Comparative Mechanisms of Cancer Chemoprevention

癌症化学预防的比较机制

• 批准号: 8074120
• 负责人: Roderick H Dashwood
• 金额: $ 177.73万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-17 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074120
• 关键词: Comparative; Mechanisms; Cancer; Chemoprevention

DESCRIPTION (provided by applicant): The NIH Roadmap stipulates that epigenetics is a research priority. Unlike genetic changes associated with cancer, epigenetic changes are potentially modifiable, and dietary factors have been shown to "de-repress" epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. The overall long-term objectives of this P01 are to better understand the mechanisms by which beneficial epigenetic changes can be brought about by dietary agents, to identify and characterize epigenetic biomarkers that can be applied in the clinical setting, and to evaluate those biomarkers in preclinical and translational studies. With three well-integrated Projects and a complementary Epigenetic/Translational Biomarkers Core, this competing continuation addresses the application (and possible risks) of dietary indoles and isothiocyanates for cancer intervention, through comparative mechanism, biomarker, and preclinical models (lymphoma, prostate, colon, lung cancer), leading to translational studies of epigenetic biomarkers in human volunteers. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (ISC), and the cruciferous vegetables from which they derive, are effective chemopreventive agents because, in addition to their blocking activities during the initiation phase, they alter the pattern of histone modifications (acetylation, methylation, phosphorylation) and histone deacetylase (HDAC) activity in cancer cells, as well as DNA promoter methylation status, thereby de-repressing epigenetically silenced genes that regulate the cell cycle and apoptosis. E. Ho will investigate "Chemoprevention of prostate cancer, HDAC inhibition, and DNA methylation" (Project 1), D.E. Williams will study "Transplacental chemoprevention of lung tumors and lymphomas" (Project 2), and R.H. Dashwood will examine "Chemoprevention of colon cancer, HDAC inhibition, and histone status" (Project 3). The overall significance of the work is that it seeks to provide new epigenetic insights into the prevention and treatment of colon, prostate, and lung cancer, as well as lymphoma, which are listed consistently among the top causes of cancer-related deaths in the US. This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet.

描述（由申请人提供）：NIH路线图规定表观遗传学是研究的优先事项。与癌症相关的遗传变化不同，表观遗传变化是潜在的可改变的，饮食因素已被证明可以“去抑制”癌细胞中表观遗传沉默的基因，引发细胞周期停滞和细胞凋亡。本P01的总体长期目标是更好地了解膳食制剂可带来有益表观遗传变化的机制，鉴定和表征可用于临床环境的表观遗传生物标志物，并在临床前和转化研究中评价这些生物标志物。 通过三个整合良好的项目和一个互补的表观遗传/翻译生物标志物核心，这个竞争性的延续通过比较机制，生物标志物和临床前模型（淋巴瘤，前列腺癌，结肠癌，肺癌）解决了饮食吲哚和异硫氰酸酯用于癌症干预的应用（和可能的风险），导致人类志愿者表观遗传生物标志物的翻译研究。 中心假说认为萝卜硫素（SFN）和吲哚-3-甲醇（ISC）以及它们所来源的十字花科蔬菜是有效的化学预防剂，因为除了它们在起始阶段的阻断活性外，它们还改变了组蛋白修饰的模式（乙酰化、甲基化、磷酸化）和癌细胞中的组蛋白脱乙酰酶（HDAC）活性，以及DNA启动子甲基化状态，从而去抑制调节细胞周期和凋亡的表观遗传学沉默基因。 E.何博士将研究“前列腺癌的化学预防、HDAC抑制和DNA甲基化”（项目1），D.E.威廉姆斯将研究“肺肿瘤和淋巴瘤的经胎盘化学预防”（项目2），R.H.达什伍德将研究“结肠癌的化学预防，HDAC抑制和组蛋白状态”（项目3）。这项工作的总体意义在于，它旨在为结肠癌、前列腺癌和肺癌以及淋巴瘤的预防和治疗提供新的表观遗传学见解，这些癌症一直被列为美国癌症相关死亡的主要原因。这种应用是创新的，及时的桥梁基本机制，临床前模型，以及人类研究的表观遗传学和饮食。