Indole-3-carbinol Inhibits 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Plus Benzo(a)pyrene–Induced Lung Tumorigenesis in A/J Mice and Modulates Carcinogen-Induced Alterations in Protein Levels

Abstract

We tested the chemopreventive efficacy of indole-3-carbinol (I3C), a constituent of Brassica vegetables, and its major condensation product, 3,3 ¶-diindolylmethane (DIM), against lung tumorigenesis induced by a mixture of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP) in A/J mice. The mixture of NNK plus BaP (2 Mmol each) was administered by gavage as eight weekly doses, whereas I3C (112 Mmol/g diet) and DIM (2 and 30 Mmol/g diet in experiments 1 and 2, respectively) were given in the diet for 23 weeks beginning at 50% of carcinogen treatment. I3C reduced NNK plus BaP-induced tumor multiplicity by 78% in experiment 1 and 86% in experiment 2; the respective reductions in tumor multiplicity by DIM were 5% and 66%. Using a quantitative proteomics method, isobaric tags for relative and absolute quantitation (iTRAQ) coupled with mass spectrometry, we identified and quantified at least 250 proteins in lung tissues. Of these proteins, nine showed differences in relative abundance in lung tissues of carcinogen-treated versus untreated mice: fatty acid synthase, transketolase, pulmonary surfactant-associated protein C (SP-C), L-plastin, annexin A1, and haptoglobin increased, whereas transferrin, A-1-antitrypsin, and apolipoprotein A-1 decreased. Supplementation of the diet of carcinogen-treated mice with I3C reduced the level of SP-C, L-plastin, annexin A1, and haptoglobin to that of untreated controls. These results were verified using immunoblotting. We show here that tumor-associated signature proteins are increased during NNK plus BaP-induced lung carcinogenesis, and I3C inhibits this effect, suggesting that the lung tumor chemopreventive activity of I3C might be related to modulation of carcinogen-induced alterations in protein levels.

Proteomic Profiling of Potential Molecular Targets of Methyl-Selenium Compounds in the Transgenic Adenocarcinoma of Mouse Prostate Model

“…4B (data not shown). These data were in excellent agreement with those of Kassie et al (23), showing ±20% range encompassing the random variations of selfpaired lung tissue samples. Therefore, we consider tag ratios within 0.8 to 1.2 not different in protein abundance from that of the reference group.…”

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

“…The second approach is exposing the A/J mouse to selected model compounds from cigarette smoke, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (B[a]P), two carcinogens widely accepted as major causes of lung cancer in smokers (43). Both models have been widely used to search for chemopreventive agents against lung tumorigenesis (42,(45)(46)(47)(48)(49)(50).…”

“…In this study, we evaluate the chemopreventive activity of kava against lung tumorigenesis induced by a mixture of NNK plus B[a]P in the A/J mouse model (47). To gain preliminary insight into the mechanism of the chemopreventive activity of kava, we evaluated kava with three treatment regimens (i.e., administered during carcinogen treatment, postcarcinogen treatment, or throughout the experiment).…”

Proteomic analysis of differentially expressed serum proteins in lung cancer

“…Most recently transferrin and its receptor have been tested to diminish tumor cells by using the receptor to attract antibodies. NNK treatment has been demonstrated to enhance the expression of fatty acid synthase, transketolase, pulmonary surfactant-associated protein C, L-plastin, annexin A1, and haptoglobin, while the expression of transferrin, α-1-antitrypsin, and apolipoprotein A-1 was decreased [29].…”