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

ArticleinCancer Prevention Research 1(7):568-76 · December 2008with2 Reads
DOI: 10.1158/1940-6207.CAPR-08-0064 · Source: PubMed
Abstract
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.
    • "We observed statistically significant reductions in tumorigenicity , as determined by number of lung tumors per mouse, of 88, 75, 53, and 51%, respectively, at the four higher doses, but not at the 1 moL/g diet dose. We also administered I3C (112 moL/g diet) beginning 1 week after the last dose of the carcinogens and observed a significant 74% reduction in lung tumor multiplicity [19]. These studies were then extended to another tumor model in which lung tumors were induced by vinyl carbamate. "
    [Show abstract] [Hide abstract] ABSTRACT: Lee W. Wattenberg, who spent his entire career at the University of Minnesota, was a true pioneer in the field of chemoprevention. This paper is a tribute to his groundbreaking research which uncovered the cancer prevention properties of many dietary compounds, including those discussed here in some detail - indole-3-carbinol and diindolylmethane. These compounds occur as glucosinolate conjugates in cruciferous vegetables and are released when one chews or otherwise macerates the vegetable. They have numerous beneficial effects including the ability to prevent cancer in laboratory animals treated with carcinogens. We review some of the early work on indole-3-carbinol and diindolylmethane which spurred subsequent studies on their efficacy and molecular mechanisms of prevention. We also present unique data on field conditions that affect levels of their glucosinolate precursors in vegetables and on the release of diindolylmethane in people who consume cruciferous vegetables. This article is protected by copyright. All rights reserved.
    Full-text · Article · Feb 2016
    • "Ferrets Maintaining normal tissue level of RA, inhibiting phosphorylation of JNK and ERK [132] Indole-3-carbinol A/J mice Inhibition of cell proliferation and induction of apoptosis [133,134] p-XSC F344 rats Inhibiting the formation of DNA adducts [135] Aspirin and phenethyl isothiocyanate "
    [Show abstract] [Hide abstract] ABSTRACT: Tobacco usage is a major risk factor in the development, progression, and outcomes for lung cancer. Of the carcinogens associated with lung cancer, tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is among the most potent ones. The oncogenic mechanisms of NNK are not entirely understood, hindering the development of effective strategies for preventing and treating smoking-associated lung cancers. Here, we introduce the NNK-induced lung cancer animal models in different species and its potential mechanisms. Finally, we summarize several chemopreventive agents developed from these animal models. © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
    Article · Jul 2015
    • "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]. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Nov 2013
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