Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis

J Natl Cancer Inst. 2005 Nov 16;97(22):1695-9. doi: 10.1093/jnci/dji377.

Abstract

Tobacco carcinogens induce Akt activation and lung carcinogenesis. We previously demonstrated that deguelin, a natural plant product, specifically inhibits the proliferation of premalignant and malignant human bronchial epithelial cells by blocking Akt activation. To evaluate the ability of deguelin to block tobacco carcinogen-induced lung tumorigenesis, we evaluated the in vivo effects of deguelin on Akt activation and lung tumorigenesis in transgenic mice in which Akt expression was induced by tamoxifen and in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Deguelin suppressed Akt activation in vivo, as measured by immunohistochemistry and immunoblotting, and statistically significantly reduced NNK/BaP-induced lung tumor multiplicity, volume, and load in A/J mice, as monitored by microcomputed tomography image analysis, with no detectable toxicity. These results indicate that deguelin warrants consideration as a chemopreventive agent for early-stage lung carcinogenesis in a clinical lung cancer chemoprevention trial.

Publication types

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

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Benzo(a)pyrene
  • Bronchial Neoplasms / drug therapy
  • Bronchial Neoplasms / enzymology
  • Bronchial Neoplasms / etiology
  • Bronchial Neoplasms / prevention & control*
  • Carcinogens
  • Cell Transformation, Neoplastic / drug effects
  • Enzyme Activation / drug effects
  • Immunoblotting
  • Immunohistochemistry
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / etiology
  • Lung Neoplasms / prevention & control*
  • Mice
  • Mice, Transgenic
  • Nitrosamines
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / enzymology
  • Respiratory Mucosa / pathology
  • Rotenone / analogs & derivatives*
  • Rotenone / pharmacology
  • Smoking / adverse effects
  • Tobacco Smoke Pollution / adverse effects*

Substances

  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • Carcinogens
  • Nitrosamines
  • Tobacco Smoke Pollution
  • Rotenone
  • Benzo(a)pyrene
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Proto-Oncogene Proteins c-akt
  • deguelin