Combinations of N-Acetyl-S-(N-2-Phenethylthiocarbamoyl)-L-Cysteine and myo-Inositol Inhibit Tobacco Carcinogen-Induced Lung Adenocarcinoma in Mice
ABSTRACT 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.
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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 micromol/g diet) and MI (56 micromol/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 cm(2)) 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 cm(2), P < 0.05). Immunoblot analyses of lung tissues for potential target identification showed that I3C (70 micromol/g diet) inhibits IkappaBalpha 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.Carcinogenesis 08/2009; 31(2):239-45. DOI:10.1093/carcin/bgp174 · 5.27 Impact Factor
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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.Nature Reviews Cancer 08/2009; 9(7):476-88. DOI:10.1038/nrc2674 · 29.54 Impact Factor
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ABSTRACT: Lung cancer is the leading cause of cancer-related death in the United States, and 85 to 90% of lung cancer cases are associated with tobacco use. Tobacco components promote lung tumorigenesis through genotoxic effects, as well as through biochemical modulation of signaling pathways such as the Akt/mammalian target of rapamycin (mTOR) pathway that regulates cell proliferation and survival. This review will describe cell surface receptors and other upstream components required for tobacco carcinogen-induced activation of Akt and mTOR. Preclinical studies show that inhibitors of the Akt/mTOR pathway inhibit tumor formation in mouse models of carcinogen-induced lung tumorigenesis. Some of these inhibitors will be highlighted, and their clinical potential for the treatment and prevention of lung cancer will be discussed.Clinical Cancer Research 12/2009; 16(1):4-10. DOI:10.1158/1078-0432.CCR-09-0234 · 8.19 Impact Factor