Lung carcinogenesis: Chemoprevention by Indole-3-carbinol

描述（由申请人提供）：肺癌是世界上最常见的癌症死亡原因。约90%的肺癌可直接归因于吸烟。尽管美国在减少烟草使用方面做出了相当大的努力，但仍有超过4500万成年美国人吸烟。戒烟者患肺癌的风险也很高。减少肺癌死亡率的一个有希望的替代方法是使用化学预防剂。目前，还没有一种有效的人类癌症化学预防剂。我们的长期目标是开发有效的肺癌化学预防剂，可以抑制当前和以前吸烟者的肺癌。我们提出，芸苔属蔬菜的一种成分吲哚-3-甲醇（I3C）抑制4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）诱导的a /J小鼠肺肿瘤发生，并调节致癌物质诱导的蛋白质水平改变。NNK与吸烟者的烟草诱发肺癌密切相关。我们的假设是基于(1)流行病学研究表明，大量食用芸苔类蔬菜与肺癌发病率呈负相关；(2)芸苔属蔬菜中I3C的母体化合物吲哚硫代葡萄糖苷含量高；(3) I3C在体外和体内肺癌模型中的防癌作用；(4) I3C对肿瘤发生相关基因/蛋白的调控。我们的目的是：(1)检测I3C对nnk诱导的A/J小鼠肺肿瘤发生的化学预防作用。小鼠在不同的时间序列或不同的持续时间内接受NNK和I3C治疗，取肺，并确定宏观和微观肿瘤的发生率和多样性。(2)在NNK-、NNK + I3C或I3C处理的A/J小鼠的II型肺细胞（产生肺腺瘤的细胞）中鉴定差异表达蛋白。为此，我们将使用相对和绝对定量（iTRAQ）蛋白质组学技术和基于抗体的蛋白质微阵列。(3)利用基于抗体的蛋白质微阵列方法，鉴定NNK、I3C或NNK和I3C处理小鼠血清和支气管肺泡灌洗液（BALF）中的差异蛋白质组学模式，并评估蛋白质水平改变的功能后果。总体而言，本项目的研究结果将为I3C作为肺癌化学预防药物的临床试验提供坚实的平台。公共卫生相关性：标准方法的失败，吸烟预防和戒烟努力，治疗和筛查，以减少肺癌死亡率激发了对化学预防的兴趣。目前，人类还没有有效的化学预防剂。在A/J小鼠模型中证实吲哚-3-甲醇（I3C）抑制肺肿瘤发生的假设，为I3C作为肺癌化学预防药物的临床试验提供了坚实的平台。

DESCRIPTION (provided by applicant): Lung cancer is the most common cause of cancer death worldwide. About 90% of all lung cancers are directly attributable to smoking. Despite considerable efforts in reducing the prevalence of tobacco use in the U.S., over 45 million adult Americans are still smokers. Former smokers are also at a high risk of lung cancer. One promising alternative approach to reduce lung cancer mortality is the use of chemopreventive agents. Currently, there is not any effective cancer chemopreventive agent for human use. Our long-term goal is to develop effective lung cancer chemopreventive agents which can inhibit lung cancer in current and former smokers. We propose that indole-3-carbinol (I3C), a constituent of Brassica vegetables, inhibits 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice and modulates carcinogen-induced alterations in protein levels. NNK is highly implicated in tobacco-induced lung cancer in smokers. Our hypothesis is based on (1) Epidemiologic studies which indicate an inverse association between high consumption of Brassica vegetables and the incidence of lung cancer; (2) The high concentration of indole glucosinolates, the parent compounds for I3C, in Brassica vegetables; (3) Cancer preventive activity of I3C in in vitro and in vivo lung cancer models; and (4) modulation by I3C of tumorigenesis-related genes/proteins. Our aims in this proposal are: (1) Test the chemopreventive efficacy of I3C against NNK-induced lung tumorigenesis in A/J mice. Mice will be treated with NNK and given I3C at different temporal sequences, or for different durations of time, lungs harvested and incidence and multiplicity of macroscopic and microscopic tumors determined. (2) Identify differentially expressed proteins in type II pneumocytes, the cells from which lung adenoma arise, of NNK-, NNK plus I3C, or I3C-treated A/J mice. For this, we will use relative and absolute quantitation (iTRAQ) proteomics technology and antibody-based protein microarray. (3) Identify, using antibody-based protein microarray approach, differential proteomic patterns in the serum and bronchoalveolar lavage fluid (BALF) of mice treated with NNK, I3C, or NNK and I3C and assess functional consequences of alterations in protein levels. Overall, the results of this project will provide a solid platform for clinical trials of I3C as a chemopreventive agent against lung cancer. PUBLIC HEALTH RELEVANCE: The failure of standard approaches, smoking prevention and cessation efforts, treatment and screening, to reduce lung cancer mortality motivated an interest in chemoprevention. At present, no effective chemopreventive agent is available for human. Proving the hypothesis that indole-3-carbinol (I3C) inhibits lung tumorigenesis in A/J mouse model provides a solid platform for clinical trials of I3C as a chemopreventive agent against lung cancer.