Lung Cancer Chemoprevention through LC-1

通过 LC-1 进行肺癌化学预防

基本信息

批准号：
7686709
负责人：
Harikrishna Nakshatri
金额：
$ 7.7万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7686709
关键词：
A/J Mouse A549 Angiogenic Switch Animal Model Animals Apoptosis Apoptotic Benzo(a)pyrene Binding Proteins Biological Availability Biological Markers Bladder Butanones CCND1 gene CDKN2A gene Cancer Cell Growth Carcinogens Cell Cycle Cell Death Cell Line Chemoprevention Chemopreventive Agent Chronic Cigarette Cisplatin Clinic Clinical Trials Complex Cyclin D1 DAP kinase Drug Kinetics EZH2 gene Enhancing Lesion Environmental Carcinogens Epidermal Growth Factor Receptor Epigenetic Process Epithelial Cell Proliferation Epithelial Cells Event FVB/N Mouse Family Gene Expression Gene Targeting Goals Growth Growth Factor Herb Histology Histones Human Implant In Vitro Incidence Inflammation Inflammatory Response Laboratories Lesion Lung Macrophage Activation Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Methylation Mutation NF-kappa B Nuclear Oral Play Polycomb Predisposition Premalignant Premalignant Cell Property Proteins Role Smoker Solid Neoplasm Staging Stimulus Structure of parenchyma of lung TNFSF10 gene TP53 gene Tanacetum parthenium Taxane Compound Testing Tobacco smoke Tobacco-Associated Carcinogen Toxic Environmental Substances Transferase Translations Tumor Suppressor Genes Tumor Suppressor Proteins Urethane Water Work Xenograft Model activating transcription factor analog bcl-1 Genes cancer cell cancer chemoprevention chemotherapy cytokine gene repression human HDAC1 protein improved in vivo inhibitor/antagonist intravenous injection kinase inhibitor leukemia lung carcinogenesis macrophage malignant breast neoplasm member neoplastic novel parthenolide prevent programs promoter response taxane transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Chronic inflammation, mediated partly by tobacco smoke or environmental toxicants, plays a significant role in initiation and progression of lung cancer. Lung cancer progression is associated with increased activity of the transcription factor NF-?B, which is a major factor executing inflammatory response. Additionally, altered epigenetic program, as a consequence of elevated expression of histone deacetylases such as HDAC1 and histone methyl transferases such as EZH2, is observed in early stages of lung cancer. Therefore, an agent that can reduce the expression and/or activity of these proteins may serve as chemopreventive agent for lung cancer. During our search for agents with anti-NF-?B activity, we identified parthenolide as a novel agent that inhibits NF-?B and sensitizes cancer cells to chemotherapy. We developed a water-soluble analogue of this compound called LC-1, which is as potent as parthenolide but shows improved bioavailability and pharmacokinetics. LC-1 not only inhibited NF-?B but also reduced the levels of HDAC1 and its associated proteins CtBP1 and EZH2. HDAC1, CtBP1 and EZH2 constitute a transcription repression complex that mediates epigenetic silencing of tumor suppressor genes such as p14ARF and death-associated protein kinase-1 (DAPK1) in lung cancer. Additionally, LC-1 induced the expression of cell cycle kinase inhibitor p21 and the tumor suppressor/pro-apoptotic gene TAp73, which is expressed at low levels in lung cancer due to promoter methylation or deletion. Furthermore, LC-1 inhibited the growth of lung cancer cells in vitro and in xenograft models. LC-1 also reduced tobacco carcinogen-induced activation of NF-?B and cyclin D1 expression in non-transformed lung epithelial cells. Hypothesis: LC-1 serves as a potent chemopreventive agent for lung cancer by inhibiting two major carcinogenic stimuli- inflammations and epigenetic silencing of tumor suppressors. Specific aims: Aim I will test the chemopreventive activity of LC-1 in Urethane (an environmental toxicant)- induced lung cancer in FVB/N mice, which is critically dependent on inflammation and NF-?B activation in lung epithelial cells. Aim 2 will test the effect of LC-1 on tobacco carcinogens 4-(methylnitrosamine)-1-3-Pyridyl-1- butanone- and benzo(a)pyrene-induced lung cancer in A/J mice, which shows extensive epigenetic silencing of tumor suppressor genes. By measuring the levels of activated NF-?B, and the expression levels of EZH2, HDAC1, CtBP1, ARF, and DAPK1 in lung tissues of untreated and LC-1 treated animals, we will investigate whether these proteins serve as biomarkers for lung cancer chemoprevention. As LC-1 will soon be tested in clinic as a treatment for leukemia, the proposed studies will enable speedy translation to clinic, particularly for current or ex-smokers.

