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Dose-Dependent Inhibition of Tobacco Smoke Carcinogen–Induced Lung Tumorigenesis in A/J Mice by Indole-3-Carbinol

Authors' Affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Fekadu Kassie, Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, MN 55455. Phone: 612-626-5143; Fax: 612-626-5135; E-mail: kassi012{at}umn.edu.

Recently, we reported inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo(a)pyrene (BaP)–induced lung tumorigenesis in A/J mice by indole-3-carbinol (I3C; 112 µmol/g diet) administered beginning at 50% in the carcinogen treatment phase. In this study, we examined the dose-dependent and postcarcinogen tumor-inhibitory activities of I3C. A mixture of NNK plus BaP (2 µmol each) administered by gavage as eight biweekly doses caused 21.1 ± 5.2 lung tumors per mouse. Carcinogen-treated mice given diets containing I3C at 1, 10, 30, 71, and 112 µmol/g, beginning at 50% in the carcinogen treatment phase, had 17.9 ± 6.1, 10.4 ± 3.7, 9.8 ± 5.1, 5.2 ± 4.0, and 2.5 ± 2.4 lung tumors per mouse, corresponding to reductions by 15%, 51%, 53%, 75%, and 88%, respectively. All reductions, except at the lowest dose level (1 µmol I3C/g diet), were significant (P < 0.001). Similarly, administration of I3C (112 µmol/g diet) beginning 1 week after the last dose of the carcinogen significantly reduced NNK plus BaP-induced lung tumor multiplicity to 5.6 ± 3.5, corresponding to a reduction by 74%. Analyses of cell proliferation and apoptosis markers revealed that I3C reduced the number of Ki-67–positive cells and expression of proliferating cell nuclear antigen, phospho-Akt, and phospho-BAD and increased cleavage of poly(ADP-ribose) polymerase, suggesting that the lung tumor inhibitory effects of I3C were mediated, at least partly, through inhibition of cell proliferation and induction of apoptosis. These results clearly show the efficacy of I3C in the prevention of tobacco carcinogen–induced lung tumorigenesis in A/J mice and provide a basis for future evaluation of this compound in clinical trials as a chemopreventive agent for current and former smokers.

Key Words: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone • benzo(a)pyrene • lung tumorigenesis • chemoprevention • indole-3-carbinol