Lung carcinogenesis: Chemoprevention by Indole-3-carbinol

描述（由申请人提供）：肺癌是全球癌症死亡的最常见原因。大约90%的肺癌直接归因于吸烟。尽管在减少美国烟草使用的流行方面做出了相当大的努力，超过4500万美国成年人仍然吸烟。以前吸烟的人患肺癌的风险也很高。降低肺癌死亡率的一种有希望的替代方法是使用化学预防剂。目前，没有任何有效的癌症化学预防剂用于人类使用。我们的长期目标是开发有效的肺癌化学预防剂，可以抑制目前和以前吸烟者的肺癌。我们提出，吲哚-3-甲醇（I3 C），芸苔属蔬菜的成分，抑制4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）诱导的A/J小鼠肺肿瘤的发生和调节致癌物诱导的蛋白质水平的变化。NNK与吸烟者中烟草诱导的肺癌高度相关。我们的假设是基于（1）流行病学研究表明大量食用芸苔属蔬菜与肺癌发病率呈负相关;（2）芸苔属蔬菜中高浓度的吲哚硫代葡萄糖甙（I3 C的母体化合物）;（3）I3 C在体外和体内肺癌模型中的癌症预防活性;（4）I3 C在体内和体外肺癌模型中的癌症预防活性。（4）I3 C对肿瘤发生相关基因/蛋白的调节。本研究的目的是：（1）检测I3 C对NNK诱导的A/J小鼠肺肿瘤发生的化学预防作用。将用NNK处理小鼠并以不同的时间顺序或不同的持续时间给予I3 C，收获肺并确定肉眼和显微镜下肿瘤的发生率和多样性。(2)鉴定NNK-、NNK + I3 C或I3 C处理的A/J小鼠II型肺细胞（肺腺瘤产生的细胞）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微阵列。(3)使用基于抗体的蛋白质微阵列方法鉴定用NNK、I3 C或NNK和I3 C处理的小鼠的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，该项目的结果将为I3 C作为肺癌化学预防剂的临床试验提供坚实的平台。

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.