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，死亡率非常高，每年在美国大约有17万人受到影响。由于大多数肺癌患者是在疾病的晚期被诊断出来的，而且现有的治疗方法通常无效，因此大多数肺癌患者的预后非常差。从理论上讲，阻断从侵袭前疾病向恶性进展的多步骤过程将降低晚期肺癌的发生率。因此，开发有效的肺癌预防药物是降低死亡率的关键。在这项研究中，我们将重点关注黄酮类木犀草素(3‘，4’，5，7-四羟基黄酮)作为潜在的肺癌化学预防药物。我们的初步研究表明，黄酮类木犀草素选择性地杀死转化的肺细胞，但不能杀死正常的肺细胞，活性氧自由基(ROS)的积累是木犀草素诱导的肺癌细胞毒性所必需的。为了进一步研究木犀草素预防肺癌的活性和机制，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。支持这一应用的假设是木犀草素诱导的ROS介导了c-jun氨基末端激酶(JNK)的激活，从而触发了转化的肺细胞中的凋亡通路的激活。这种细胞凋亡的激活有助于木犀草素对肺癌的化学预防作用。我们将从以下几个方面对这一假说进行验证：1)确定木犀草素诱导肺癌细胞中ROS积聚的机制；2)确定木犀草素诱导肺癌细胞凋亡的机制；3)确定木犀草素对肺癌细胞的选择性细胞毒作用机制。该项目的成功将为今后在动物和人体内检测木犀草素对肺癌的预防活性及其机制的研究奠定基础，并可能导致木犀草素在临床上应用于人类肺癌的预防。

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.