Anticarcinogenic effects of naturally occurring coumarins on mammary carcinogenes

天然香豆素对乳腺癌致癌物的抗癌作用

• 批准号: 7108570
• 负责人: HEATHER E KLEINER
• 金额: $ 15.59万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108570
• 关键词: MCF7 cell; alpha benzopyrone; antineoplastics; apoptosis; biological products; breast neoplasms; cancer prevention; carcinogenesis; chemoprevention; cytochrome P450; enzyme induction /repression; enzyme inhibitors; glutathione transferase; green fluorescent proteins; high performance liquid chromatography; laboratory mouse; laboratory rat; neoplastic growth; ornithine decarboxylase; scintillation counter; tissue /cell culture; transcription factor

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.

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。 LSU非常专注于翻译研究，并有很多机会教授医学和研究生。我的直接职业目标是获得资金，以进一步开发下面所述的项目，以便在未来两年内争夺R01的资金。长期目标包括与LSU的其他研究人员在人类化学预防临床试验中合作，除了进行自己的研究项目外。我打算留在学术界和指导学生。这项K-22职业转型奖将使我能够研究自然存在的香豆素（NOC）和1'-乙酰氧基羟基甲酸（ACA）在乳腺癌发生的人和啮齿动物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从早期（启动）到后期（促进/进展）的致癌过程中广泛的活性。具体目的是：1）确定GST诱导的作用和/或P450对NOC对乳腺肿瘤起始的抑制作用的抑制作用； 2）确定鸟氨酸脱羧酶抑制（ODC，一种参与转化的假定癌基因），细胞增殖和凋亡诱导在极光和ACA对与直接作用的雌性大鼠乳腺大鼠乳腺癌癌癌作用的影响中的作用。 3）进一步检查了Auraptene和ACA诱导的ODC抑制和诱导凋亡的机制。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ODC的抑制是否导致凋亡的诱导。由于NOC和ACA在人类饮食（柑橘类水果，芹菜，生姜）中很丰富，因此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值得进一步研究的有益抗癌活性。