RT Journal Article
SR Electronic
T1 Dose-Dependent Inhibition of Tobacco Smoke Carcinogen–Induced Lung Tumorigenesis in A/J Mice by Indole-3-Carbinol
JF Cancer Prevention Research
JO Cancer Prev Res (Phila)
FD American Association for Cancer Research
SP 568
OP 576
DO 10.1158/1940-6207.CAPR-08-0064
VO 1
IS 7
A1 Kassie, Fekadu
A1 Matise, Ilze
A1 Negia, Mesfin
A1 Upadhyaya, Pramod
A1 Hecht, Stephen S.
YR 2008
UL http://cancerpreventionresearch.aacrjournals.org/content/1/7/568.abstract
AB 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.