An NF-kB inhibitor as a post-carcinogen lung cancer chemopreventive agent

NF-kB 抑制剂作为致癌后肺癌化学预防剂

• 批准号: 8045025
• 负责人: CHENGGUO XING
• 金额: $ 7.32万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-07 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045025
• 关键词: A/J Mouse; Apoptosis; Benzo(a)pyrene; Biological Markers; Butanones; Carcinogens; Chalcone; Chalcones; Chemoprevention; Chemopreventive Agent; Clinical Trials; Consumption; Data; Development; Evaluation; Future; Goals; Grant; Interdisciplinary Study; Investigation; Lead; Literature; Lung Adenoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Modification; NF-kappa B; Oral; Outcomes Research; Pathway interactions; Pharmaceutical Chemistry; Premalignant; Prevention; Prevention Research; Quality of life; Relative (related person); Reporting; Research; Smoker; Structure of parenchyma of lung; Testing; Tissues; Treatment Protocols; Work; Xenograft procedure; anticancer activity; base; cancer chemoprevention; cancer prevention; cellular targeting; design; experience; improved; in vivo; inhibitor/antagonist; innovation; insight; lung tumorigenesis; p65; prevent; programs; response; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Chalcone-based NF-?B inhibition for post-carcinogen lung cancer chemoprevention Chalcone-based compounds have demonstrated chemopreventive activities against various types of malignancies, including post-carcinogen lung tumorigenesis, potentially via inhibiting the activation of NF-?B pathway. Their chemopreventive efficacy, however, has never been optimized, which may potentially delay the translational development and reduce their potential impact to cancer prevention. We have recently optimized chalcone-based compounds to improve their NF-?B inhibitory activities, leading to a set of lead candidates with distinct NF-?B inhibitory profiles and one lead compound demonstrating potent anticancer activity in vivo against lung cancer xenograft, which is hypothesized to have significantly more potent chemopreventive activity against post-carcinogen lung tumorigenesis. The goal of this research is to identify a safe and more efficacious chalcone-based chemopreventive agent against post-carcinogen lung cancer development, which may eventually help former smoker to prevent lung cancer development, and to establish the importance of NF-?B inhibition in chemoprevention. Experimentally, we will synthesize six chalcone lead compounds, including the one that has demonstrated post-carcinogen lung cancer chemopreventive activity. These chalcones will be evaluated in A/J mice for their post-carcinogen chemopreventive efficacy. The chemopreventive efficacies among these candidates in combination with their pre-determined NF-?B inhibitory activities will establish the relationship between chemoprevention and NF-?B inhibition, which will indirectly determine the relative importance of NF-?B inhibition in chalcone-induced chemoprevention. The relevance of NF-?B inhibition to chemoprevention will be further explored by analyzing NF-?B biomarkers, such as I?Ba and p-P65, in the lung adenoma tissues.

描述(由申请人提供)： 查尔酮类化合物对致癌后肺癌的化学预防作用研究表明，查尔酮类化合物对包括致癌后肺癌在内的多种恶性肿瘤具有化学预防作用，其机制可能是通过抑制核因子-βB途径的激活来实现的。然而，它们的化学预防效果从未得到优化，这可能会推迟翻译发育，并降低它们对癌症预防的潜在影响。我们最近优化了基于查尔酮的化合物以提高它们的核因子-β抑制活性，导致了一组具有不同核因子-βB抑制谱的候选先导化合物和一个先导化合物在体内显示了对肺癌异种移植瘤的有效抗癌活性，这被认为对致癌后肺癌的发生具有显著更强的化学预防活性。本研究的目的是寻找一种安全有效的查尔酮为基础的化学预防药物，以预防致癌后肺癌的发生，最终帮助吸烟者预防肺癌的发生，并确定抑制核因子-βB在化学预防中的重要性。在实验上，我们将合成六种查尔酮先导化合物，其中包括一种具有致癌后肺癌化学预防活性的化合物。这些查尔酮将在A/J小鼠身上评估其致癌后化学预防效果。这些候选者之间的化学预防效果与它们预先确定的核因子？B抑制活性将建立化学预防与核因子？B抑制之间的关系，这将间接决定核因子-？B抑制在查尔酮诱导的化学预防中的相对重要性。通过分析肺腺瘤组织中的I？BA和p-p65等核因子-βB生物标志物，将进一步探讨核因子-βB抑制与化学预防的相关性。