描述（由申请人提供）：慢性炎症部分由烟草烟雾或环境毒物介导，在肺癌的启动和进展中起着重要作用。肺癌的进展与转录因子NF-？B的活性增加有关，这是执行炎症反应的主要因素。此外，在肺癌的早期阶段观察到了组蛋白脱乙酰基酶（如HDAC1和组蛋白甲基转移酶）的表达升高，其表观遗传程序的改变。因此，可以减少这些蛋白质表达和/或活性的药物可以作为肺癌的化学预防剂。在搜索具有抗NF- b活性的药物的过程中，我们确定了parthenolide是一种抑制NF-？B并使癌细胞对化学疗法敏感的新型药物。我们开发了一种称为LC-1的化合物的水溶性类似物，该化合物与Parthenolide一样有效，但显示出改善的生物利用度和药代动力学。 LC-1不仅抑制了NF-？b，而且还降低了HDAC1及其相关蛋白CTBP1和EZH2的水平。 HDAC1，CTBP1和EZH2构成了一种转录抑制复合物，可介导肺癌中肿瘤抑制基因的表观遗传沉默和诸如P14ARF和死亡相关蛋白激酶-1（DAPK1）中的表观遗传沉默。此外，LC-1诱导细胞周期激酶抑制剂p21和肿瘤抑制剂/促凋亡基因TAP73的表达，该基因TAP73在启动子甲基化或缺失引起的肺癌中以低水平表达。此外，LC-1在体外和异种移植模型中抑制了肺癌细胞的生长。 LC-1还降低了非转化的肺上皮细胞中NF-？B和细胞周期蛋白D1表达的烟草致癌的激活。假设：LC-1通过抑制两种主要的致癌刺激和肿瘤抑制剂的表观遗传沉默，是肺癌的有效化学预防剂。具体目的：目标我将测试LC-1在氨基甲烷（一种环境有毒物）中的化学预防活性 - FVB/N小鼠诱导的肺癌，这在肺上皮细胞中严重取决于炎症和NF-？B激活。 AIM 2将测试LC-1对烟草致癌物4-（甲基硝基胺）-1-3-吡啶基-1-丁酮和苯甲酸酯和苯甲酸酯（A）pyrene诱导的肺癌的作用，这显示出广泛的肿瘤抑制基因的表观遗传沉积物。通过测量未经治疗和LC-1治疗的动物的肺组织中EZH2，HDAC1，CTBP1，ARF和DAPK1的表达水平以及EZH2，HDAC1，CTBP1，ARF和DAPK1的表达水平。由于LC-1将很快在诊所中作为白血病的治疗方法进行测试，因此拟议的研究将迅速转化为诊所，特别是对于当前或前吸烟者。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco-associated cancers, lung and bladder cancer, by targeting NF-κB and generating reactive oxygen species.

DOI：
10.1002/ijc.25587
发表时间：
2011-05-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Shanmugam, Rajasubramaniam;Kusumanchi, Praveen;Appaiah, Hitesh;Cheng, Liang;Crooks, Peter;Neelakantan, Sundar;Peat, Tyler;Klaunig, James;Matthews, William;Nakshatri, Harikrishna;Sweeney, Christopher J.
通讯作者：
Sweeney, Christopher J.