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膳食成分的有效组合来增强癌症化学预防是一种有吸引力的策略，因为这些成分之间可能存在协同相互作用。然而，由于目前对膳食成分相互作用的了解不足，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黄酮（OH-PMF，来自橙皮）及其组合对结肠癌发生的抑制作用，并确定它们的相互作用模式和所涉及的分子机制。长期目标是制定基于饮食的结肠癌预防策略。我们的初步结果表明，5HPMF 和 5HHMF（两种主要的 OH-PMF）的组合不仅可以抑制培养中的结肠癌细胞生长，而且可以抑制氧化偶氮甲烷（AOM）治疗的大鼠中异常隐窝病灶（ACF）的形成。基于这些结果，我们的中心假设是5HPMF和5HHMF协同作用，通过协同下调EGFR和K-Ras来增强对结肠癌发生的抑制作用。我们的理由是，该项目的成功完成可能会导致通过使用来自橙皮的 5HPMF 和 5HHMF 的优化组合来开发预防结肠癌的新策略。该假设将通过两个具体目标进行检验：1）确定 5HPMF、5HHMF 及其组合在 AOM 诱导的大鼠结肠癌模型中的抑制作用； 2)阐明5HPMF、5HHMF及其组合抑制结肠癌发生的分子机制。该项目的创新点在于：1）将研究两种来自橙皮的新型黄酮类化合物，这些化合物尚未被研究用于预防结肠癌； 2) 重点是开发两种化合物之间的协同相互作用，以实现其最大功效，而不是单一孤立化合物的活性。从拟议研究中获得的信息将有助于开发联合使用 5HPMF 和 5HHMF 预防结肠癌的新策略。 公共健康相关性：拟议的研究重点是生物活性膳食成分之间的潜在协同作用，这是癌症预防的一个重要且尚未得到充分研究的领域。我们在该项目中的贡献预计将是详细了解两种未开发的羟基化多甲氧基黄酮（OH-PMF，来自橙皮）之间的相互作用模式，以抑制结肠癌的发生。这一贡献意义重大，因为它将提供使用 OH-PMF 组合开发新型结肠癌化学预防策略所需的知识，以最大限度地发挥其有效性，这可能对公众健康产生巨大的积极影响。