Developing a Post-carcinogen Lung Cancer Chemopreventive Agent

描述(申请人提供)：由于戒烟者罹患肺癌的风险较高，而所有新发肺癌病例中约有一半为吸烟者，因此迫切需要开发安全有效的化学预防药物来帮助戒烟者控制这种致命的疾病。我们的长期目标是开发一种基于天然食品和饮料的补充和替代医学(CAM)模式，以帮助戒烟者预防或延缓肺癌的发展。我们最近的研究结果有力地支持了这样的观点，即Kava，一种在南太平洋群岛长期存在的饮料，有望通过抑制核因子-kB的激活来预防致癌后肺癌的发展。我们的初步数据还表明，Kava的化学预防效果可以通过丰富其化学预防成分来提高。这样的优化也可能带来更好的安全性。因此，该应用的目的是提高Kava的致癌后化学预防效果，建立Kava的化学预防安全性，确定与商业Kava相关的潜在肝毒性的来源，并探索导致Kava诱导的化学预防的机制，如核因子-kB抑制。具体地说，将追求以下四个目标：目的1.确定Kava组分对肺腺瘤形成的致癌后化学预防效果，并建立最具化学预防作用的组分抑制肺腺癌进展的有效性目标2.确定与商业Kava相关的肝毒性的来源目的3.对未来化学预防Kava产品的QC/QA最具化学预防作用的Kava制剂的主要化学成分进行表征目标4.确定最具化学预防作用的Kava制剂对关键信号通路的影响，包括NF-kB途径一旦实现这些目标，我们将(A)鉴定出比现有商业产品更有效和更安全的Kava制剂(B)确定其防止肺癌进展为腺癌的功效，(C)将商品卡瓦的肝毒性来源归因于非极性部分；(D)确定活性/标志性化学物质的特征，以更好地控制/保证未来Kava产品的质量；(E)提供关于关键信号通路的机械性见解，并可能提供Kava诱发致癌后肺癌化学预防的分子靶点。 公共卫生相关性：肺癌是所有恶性肿瘤中最主要的死亡原因。曾经吸烟的人患肺癌的风险很高。本研究致力于确定一种基于KAVA的安全的CAM模式，该模式可以预防NNK/B[a]P致癌后方案在A/J小鼠体内诱导的肺肿瘤的发生，其结果有望为开发一种有助于戒烟者预防/延迟肺癌的化学预防性CAM模式奠定基础。

DESCRIPTION (provided by applicant): Since former smokers are at an elevated risk to develop lung cancer and about half of all new lung cancer incidences are among former smokers, there is an urgent need to develop safe and efficacious chemopreventive agents to help former smokers control this deadly disease. Our long-term goal is to develop a Complementary and Alternative Medicine (CAM) modality based on natural food and beverages that will help former smokers to prevent or delay lung cancer development. The results of our recent studies strongly support the notion that kava, a long-standing beverage in the South Pacific Islands, is promising to prevent post-carcinogen lung cancer development, potentially through suppressing NF-kB activation. Our preliminary data also suggest that kava's chemopreventive efficacy can be improved by enriching its chemopreventive constituents. Such optimization may also lead to improved safety. The objectives of this application, therefore, are to improve kava's post-carcinogen chemopreventive efficacy, to establish chemopreventive kava's safety, to identify the origin of potential hepatotoxicity associated with commercial kava, and to explore the mechanisms, such as NF-kB inhibition, that are responsible for kava-induced chemoprevention. Specifically, the following four Aims will be pursued: Aim 1. Determine the post-carcinogen chemopreventive efficacy of kava fractions against lung adenoma formation and establish the efficacy of the most chemopreventive fraction to inhibit lung lesion progression to adenocarcinoma Aim 2. Identify the origin of hepatotoxicity associated with commercial kava Aim 3. Characterize major chemicals in the most chemopreventive kava preparation for QC/QA of the future chemopreventive kava product Aim 4. Determine the effects of the most chemopreventive kava preparation on key signaling pathways, including the NF-kB pathway Upon accomplishing these aims, we will have (a) identified a kava preparation more efficacious and safer than the existing commercial product, (b) established its efficacy to prevent lung cancer progression to adenocarcinomas, (c) ascribed the origin of hepatoxicity associated with commercial kava to the non-polar fraction; (d) characterized active/signature chemicals for better QC/QA of the future kava product; and (e) provided mechanistic insights concerning key signaling pathways and possibly the molecular targets for kava-induced post-carcinogen lung cancer chemoprevention. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of death among all malignancies. Former smokers are at a high risk to develop lung cancer. This research focuses on identifying a kava-based safe CAM modality that can prevent NNK/B[a]P-induced lung tumorigenesis in A/J mice with post-carcinogen regimen, the outcome of which is expected to set the foundation for developing a chemopreventive CAM modality that will help former smokers to prevent/delay lung cancer.