Anticarcinogenic effects of naturally occurring coumarins on mammary carcinogenes

描述（由申请人提供）：我是路易斯安那州立大学（LSU）药理学系和Feist-Weiller癌症中心的新助理教授。路易斯安那州立大学非常注重转化研究，并有丰富的机会教医学和研究生。我的近期职业目标是获得资金，以进一步发展下面描述的项目，以便在未来2年内竞争R 01资金。长期目标包括与路易斯安那州立大学的其他研究人员合作进行人类化学预防临床试验，以及进行我自己的研究项目。我打算留在学术界指导学生。这个K-22职业过渡奖将使我能够研究天然香豆素（NOC）和1 '-乙酰氧基胡椒酚乙酸酯（ACA）在人类和啮齿动物乳腺癌模型中的抑制作用的程度和机制。我们假设这些化合物将有效阻断致癌过程中从早期阶段（起始）到后期阶段（促进/进展）的广泛活动。具体目标是：1）确定GST诱导和/或P450抑制对NOC对乳腺肿瘤起始的抑制作用的作用; 2）确定鸟氨酸脱羧酶抑制的作用。（ODC，一种参与转化的假定癌基因）、细胞增殖和诱导凋亡，在直接作用致癌物N-甲基亚硝基脲处理的雌性大鼠中，金萝卜素和ACA对乳腺癌发生的影响; 3）进一步探讨ODC抑制金萝卜素和ACA诱导细胞凋亡的机制。将使用几种方法来确定这些化合物是否影响ODC的转录调节，以及ODC的抑制是否导致细胞凋亡的诱导。由于NOC和ACA在人类饮食（柑橘类水果，芹菜，生姜）中含量丰富，它们有可能影响人类癌症风险。值得注意的是，这些天然产物具有一系列有益的抗癌活性，值得进一步研究。

DESCRIPTION (provided by applicant): I am a new Assistant Professor in the Department of Pharmacology and Feist-Weiller Cancer Center at Louisiana State University (LSU). LSU has a strong focus on translational research, and has rich opportunities to teach medical and graduate students. My immediate career goals are to secure funding to further develop the project described below in order to compete for R01 funding within the next 2 years. Long-term goals include collaborating with other investigators at LSU on human chemoprevention clinical trials, in addition to conducting my own research project. I intend to stay in academia and mentor students. This K-22 Career Transition Award will enable me to study the extent and mechanisms of the inhibitory effects of naturally occurring coumarins (NOCs) and 1'-acetoxychavicol acetate (ACA) in human and rodent models of mammary carcinogenesis. We hypothesize that these compounds will be effective at blocking a broad range of activities in the carcinogenic process, from the early stages (initiation) to the later stages (promotion/ progression). The specific aims are: 1) To determine the role(s) of GST induction and/or P450 inhibition on NOCs' inhibitory effects on mammary tumor initiation; 2) Determine the roles of ornithine decarboxylase inhibition (ODC, a putative oncogene involved in transformation), cell proliferation, and induction of apoptosis in the effects of auraptene and ACA on mammary carcinogenesis in female rats treated with the direct-acting carcinogen N-methylnitrosourea; and 3) To further examine the mechanisms of ODC inhibition and induction of apoptosis induced by auraptene and ACA. Several approaches will be used to determine whether these compounds affect the transcriptional regulation of ODC, and whether the inhibition of ODC leads to the induction of apoptosis. Since NOCs and ACA are abundant in the human diet (citrus fruits, celery, ginger) they have the potential to impact human cancer risk. Notably, these natural products possess a range of beneficial anticarcinogenic activities worthy of further study.