase, extracellular signal-regulated protein kinase, p38 protein kinase and Akt), transcription factors (activator protein-1 and nuclear factor kappa B) and inflammatory protein (cyclooxygenase 2). TPA-induced epidermal cell apoptosis was also decreased by pre-treatment with most PBP fractions. Higher levels of p53 and p21 in skin cells pre-treated with PBP fractions followed by TPA treatment as compared to only TPA-treated animals suggested possible activation of a cell cycle checkpoint.
  
  
  CONCLUSIONS
  PBP-2 was observed to be the most potent polymeric polyphenol fraction and PBP-4 and PBP-5 showed only marginal activity, whereas PBP-1 and PBP-3 displayed intermediate efficacies. In conclusion, the protective effects of PBP fractions could be attributed to inhibition of TPA-induced cellular proliferation.
authors.affiliation: Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Krishnan
authors.forename: A
authors.initials: A
authors.lastname: Ramchandani
authors.forename: G
authors.initials: G
authors.lastname: Maru
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D059808:Polyphenols; D011230:Precancerous Conditions / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000473:pathology*; D013662:Tea / Q000737:chemistry*; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D005419:Flavonoids; D018836:Inflammation Mediators; D010636:Phenols; D011108:Polymers; D059808:Polyphenols; D047428:Protein Kinase Inhibitors; D013662:Tea; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D051057:Proto-Oncogene Proteins c-akt; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate