Combinations of N-Acetyl-S-(N-2-Phenethylthiocarbamoyl)-L-Cysteine and myo-Inositol Inhibit Tobacco Carcinogen-Induced Lung Adenocarcinoma in Mice
University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA. Cancer Prevention Research
(Impact Factor: 4.44).
10/2008; 1(4):285-97. DOI: 10.1158/1940-6207.CAPR-08-0012
We have previously generated convincing evidence that combinations of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine (PEITC-NAC; 3 micromol/g diet) and myo-inositol (MI; 56 micromol/g diet) were significantly more effective than the individual compounds as inhibitors of tobacco smoke carcinogen-induced lung tumorigenesis in A/J mice. In this study, we further investigated the efficacy of combinations of PEITC-NAC (9 or 15 micromol/g diet) and MI (56 micromol/g diet). Female A/J mice were treated with a mixture of the tobacco smoke carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene by gavage once weekly for 8 weeks. PEITC-NAC plus MI was given in the diet beginning at 1 day after the 4th of eight carcinogen treatments (temporal sequence A) or 1 week after the last carcinogen treatment (temporal sequence B). Regardless of the dose of carcinogen or PEITC-NAC plus MI, or temporal sequence, administration of PEITC-NAC plus MI significantly reduced the multiplicity of gross tumors and, in most instances, adenocarcinoma. PEITC-NAC plus MI was particularly effective against bigger tumors. The observed inhibition of lung tumorigenesis by PEITC-NAC plus MI was attributed, at least partly, to inhibition of cell proliferation and induction of apoptosis. These results clearly show the efficacy of PEITC-NAC plus MI in the prevention of tobacco carcinogen-induced lung adenocarcinoma in A/J mice and provide a basis for future evaluation of PEITC-NAC plus MI in clinical trials as a chemopreventive agent for current and former smokers.
Available from: Alissa K Greenberg
- "In addition, the activity of AKT  and PI3K  has been evaluated in the patients who had received myo-inositol, and regression of dysplasia correlates with decreased PI3K activity. In several studies, oral inositol inhibited lung tumorigensis in mice exposed to carcinogens . It has been effective when given before, during and even immediately after exposure. "
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ABSTRACT: Decreasing the risk of lung cancer, or preventing its development in high-risk individuals, would have a huge impact on public health. The most effective means to decrease lung cancer incidence is to eliminate exposure to carcinogens. However, with recent advances in the understanding of pulmonary carcinogenesis and the identification of intermediate biomarkers, the prospects for the field of chemoprevention research have improved dramatically. Here we review the most recent research in lung cancer chemoprevention-focusing on those agents that have been investigated in human clinical trials. These agents fall into three major categories. First, oxidative stress plays an important role in pulmonary carcinogenesis; and therefore, antioxidants (including vitamins, selenium, green tea extracts, and isothiocyanates) may be particularly effective in preventing the development of lung cancer. Second, inflammation is increasingly accepted as a crucial factor in carcinogenesis, and many investigators have focused on anti-inflammatory agents, such as glucocorticoids, NSAIDs, statins, and PPARγ agonists. Finally, the PI3K/AKT/mTOR pathway is recognized to play a central role in tobacco-induced carcinogenesis, and inhibitors of this pathway, including myoinositol and metformin, are promising agents for lung cancer prevention. Successful chemoprevention will likely require targeting of multiple pathways to carcinogenesis-both to minimize toxicity and maximize efficacy.
Available from: Ilze Matise
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ABSTRACT: In previous studies, we reported that indole-3-carbinol (I3C) and myo-inositol (MI) inhibit lung adenoma induced by tobacco smoke carcinogens in A/J mice. In this paper, we extended our work
and examined the effects of I3C (70 or 30 μmol/g diet) and MI (56 μmol/g diet) against vinyl carbamate (VC)-induced lung adenocarcinoma
by administering the agents from 1 week after the second of two injections of VC until termination of the study at week 18.
The higher dose of I3C decreased multiplicities of tumors on the surface of the lung (26%, P = 0.0005), carcinoma incidence (38%), multiplicity (67%, P < 0.0001) and size (complete abolition of carcinoma with an area of >1.0 cm2) as well as adenoma with cellular pleomorphism (46%, P < 0.0001). The lower dose of I3C was less effective. MI decreased multiplicities of pulmonary surface tumors (20%, P = 0.0005), adenoma with cellular pleomorphism (40%, P < 0.0001) and lung adenoma (52%, P < 0.0001) and the proportion of the biggest carcinoma (carcinoma with an area of >1.0 cm2, P < 0.05). Immunoblot analyses of lung tissues for potential target identification showed that I3C (70 μmol/g diet) inhibits
IkappaBα degradation, nuclear factor-kappaB activation, expression of cyclooxygenase-2, phospho-Akt and fatty acid synthase
(FAS) and activates caspase-3 and poly ADP ribose polymerase cleavage. The effect of MI was limited to inhibition of phospho-Akt
and FAS expression. Our data show that I3C and MI inhibit lung carcinoma and provide a basis for future evaluation of these
compounds in clinical trials as chemopreventive agents for current and former smokers.
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ABSTRACT: Chemoprevention of lung carcinogenesis is one approach to controlling the epidemic of lung cancer caused by cigarette smoking. The target for chemoprevention should be the activities of the multiple carcinogens, toxicants, co-carcinogens, tumour promoters and inflammatory compounds in cigarette smoke. At present there are many agents, both synthetic and naturally occurring, that prevent lung tumour development in well-established animal models. It seems likely that logically constructed mixtures of these agents, developed from the ground up, will be necessary for the prevention of lung carcinogenesis.
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