Lung carcinogenesis: Chemoprevention by Indole-3-carbinol

肺癌发生：3-吲哚甲醇的化学预防

• 批准号: 8204863
• 负责人: Fekadu Kassie
• 金额: $ 24.31万
• 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/8204863
• 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; Health; 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; smoking cessation; 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）：肺癌是全世界癌症死亡的最常见原因。大约 90% 的肺癌可直接归因于吸烟。尽管美国在降低烟草使用率方面做出了巨大努力，但仍有超过 4500 万美国成年吸烟者。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前景的替代方法是使用化学预防剂。目前，还没有任何有效的人类使用的癌症化学预防剂。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) 可抑制 4-(甲基亚硝基氨基)-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引起的蛋白质水平改变。 NNK 与吸烟者烟草诱发的肺癌密切相关。我们的假设基于（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) 芸苔类蔬菜中 I3C 的母体化合物吲哚芥子油苷的浓度很高； (3) I3C在体外和体内肺癌模型中的癌症预防活性； (4) I3C 对肿瘤发生相关基因/蛋白质的调节。我们本提案的目的是：（1）测试 I3C 对 A/J 小鼠中 NNK 诱导的肺部肿瘤发生的化学预防功效。将用NNK治疗小鼠，并在不同的时间顺序或不同的持续时间给予I3C，收获肺并确定宏观和微观肿瘤的发生率和复数。 (2) 鉴定 NNK-、NNK 加 I3C 或 I3C 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、I3C 或 NNK 和 I3C 治疗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 作为肺癌化学预防剂的临床试验提供坚实的平台。公共卫生相关性：标准方法、吸烟预防和戒烟工作、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，尚无针对人类有效的化学预防剂。证明吲哚-3-甲醇 (I3C) 在 A/J 小鼠模型中抑制肺部肿瘤发生的假设为 I3C 作为肺癌化学预防剂的临床试验提供了坚实的平台。