In an extension of our earlier studies, we examined the inhibitory effects of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine (PEITC-NAC), myo-inositol (MI) and indole-3-carbinol (I3C) or 3,3'-diindolylmethane (DIM), alone and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (BaP)-induced A/J mouse lung tumorigenesis and proliferation of A549 cells and human bronchial epithelial cells (HBECs) and relevant potential mechanisms. Mice treated with NNK plus BaP and fed non-supplemented diet had 13.0 + or - 4.1 lung tumors per mouse. Dietary feeding of mice with PEITC-NAC (5 mumol/g diet), I3C (5 mumol/g diet) or MI (56 mumol/g diet), beginning at 50% in the carcinogen treatment phase, significantly reduced tumor multiplicity to 8.2 + or - 2.0, 8.4 + or - 1.5 and 6.8 + or - 1.7 tumors per mouse, respectively. In mice given combinations of the chemopreventive agents, lung tumor multiplicity was significantly reduced to 6.3 + or - 2.2, 4.9 + or - 1.8, 4.8 + or - 1.9 and 3.6 + or - 1.4 by PEITC-NAC plus I3C, PEITC-NAC plus MI, I3C plus MI or PEITC-NAC plus I3C plus MI, respectively. Post-carcinogen administration of combinations of the agents also caused significant but weaker effects. Assessment of the anti-proliferative effects of the individual agents or their combinations showed significant reductions in the proliferation of cigarette smoke condensate (CSC)-pretreated HBEC (reduction by 30-41% at 48 h and 41-58% at 72 h) and A549 cells (30-43% at 48 h and 40-59% at 72 h), but not in dimethyl sulfoxide-pretreated HBEC. Combinatorial treatment with the agents also caused marked reductions in the activation of Akt, extracellular signal-regulated kinase and nuclear factor-kappaB in lung tumor tissues, CSC-pretreated HBEC and A549 cells. In conclusion, our studies demonstrated the promise of combinations of PEITC-NAC, I3C/DIM and MI for the chemoprevention of lung carcinogenesis in current and former smokers.
MicroRNAs (miRNAs) represent a class of naturally occurring small noncoding RNA molecules that regulate genes by either inducing mRNA degradation or inhibiting translation. The expression of miRNAs is deregulated in several cancers, including lung cancer. However, most studies have been carried out using full-blown cancer tissues and the regulation of miRNAs during early-stage tumorigenesis is unknown. In the present study, we used an in vitro model of lung tumorigenesis to assess the effect of chronic treatment with tobacco compounds on the expression of miR-21, one of the most deregulated miRNAs in lung cancer, in human bronchial epithelial cells (HBEC). Freshly prepared NNK (10 µM) and nicotine (10 µM) were added to the culture media containing NHBC every 3 days for 3 weeks. Beginning the second week of NNK plus nicotine treatment, the dietary chemopreventive agent diindolylmethane (DIM) was added, every 3 days, to the culture media until the termination of the study. Then, the cells were harvested, RNA prepared and the expression level of miR-21 and its target genes PDCD4 and RECK were analyzed by QRT-PCR. Levels of PDCD4 and RECK were also examined by Western immunoblotting. NNK plus nicotine treatment significantly elevated miR-21 levels but markedly decreased expression of PDCD4 and RECK at both gene and protein levels. The effect of the tobacco compounds on miR-21 as well PDCD4 and RECK was reversed by treatment with DIM. This study shows that miR-21 levels are deregulated beginning the early phase of lung tumorigenesis and miR-21 is a valuable target for chemopreventive agents. Citation Information: Cancer Prev Res 2010;3(1 Suppl):PR-06.
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