Effects of natural coumarins on mammary carcinogenesis

描述(由申请人提供)：我是路易斯安那州立大学药理学系和费斯特-韦勒癌症中心的新助理教授。路易斯安那州立大学非常注重翻译研究，并有丰富的机会教授医学和研究生。我目前的职业目标是获得资金，以进一步发展下面描述的项目，以便在未来两年内竞争R01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。这一K-22职业转折奖将使我能够研究天然香豆素(NOCs)和1‘-乙酰氧基氨基酚醋酸酯(ACA)在人和啮齿动物乳腺癌发生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地阻断致癌过程中的广泛活动，从早期阶段(启动)到后期阶段(促进/进展)。这些研究的具体目的是：1)确定GST诱导和/或P450抑制对NOC抑制乳腺癌启动的作用(S)；2)确定鸟氨酸脱羧酶抑制(ODC，一种可能参与转化的癌基因)、细胞增殖和诱导细胞凋亡在Auapene和ACA对直接作用致癌物N-甲基亚硝脲处理的雌性大鼠乳腺癌发生中的作用；3)进一步研究ODC抑制和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的转录调控，以及抑制ODC是否导致诱导细胞凋亡。由于NOCs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患癌症的风险。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.