Lung carcinogenesis: Chemoprevention by Indole-3-carbinol

肺癌发生：3-吲哚甲醇的化学预防

• 批准号: 7762766
• 负责人: Fekadu Kassie
• 金额: $ 25.07万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762766
• 关键词: A/J Mouse; Accounting; Adenocarcinoma; Adult; American; Anchorage-Independent Growth; Antibodies; Apoptosis; Biological Markers; Brassica; Bronchoalveolar Lavage Fluid; Butanones; Cancer Etiology; Cancer Model; Carcinogen exposure; Carcinogens; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Trials; Consumption; Country; Data; Development; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Failure; Gene Proteins; Glucosinolates; Goals; Harvest; High-Risk Cancer; Human; Hyperplasia; In Vitro; Incidence; Individual; Indole-3-Carbinol; Indoles; International Agency for Research on Cancer; Lesion; Lung; Lung Adenoma; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Microscopic; Mus; Parents; Pattern; Phenotype; Prevalence; Preventive; Process; Protein Microchips; Proteins; Proteomics; Public Health; RNA Interference; Relative (related person); Resources; Screening procedure; Serum; Smoker; Smoking; Smoking Prevention; Solid; Staging; Subfamily lentivirinae; Surface; Survival Rate; Technology; Testing; Time; Tobacco; Tobacco use; Tumor Burden; Vegetables; Western Blotting; Xenograft Model; adenoma; alveolar type II cell; base; cancer cell; cost; cruciferous vegetable; high risk; in vivo; interest; laser capture microdissection; lung carcinogenesis; lung tumorigenesis; mortality; mouse model; pre-clinical; protein expression; public health relevance; tumor; tumor growth; tumorigenesis

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.

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。尽管在美国降低烟草使用率的流行率方面做出了巨大努力，但仍有超过4500万的成年美国人仍然吸烟。前吸烟者也处于肺癌的高风险。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。当前，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，这些药物可以抑制当前和前吸烟者的肺癌。我们提出，甘蓝植物的组成部分吲哚-3-甲醇（I3C）抑制4-（甲基硝基氨基氨基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的肺部肿瘤，在A/J小鼠中诱导的肺部肿瘤，并调节蛋白质中的蛋白质降低。 NNK在吸烟者中高度涉及烟草诱导的肺癌。我们的假设是基于（1）流行病学研究，表明甘蓝蔬菜的高消耗与肺癌的发生之间存在反向关联。 （2）高浓度的吲哚葡萄糖苷酸，在甘蓝蔬菜中的母体I3C的母体化合物； （3）I3C在体外和体内肺癌模型中的癌症预防活性； （4）通过I3C调节肿瘤发生相关的基因/蛋白质。我们在该提案中的目的是：（1）测试I3C对A/J小鼠中NNK诱导的肺肿瘤发生的化学预防疗效。小鼠将在不同的时间序列或不同的时间持续时间内用NNK处理，并在不同的时间序列中进行I3C处理，肺部收获以及确定的宏观和微观肿瘤的发病率和多重性。 （2）在II型肺炎细胞中鉴定出差异表达的蛋白质，即肺腺瘤所产生的细胞，NNK-，NNK Plus I3C或I3C处理的A/J小鼠。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微阵列。 （3）使用基于抗体的蛋白质微阵列方法，在血清和支气管肺泡灌洗液（BALF）中的差异蛋白质组学模式（BALF）的小鼠的小鼠的差异，I3C或NNK和I3C和I3C以及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I3C作为针对肺癌的化学预防剂的临床试验提供一个可靠的平台。公共卫生相关性：标准方法的失败，预防吸烟和戒烟工作，治疗和筛查，以降低肺癌死亡率激发了对化学预防的兴趣。目前，人类尚无有效的化学预防剂。证明吲哚-3-甲醇（I3C）在A/J小鼠模型中抑制肺肿瘤发生的假设为I3C作为针对肺癌的化学预防剂的临床试验提供了一个坚实的平台。