Developing a Post-carcinogen Lung Cancer Chemopreventive Agent

描述（由申请人提供）：由于前吸烟者患肺癌的风险较高，并且大约一半的新肺癌发病率是在前吸烟者中，因此迫切需要开发安全有效的化学预防剂来帮助前吸烟者控制这种致命疾病。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，帮助前吸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一种观点，即卡瓦茶，南太平洋岛屿上一种长期存在的饮料，有望通过抑制NF-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，通过丰富卡瓦的化学预防成分，可以提高卡瓦的化学预防功效。这种优化也可能导致安全性的提高。因此，本应用的目的是提高卡瓦的致癌后化学预防功效，建立化学预防卡瓦的安全性，确定与商业卡瓦相关的潜在肝毒性的来源，并探索卡瓦诱导的化学预防的机制，如NF-kB抑制。具体而言，将实现以下四个目标：目标1。确定卡瓦提取物致癌后对肺腺瘤形成的化学预防作用，确定最有效的化学预防作用对肺腺癌进展的抑制作用。确定与商业卡瓦Aim 3相关的肝毒性的来源。对化学预防卡瓦制剂中的主要化学成分进行表征，为未来化学预防卡瓦产品的QC/QA提供依据。确定最具化学预防作用的卡瓦制剂对关键信号通路的影响，包括NF-kB通路在实现这些目标后，我们将(a)确定一种比现有商业产品更有效和更安全的卡瓦制剂，(b)确定其预防肺癌进展为腺癌的功效，(c)将与商业卡瓦相关的肝毒性的起源归功于非极性部分；(d)表征活性/特征化学物质，以便更好地对未来的卡瓦产品进行QC/QA；(e)为kava诱导的致癌后肺癌化学预防的关键信号通路和可能的分子靶点提供了机制见解。

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.