Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice

Cancer Lett. 2016 Feb 1;371(1):71-8. doi: 10.1016/j.canlet.2015.11.010. Epub 2015 Nov 12.

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.

Keywords: PhIP; Prostate carcinogenesis; Tocopherols; mPIN; p-AKT.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Animals
  • Anticarcinogenic Agents / administration & dosage
  • Anticarcinogenic Agents / pharmacology*
  • Cyclooxygenase 2 / metabolism
  • Cytochrome P-450 CYP1A2 / genetics
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Diet*
  • Disease Models, Animal
  • Humans
  • Imidazoles*
  • Ki-67 Antigen / metabolism
  • Male
  • Mice, Transgenic
  • NF-E2-Related Factor 2 / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation
  • Prostatic Intraepithelial Neoplasia / chemically induced
  • Prostatic Intraepithelial Neoplasia / enzymology
  • Prostatic Intraepithelial Neoplasia / genetics
  • Prostatic Intraepithelial Neoplasia / pathology
  • Prostatic Intraepithelial Neoplasia / prevention & control*
  • Prostatic Neoplasms / chemically induced
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / prevention & control*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Tocopherols / administration & dosage
  • Tocopherols / pharmacology*
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Anticarcinogenic Agents
  • Imidazoles
  • Ki-67 Antigen
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • 3-nitrotyrosine
  • Tyrosine
  • 8-Hydroxy-2'-Deoxyguanosine
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • CYP1A2 protein, human
  • Cytochrome P-450 CYP1A2
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Deoxyguanosine
  • Tocopherols