title: Inhibition of adenoma progression to adenocarcinoma in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis model in A/J mice by tea polyphenols and caffeine.
abstract: The present study investigated the inhibitory effects of Polyphenon E [a standardized green tea polyphenol preparation containing 65% (-)-epigallocatechin-3-gallate] and caffeine on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor progression from adenoma to adenocarcinoma. Female A/J mice were treated with a single dose of NNK (103 mg/kg body weight, i.p.) and kept for 20 weeks for the mice to develop lung adenomas. The mice were then given a solution of 0.5% Polyphenon E or 0.044% caffeine as the sole source of drinking fluid until week 52. Both treatments significantly decreased the number of visible lung tumors. Histopathologic analysis indicated that Polyphenon E administration significantly reduced the incidence (by 52%) and multiplicity (by 63%) of lung adenocarcinoma. Caffeine also showed marginal inhibitory effects in incidence and multiplicity of adenocarcinoma (by 48% and 49%, respectively). Markers of cell proliferation, apoptosis, and related cell signaling were studied by immunohistochemistry, and the labeling index and staining intensity were quantified by the Image-Pro system. Polyphenon E and caffeine treatment inhibited cell proliferation (by 57% and 50%, respectively) in adenocarcinomas, enhanced apoptosis in adenocarcinomas (by 2.6- and 4-fold, respectively) and adenomas (both by 2.5-fold), and lowered levels of c-Jun and extracellular signal-regulated kinase (Erk) 1/2 phosphorylation. In the normal lung tissues, neither agent had a significant effect on cell proliferation or apoptosis. The results show that tea polyphenols (and perhaps caffeine) inhibit the progression of NNK-induced lung adenoma to adenocarcinoma. This effect is closely associated with decreased cell proliferation, enhanced apoptosis, and lowered levels of c-Jun and Erk1/2 phosphorylation.
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 16445-0687, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.forename: Guangyu
authors.initials: G
authors.lastname: Yang
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Reuhl
authors.forename: Xingpei
authors.initials: X
authors.lastname: Hao
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000236:Adenoma / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000627:therapeutic use*; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000627:therapeutic use*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009602:Nitrosamines / Q000008:administration & dosage / Q000633:toxicity; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D059808:Polyphenols; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013662:Tea / Q000737:chemistry*; D013997:Time Factors
chemical_list: D005419:Flavonoids; D009602:Nitrosamines; D010636:Phenols; D059808:Polyphenols; D018809:Proliferating Cell Nuclear Antigen; D013662:Tea; D002110:Caffeine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D002392:Catechin; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C472086:polyphenon E