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

Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA.
Cancer Prevention Research (Impact Factor: 4.44). 12/2008; 1(7):568-76. DOI: 10.1158/1940-6207.CAPR-08-0064
Source: PubMed


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 micromol/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 micromol 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 micromol/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 micromol I3C/g diet), were significant (P < 0.001). Similarly, administration of I3C (112 micromol/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.

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    • "The I3C content in these vegetables ranges approximately between 15 and 500 mg/kg of fresh weight [29]. These vegetables contain glucobrassicin, an indolylmethyl glucosinolate, which is a common form of I3C, however its molecular weight is nearly three times higher than the pure substance [30] [31]. The estimated per capita intake of glucobrassicin in the United States is 8.1 mg/d while that in the United Kingdom is 19.4 mg/d [32]. "
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    ABSTRACT: Bisphenol A (BPA) is a chemical that has been investigated for it potential to cause prostate diseases. In this study, pregnant Sprague-Dawley rats were treated with 25 or 250μg/kg BPA from gestational day (GD) 10 to GD21 with or without concurrent indole-3-carbinol (I3C) feeding. I3C is a phytochemical, and it affords chemoprotection against many types of neoplasia. Male F1 rats from different litters were euthanized on post-natal day (PND) 21 and PND180. BPA-treated groups showed a significant increase in histopathological lesions, but I3C feeding reversed many of these changes, mainly at PND180. Maternal I3C feeding increased prostate epithelial apoptosis in the BPA-treated groups and across age groups. Furthermore, I3C induced partial normalization of the prostate histoarchitecture. The results pointed to a protective effect of maternal I3C feeding during pregnancy in the BPA-exposed male offspring, thereby indicating reduction in the harmful effects of gestational BPA imprinting on the prostate.
    Reproductive Toxicology 11/2013; 43. DOI:10.1016/j.reprotox.2013.11.001 · 3.23 Impact Factor
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    • "Moreover in this model, various compounds have shown their positive effects during initiation and post initiation (Wattenberg et al., 2000). [B(a)P] a most potent lung tobacco carcinogen have been strongly implicated in the etiology of smoking induced lung cancer patients (Kassie et al., 2008). "
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    ABSTRACT: The aim of this study is to evaluate the antitumor effect of indirubin-3-monoxime and its mode of action in benzo(α)pyrene [B(α)P] induced lung cancer in A/J mice. Light microscopic examination of lung sections of [B(α)P] induced lung cancer mice revealed the presence of adenocarcinoma characterized by extensive proliferation of alveolar epithelium and loss of alveolar spaces. The control lung tissue showed a normal architecture with clear alveolar spaces. Interestingly the indirubin-3-monoxime treated groups showed the reduced adenocarcinoma with appearance of alveolar spaces. Transmission Electron Microscopic (TEM) studies of lung sections of [B(α)P] induced lung cancer mice showed the presence of phaemorphic cells with dense granules and increased mitochondria. The lung sections of mice treated with indirubin-3-monoxime showed the presence of shrunken, fragmented, and condensed nuclei implying apoptosis. The effects were dose dependent and prominent in 10 mg/kg/5 d/week groups suggesting the therapeutic role of indirubin analogue against this deadly human malignancy. Here, our results indicate that indirubin-3-monoxime brings antitumor effect against [B(α)P] induced lung cancer by its apoptotic action in A/J mice.
    Microscopy Research and Technique 10/2010; 73(11):1053-8. DOI:10.1002/jemt.20832 · 1.15 Impact Factor
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    • "Mouse models for human lung cancer have proven to be valuable tools for understanding the basic tumor biology as well as for the development and validation of new approaches to cancer prevention and therapy [6]. While very few mouse strains exhibit spontaneous lung tumor development, an increasing number of models has been developed either by treatment with tobacco carcinogens [7], [8], [9], [10], [11], [12] or tobacco (or cigarette) smoke [13], [14], [15] as well as by introduction of mutant oncogenes or transgenes such as mutant Kras [16] or epidermal growth factor receptor (Egfr) [17], [18] or a combination of transgenes and carcinogens [19]. We have previously shown that mice with deletion of both alleles of the Gprc5a gene develop spontaneous lung adenomas and adenocarcinomas between the ages 12 and 24 months indicating that this gene is a mouse lung-specific tumor suppressor [20]. "
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    ABSTRACT: Improved understanding of lung cancer development and progression, including insights from studies of animal models, are needed to combat this fatal disease. Previously, we found that mice with a knockout (KO) of G-protein coupled receptor 5A (Gprc5a) develop lung tumors after a long latent period (12 to 24 months). To determine whether a tobacco carcinogen will enhance tumorigenesis in this model, we administered 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) i.p. to 2-months old Gprc5a-KO mice and sacrificed groups (n=5) of mice at 6, 9, 12, and 18 months later. Compared to control Gprc5a-KO mice, NNK-treated mice developed lung tumors at least 6 months earlier, exhibited 2- to 4-fold increased tumor incidence and multiplicity, and showed a dramatic increase in lesion size. A gene expression signature, NNK-ADC, of differentially expressed genes derived by transcriptome analysis of epithelial cell lines from normal lungs of Gprc5a-KO mice and from NNK-induced adenocarcinoma was highly similar to differential expression patterns observed between normal and tumorigenic human lung cells. The NNK-ADC expression signature also separated both mouse and human adenocarcinomas from adjacent normal lung tissues based on publicly available microarray datasets. A key feature of the signature, up-regulation of Ube2c, Mcm2, and Fen1, was validated in mouse normal lung and adenocarcinoma tissues and cells by immunohistochemistry and western blotting, respectively. Our findings demonstrate that lung tumorigenesis in the Gprc5a-KO mouse model is augmented by NNK and that gene expression changes induced by tobacco carcinogen(s) may be conserved between mouse and human lung epithelial cells. Further experimentation to prove the reliability of the Gprc5a knockout mouse model for the study of tobacco-induced lung carcinogenesis is warranted.
    PLoS ONE 07/2010; 5(7):e11847. DOI:10.1371/journal.pone.0011847 · 3.23 Impact Factor
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