Lung carcinogenesis: Chemoprevention by Indole-3-carbinol

描述(申请人提供)：肺癌是全球最常见的癌症死亡原因。约90%的肺癌与吸烟直接相关。尽管在降低美国烟草使用率方面做出了相当大的努力，但仍有超过4500万美国成年人吸烟。曾经吸烟的人患肺癌的风险也很高。降低肺癌死亡率的一个有希望的替代方法是使用化学预防药物。目前，还没有任何有效的人类使用的癌症化学防御剂。我们的长期目标是开发有效的肺癌化学预防药物，可以抑制现在和以前吸烟者的肺癌。我们认为吲哚-3-甲醇(I3C)是十字花科蔬菜的一种成分，它抑制4-(甲基亚硝基)-1-(3-吡啶)-1-丁酮(NNK)诱导的A/J小鼠肺癌的发生，并调节致癌物诱导的蛋白质水平的变化。NNK与烟草引起的吸烟者肺癌密切相关。我们的假设是基于(1)流行病学研究，这些研究表明大量食用油菜籽蔬菜与肺癌发病率呈负相关；(2)油菜籽蔬菜中I3C的母体化合物吲哚硫代葡萄糖苷的浓度很高；(3)I3C在体外和体内的肺癌模型中具有预防癌症的活性；以及(4)I3C对肿瘤发生相关基因/蛋白的调控。本研究的目的是：(1)检测I3C对NNK诱导的A/J小鼠肺癌的化学预防作用。小鼠将接受NNK治疗，并在不同的时间顺序下给予I3C，或在不同的时间段内，采集肺组织，并测定肉眼和微观肿瘤的发生率和多发性。(2)鉴定NNK-、NNK+I3C或I3C处理的A/J小鼠II型肺泡细胞中差异表达的蛋白质。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芯片。(3)使用基于抗体的蛋白质芯片方法，鉴定NNK、I3C或NNK和I3C处理的小鼠血清和支气管肺泡灌洗液(BALF)中的差异蛋白质组模式，并评估蛋白质水平变化的功能后果。总体而言，该项目的结果将为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、预防吸烟和戒烟努力、治疗和筛查在降低肺癌死亡率方面的失败激发了人们对化学预防的兴趣。目前，人类尚无有效的化学预防药物。证明了吲哚-3-甲醇(I3C)在A/J小鼠模型中抑制肺癌发生的假设，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.