Nutrient Flavonoids and Lung Cancer Prevention

描述（由申请人提供）： 肺癌是一个主要的健康问题，具有非常高的死亡率，在美国每年约有170，000人受到折磨。由于大多数肺癌患者在疾病的晚期被诊断出来，并且可用的治疗通常无效，因此大多数肺癌患者的预后非常差。从理论上讲，阻断癌前病变发展为恶性肿瘤的多步骤过程将降低晚期肺癌的发病率。因此，开发有效的肺癌预防药物对降低死亡率至关重要。在本研究中，我们将重点关注黄酮类化合物木樨草素（3 '，4'，5，7-四羟基黄酮）作为一种潜在的肺癌化学预防剂。我们的初步研究表明，黄酮类化合物木犀草素选择性地杀死转化，但不是正常的肺细胞和活性氧（ROS）的积累是必不可少的木犀草素诱导的细胞毒性在肺癌细胞。为进一步研究木犀草素在肺癌预防中的活性和机制奠定基础，我们计划在体外细胞培养系统中确定木犀草素杀死肺癌细胞的潜在机制。驱动该应用的假设是木犀草素诱导的ROS介导c-Jun N-末端激酶（JNK）的活化，其随后触发转化的肺细胞中的凋亡途径的活化。这种细胞凋亡的激活有助于毛地黄黄酮对肺癌的化学预防活性。我们将在以下具体目标中检验这一假设：1）确定木犀草素诱导肺癌细胞中ROS积累的机制，2）确定木犀草素诱导肺癌细胞凋亡的机制，和3）确定木犀草素在肺癌细胞中选择性细胞毒性的机制。该项目的成功将导致未来在动物和人类中开展研究，以测试木犀草素对肺癌的预防活性和体内机制，这可能导致木犀草素用于人类肺癌预防的临床应用。

DESCRIPTION (provided by applicant): Lung cancer is a major health concern with a very high mortality rate, afflicting approximately 170,000 people each year in the United States. Because most lung cancer patients are diagnosed at a late stage of the disease and available therapies are usually ineffective, the prognosis is very poor for most lung cancer patients. Theoretically, blockage of the multiple-step process of the progression from preinvasive disease to malignancy will reduce the incidence of advanced lung cancer. Therefore, development of effective prevention agents against lung cancer is critical for reducing mortality. In this study, we will focus on the flavonoid luteolin (3',4',5,7-tetrahydroxyflavone) as a potential lung cancer chemoprevention agent. Our preliminary studies demonstrate that the flavonoid luteolin selectively kills transformed but not normal lung cells and that reactive oxygen species (ROS) accumulation is essential for the luteolin-induced cytotoxicity in lung cancer cells. To establish the basis of future studies on the activity and mechanism of luteolin in lung cancer prevention, we plan to determine the underlying mechanism by which luteolin kills lung cancer cells in an in vitro cell culture system. The hypothesis driving this application is that luteolin-induced ROS mediates activation of c-Jun N- terminal kinase (JNK), which subsequently triggers activation of apoptosis pathways in transformed lung cells. This activation of apoptosis contributes to the chemopreventive activity of luteolin against lung cancer. We will test this hypothesis in the following specific aims: 1) to determine the mechanism by which luteolin induces ROS accumulation in lung cancer cells, 2) to determine the mechanism by which luteolin induces apoptosis in lung cancer cells, and 3) to determine the mechanism of selective cytotoxicity of luteolin in lung cancer cells. The success of this project would lead to development of future studies in animals and humans to test the preventive activity and mechanism of luteolin against lung cancer in vivo, which may lead to the clinical application of luteolin for human lung cancer prevention.