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。路易斯安那州立大学非常注重转化研究，并拥有丰富的教授医学生和研究生的机会。我近期的职业目标是获得资金来进一步开发下述项目，以便在未来 2 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，以及开展我自己的研究项目。我打算留在学术界并指导学生。这个 K-22 职业转型奖将使我能够研究天然香豆素 (NOC) 和 1'-乙酰氧基恰维酚醋酸酯 (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止致癌过程中从早期（起始）到后期（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 对乳腺肿瘤发生的抑制作用的作用； 2) 确定鸟氨酸脱羧酶抑制（ODC，一种推定的参与转化的致癌基因）、细胞增殖和诱导细胞凋亡在 auraptene 和 ACA 对用直接致癌物 N-甲基亚硝基脲治疗的雌性大鼠乳腺癌发生中的作用; 3)进一步研究aurapten和ACA诱导ODC抑制和诱导细胞凋亡的机制。将使用多种方法来确定这些化合物是否影响 ODC 的转录调节，以及 ODC 的抑制是否会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，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有益的抗癌活性，值得进一步研究。