Diindolylmethane:Inhibition of lung squamous cell carcinoma by targeting Akt.

二吲哚基甲烷：通过靶向 Akt 抑制肺鳞状细胞癌。

基本信息

批准号：
8383028
负责人：
Fekadu Kassie
金额：
$ 19.84万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-13 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383028
关键词：
A/J Mouse Affect Apoptosis Apoptotic Bioluminescence Cancer Etiology Carcinogens Carcinoma in Situ Cell Proliferation Cell Survival Cells Cessation of life Chemopreventive Agent Clinical Trials Consumption Data Development Diet Dose Dysplasia Early treatment Epidemiologic Studies Event Glucosinolates Goals Growth Human Hyperplasia Immunohistochemistry In Vitro Incidence Laboratories Lesion Luciferases Lung Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Metaplasia Methods Modeling Mus Normal Cell Patients Physiological Play Population Premalignant Preventive Process Proteins Reporter Research Role Signal Pathway Smoker Specimen Squamous Cell Squamous Cell Lung Carcinoma Squamous cell carcinoma Structure of parenchyma of lung Survival Rate Testing Time Tobacco-Associated Carcinogen Tumor Tissue United States Vegetables Western Blotting Xenograft Model base cigarette smoking clinical application combat cruciferous vegetable diindolylmethane disorder control exposed human population high risk human FRAP1 protein improved in vitro Assay lung carcinogenesis lung tumorigenesis molecular imaging mortality mouse model overexpression prevent protein expression survivin treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The main goal of this project is to assess the efficacy of diindolylmethane (DIM), a bioactive compound from cruciferous vegetables, to block the malignant progression of bronchial preneoplastic lesions to lung squamous cell carcinoma (SCC) by targeting the Akt signaling pathway. Preliminary studies showed that exposure of human bronchial cells to physiologically relevant concentrations of DIM caused antiproliferative and apoptotic effects in tobacco carcinogen-transformed bronchial cells but not in normal bronchial cells. Further, we observed that DIM inhibits activation/expression of proteins involved in the Akt signaling pathway. Over- expression of constitutively activated Akt in cigarette smoke-transformed bronchial cells markedly reduced the apoptotic effects of DIM, indicating that the growth inhibitory and apoptotic activities of DIM are mediated by targeting Akt. In the present application, we will extend our studies to a mouse model of lung SCC and assess if DIM causes regression of bronchial preneoplastic lesions by inhibiting Akt activation. Moreover, we will conduct, using a molecular imaging approach, proof-of-concept studies to confirm that DIM targets Akt activation. Hypothesis: Akt activation plays a critical role in the progression of bronchial preneoplastic lesions to lung squamous cell carcinoma (SCC) and targeting Akt by DIM reverses this process. N-nitroso-tris- chloroethylurea (NTCU)-induced mouse model of lung SCC will be used to test the hypothesis. Specific Aim 1: To determine if DIM-inhibits NTCU-induced lung SCC and whether the Akt signaling pathway is the critical target for the chemopreventive activities of DIM. Specific Aim 2: To examine, using luciferase complementation-based molecular imaging platform, the role of phospho-Akt targeting on DIM-induced antiproliferative and apoptotic effects in vitro and tumor growth in xenograft models of lung cancer. Impact/Significance: The results of this study could provide a mechanistic basis and rationale for clinical trials of DIM asa chemopreventive agent in populations that are at high risk to develop lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer-related mortality. Although treatment methods have advanced during the last decades, lung cancer mortality is not significantly reduced. One potential approach to combat lung cancer is to develop chemopreventive agents. This project focuses on examining the efficacy of diindollylmethane, a constituent of vegetables, to prevent lung cancer in a mouse model and should allow further development of this compound for clinical applications.

描述（由申请人提供）：该项目的主要目的是评估从十字花科蔬菜中的生物活性化合物二丁烷基甲烷（DIM）的疗效，以通过靶向AKT信号传导途径来阻止支气管前肿瘤病变到肺鳞状细胞癌（SCC）的恶性进展。初步研究表明，将人支气管细胞暴露于生理相关的昏暗浓度上，导致烟草癌转化的支气管细胞的抗增殖和凋亡作用，但在正常支气管细胞中却没有。此外，我们观察到昏暗的抑制了参与AKT信号通路的蛋白质的激活/表达。烟雾转化的支气管细胞中组成型激活的AKT的过度表达显着降低了昏暗的凋亡作用，表明dim的生长抑制性和凋亡活性是通过靶向Akt介导的。在本应用中，我们将将研究扩展到肺SCC的小鼠模型，并通过抑制AKT激活来评估DIM是否导致支气管前肿瘤病变的回归。此外，我们将使用分子成像方法进行概念验证研究，以确认该靶向Akt激活的敏感。假设：AKT激活在支气管前塑性病变对肺鳞状细胞癌（SCC）的进展中起着至关重要的作用，并通过DIM逆转此过程来靶向AKT。 N-硝基 - 三氯乙烯（NTCU）诱导的肺SCC小鼠模型将用于检验该假设。特定目标1：确定DIM抑制NTCU诱导的肺SCC以及AKT信号通路是否是DIM的化学预防活性的关键目标。具体目标2：使用基于荧光素酶互补的分子成像平台检查，磷酸化靶向在肺癌异种移植模型中，磷酸化靶向靶向对DIM诱导的抗增殖和凋亡效应的作用。影响/意义：这项研究的结果可以为人群中昏暗的ASA化学预防剂的临床试验提供机械基础和基本原理，而该试验的人群中有很高的肺癌风险。公共卫生相关性：肺癌是癌症相关死亡率的主要原因。尽管在过去的几十年中，治疗方法已经进步，但肺癌死亡率并未显着降低。打击肺癌的一种潜在方法是开发化学预防剂。该项目的重点是研究蔬菜组成部分二丹甘氨酸的功效，以防止小鼠模型中的肺癌，并应进一步开发该化合物以用于临床应用。