Inhibition of lung carcinogenesis and critical cancer-related signaling pathways by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine, indole-3-carbinol and myo-inositol, alone and in combination
Inhibition of lung carcinogenesis and critical cancer-related signaling pathways by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine, indole-3-carbinol and myo-inositol, alone and in combination
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DOI：
10.1093/carcin/bgq139
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发表时间：
2010-09-01
期刊：
影响因子：
4.7
通讯作者：
Hecht, Stephen S.
中科院分区：
文献类型：
--
作者：
Kassie, Fekadu;Melkamu, Tamene;Hecht, Stephen S.
在我们早期研究的扩展中，我们检查了N-乙酰基-S-（N-2-苯乙基硫代氨基甲酰基）-L-半胱氨酸（PEITC-NAC）、肌醇（MI）和吲哚-3-甲醇（I3 C）或3，3 ′-二吲哚基甲烷（DIM），单独或组合，在4- 1-甲基亚硝胺（3-吡啶基）-1-丁酮（NNK）加苯并[a]芘（BaP）诱导的A/J小鼠肺肿瘤发生和A549细胞和人支气管上皮细胞的增殖（HBEC）和相关潜在机制。用NNK加BaP处理并喂食未补充饮食的小鼠每只小鼠具有13.0 +/-4.1个肺肿瘤。在致癌物处理阶段，从50%开始，用PEITC-NAC（5 μ mol/g饮食）、I3 C（5 μ mol/g饮食）或MI（56 μ mol/g饮食）对小鼠进行饮食喂养，将肿瘤多样性分别显著降低至每只小鼠8.2 +/- 2.0、8.4 +/- 1.5和6.8 +/- 1.7个肿瘤。在给予化学预防剂组合的小鼠中，PEITC-NAC + I3 C、PEITC-NAC + MI、I3 C + MI或PEITC-NAC + I3 C + MI分别将肺肿瘤多样性显著降低至6.3 +/- 2.2、4.9 +/- 1.8、4.8 +/- 1.9和3.6 +/- 1.4。致癌物后给药的药物组合也造成了显着的，但较弱的影响。对单个药剂或其组合的抗增殖作用的评估显示，香烟烟雾冷凝物（CSC）预处理的HBEC（在48小时降低30-41%，在72小时降低41-58%）和A549细胞（在48小时降低30-43%，在72小时降低40-59%）的增殖显著降低，但在二甲基亚砜预处理的HBEC中没有。与试剂的组合治疗也引起肺肿瘤组织、CSC预处理的HBEC和A549细胞中Akt、细胞外信号调节激酶和核因子-kappaB的活化的显著减少。总之，我们的研究证明了PEITC-NAC，I3 C/DIM和MI的组合用于当前和以前吸烟者肺癌发生的化学预防的前景。
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 +/- 4.1 lung tumors per mouse. Dietary feeding of mice with PEITC-NAC (5 mu mol/g diet), I3C (5 mu mol/g diet) or MI (56 mu mol/g diet), beginning at 50% in the carcinogen treatment phase, significantly reduced tumor multiplicity to 8.2 +/- 2.0, 8.4 +/- 1.5 and 6.8 +/- 1.7 tumors per mouse, respectively. In mice given combinations of the chemopreventive agents, lung tumor multiplicity was significantly reduced to 6.3 +/- 2.2, 4.9 +/- 1.8, 4.8 +/- 1.9 and 3.6 +/- 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.