Synergistic chemoprevention of colon cancer by hydroxylated polymethoxyflavones

羟基化多甲氧基黄酮对结肠癌的协同化学预防

• 批准号: 7990330
• 负责人: Hang Xiao
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990330
• 关键词: Abbreviations; Aberrant crypt foci; Acetates; Adenomatous Polyposis Coli; Analysis of Variance; Anthracenes; Area; Azoxymethane; Binding; Blood; Bromides; Cancer Cell Growth; Cell Culture Techniques; Chemoprevention; Chemopreventive Agent; Colon Carcinoma; Colonic Neoplasms; Development; Diet; Dietary Component; Dose; Effectiveness; Epidermal Growth Factor Receptor; Experimental Animal Model; Flavonoids; Foundations; Goals; Growth; Human; Immunohistochemistry; In Vitro; Incidence; Industry; Intake; Juice; Knowledge; Lead; Malignant Neoplasms; Methylnitronitrosoguanidine; Modeling; Molecular; Mucins; Oranges; Pentas; Preventive; Public Health; RXR; Rattus; Relative (related person); Research; Signal Pathway; Solid; Testing; Tissue Sample; Work; base; cancer cell; cancer chemoprevention; cancer prevention; colon cancer cell line; colon carcinogenesis; dimethylbenzanthracene; experience; in vivo; innovation; methylurea; nobiletin; novel; novel strategies; public health relevance; research study; response; tumor; wasting

DESCRIPTION (provided by applicant): Enhancing cancer chemoprevention through rational selection of efficacious combinations of bioactive dietary components is an attractive strategy, due to possible synergistic interactions among these components. However, the use of this approach has been greatly limited by the current poor understanding of dietary component interactions. To explore this promising approach, this project aims to determine the inhibitory effects of two hydroxylated polymethoxyflavones (OH-PMFs, from orange peel) and their combinations on colon carcinogenesis, and also to determine their mode of interaction and the molecular mechanisms involved. The long-term goal is to develop diet-based strategies for colon cancer prevention. Our preliminary results demonstrated that the combination of 5HPMF and 5HHMF (two major OH-PMFs) produced strong synergy not only in inhibiting colon cancer cell growth in culture, but also in inhibiting the formation of aberrant crypt foci (ACF) in azoxymethane (AOM)-treated rats. Based on these results, our central hypothesis is that 5HPMF and 5HHMF act synergistically and produce enhanced inhibitory effects on colon carcinogenesis by synergistically downregulating EGFR and K-Ras. Our rationale is that the successful completion of this project could lead to the development of a novel strategy for colon cancer prevention by using optimized combinations of 5HPMF and 5HHMF from orange peel. The hypothesis will be tested by pursuing two specific aims: 1) Determine the inhibitory actions of 5HPMF, 5HHMF, and their combination in an AOM-induced rat colon carcinogenesis model; and 2) Elucidate the molecular mechanisms of inhibition of colon carcinogenesis by 5HPMF, 5HHMF, and their combination. The innovation in this project is that: 1) it will investigate two novel flavonoid compounds from orange peel, that have not been studied for colon cancer prevention; and 2) The emphasis is on the development of synergistic interactions between the two compounds for their maximized effectiveness, rather than the activities of single isolated compounds. The information obtained from the proposed studies will facilitate the development of novel strategies using 5HPMF and 5HHMF in combination for colon cancer prevention. PUBLIC HEALTH RELEVANCE: The proposed studies focus on potential synergy among bioactive dietary components that is an important and under-investigated area of cancer prevention. Our contribution in this project is expected to be a detailed understanding of the mode of interaction between two unexploited hydroxylated polymethoxyflavones (OH-PMFs, from orange peel) in combination in inhibiting colon carcinogenesis. This contribution is significant because it will provide the knowledge needed to develop a novel colon cancer chemoprevention strategy using combinations of OH-PMFs for their maximized effectiveness, which could have a large positive impact on public health.

描述（由申请人提供）：通过合理选择生物活性饮食成分的有效组合来增强癌症化学预防，这是一个有吸引力的策略，这是由于这些成分之间的协同相互作用。但是，由于当前对饮食成分相互作用的不良理解，这种方法的使用受到了极大的限制。为了探索这种有希望的方法，该项目旨在确定两种羟基化多甲氧基氟法酮（OH-PMF，来自橙皮）及其对结肠致癌的组合的抑制作用，并确定它们的相互作用方式和涉及的分子机制。长期目标是制定预防结肠癌的饮食策略。我们的初步结果表明，5HPMF和5HHMF（两个主要的OH-PMF）的组合不仅在抑制培养物中的结肠癌细胞生长方面产生了强大的协同作用，而且还抑制了在硫烷（AOM）易于生存的大鼠中形成异常的隐层（ACF）。基于这些结果，我们的中心假设是5HPMF和5HHMF协同作用，并通过协同下调EGFR和K-RAS对结肠癌的抑制作用增强。我们的理由是，通过使用Orange Peel的5HPMF和5HHMF的优化组合，该项目的成功完成可能会导致预防结肠癌预防的新型策略。该假设将通过追求两个具体目的来检验：1）确定5HPMF，5HHMF的抑制作用及其在AOM诱导的大鼠结肠癌发生模型中的组合； 2）阐明了5HPMF，5HHMF及其组合的结肠癌发生的分子机制。该项目的创新是：1）它将研究橙皮的两种新型类黄酮化合物，这些化合物尚未用于预防结肠癌； 2）重点是两种化合物之间的协同相互作用的发展，以最大化的有效性，而不是单个隔离化合物的活性。从拟议的研究中获得的信息将促进使用5HPMF和5HHMF结合结肠癌预防结合的新型策略。 公共卫生相关性：拟议的研究集中于生物活性饮食成分之间的潜在协同作用，这是癌症预防的重要且受过审查的领域。预计我们在该项目中的贡献将是对两种未开发的羟基化多甲氧基氟法酮（OH-PMFS，来自橙皮的OH-PMF）之间的相互作用方式的详细理解，以抑制结肠癌发生。这项贡献很重要，因为它将提供使用OH-PMF的组合来最大程度地发挥其最大的有效性来制定新型结肠癌化学预防策略所需的知识，这可能会对公共卫生产生巨大的积极影响。