title: Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice.
abstract: Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer.
authors.affiliation: Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA; Joint Graduate Program in Toxicology, Piscataway, NJ, USA.
authors.forename: Jayson X
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
authors.forename: Guangxun
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA.
authors.forename: Mao-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Reuhl
authors.affiliation: Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA; Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
authors.affiliation: Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Maarten C
authors.initials: MC
authors.lastname: Bosland
authors.affiliation: Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Piscataway, NJ, USA; Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA. Electronic address: csyang@pharmacy.rutgers.edu.
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D019048:Prostatic Intraepithelial Neoplasia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D024505:Tocopherols / Q000008:administration & dosage / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D007093:Imidazoles; D019394:Ki-67 Antigen; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D003849:Deoxyguanosine; D024505:Tocopherols
keywords: PhIP; Prostate carcinogenesis; Tocopherols; mPIN; p-AKT