Developing a Post-carcinogen Lung Cancer Chemopreventive Agent

开发致癌后肺癌化学预防剂

• 批准号: 8509621
• 负责人: CHENGGUO XING
• 金额: $ 20万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509621
• 关键词: A/J Mouse; Adenocarcinoma; Animal Model; Basic Science; Benzo(a)pyrene; Beverages; Butanones; Cancer Biology; Carcinogens; Cause of Death; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Trials; Complementary and alternative medicine; Consumption; Data; Development; Disease; Dose; Evaluation; Female; Food; Foundations; Fractionation; Future; Goals; Grant; Growth; Hepatocyte; Hepatotoxicity; Human; In Vitro; Inbred F344 Rats; Incidence; Kava; Lead; Lesion; Lipopolysaccharides; Liver; Lung; Lung Adenoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modality; Modeling; Molecular Target; Monkeys; Mus; NF-kappa B; Oral; Outcome; Pacific Islands; Pathology; Pathway interactions; Pharmaceutical Chemistry; Preparation; Preventive; Proteins; Quality Control; Quality of life; Rattus; Regimen; Research; Resources; Risk; STAT3 gene; Safety; Sequence Determination; Signal Pathway; Smoker; Structure of parenchyma of lung; Testing; Time; Toxic effect; Toxicology; Transcription Factor AP-1; United States National Institutes of Health; Validation; Work; Xenograft procedure; adenoma; base; cancer chemoprevention; high risk; improved; in vivo; insight; lung tumorigenesis; multidisciplinary; pre-clinical research; prevent; public health relevance; research study; response; tumor progression; tumorigenesis; validation studies

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.

描述（由申请人提供）：由于以前的吸烟者患肺癌的风险较高，并且大约一半的新肺癌事件发生在以前的吸烟者中，因此迫切需要开发安全有效的化学预防剂，以帮助前吸烟者控制这种致命的疾病。我们的长期目标是基于天然食品和饮料开发一种互补和替代医学（CAM）方式，这将有助于前吸烟者预防或延迟肺癌的发展。 我们最近的研究的结果强烈支持这样的观念：南太平洋岛屿长期存在的饮料Kava有望防止癌后肺癌的发展，这可能是通过抑制NF-KB激活而来的。我们的初步数据还表明，可以通过富集其化学预防成分来提高Kava的化学预防功效。这种优化也可能导致安全性的提高。 因此，该应用的目的是提高卡瓦后的化学抗化后疗效，以建立化学预防kava的安全性，以确定与商业Kava相关的潜在肝毒性的起源，并探索诸如NF-KB抑制的机制，例如负责Kava-kava-kava诱导的kava-kava诱导的化学。具体而言，将追求以下四个目标：目标1。确定卡瓦馏分反对肺腺瘤形成的毒性后化学预防疗效的功效，并确定化学预防分数​​的疗效最终抑制肺癌进展到腺癌的目标2。确定抗腺癌的特征。 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腺癌，（c）将与商业Kava相关的肝毒性起源归因于非极性分数； （d）表征了未来Kava产品更好的QC/QA的活动/签名化学品； （e）提供了有关关键信号通路以及KAVA诱导的癌后肺癌化学预防的机械见解。 公共卫生相关性：肺癌是所有恶性肿瘤中死亡的主要原因。前吸烟者患肺癌的风险很高。这项研究的重点是识别基于KAVA的安全凸轮模式，该模态可以防止使用后car霉菌素治疗的A/J小鼠中NNK/B [A] P诱导的肺肿瘤发生，预计其结果将为预防化的cAM型型造成基础，从而有助于前吸烟者预防/延迟肺癌。