Synergistic chemoprevention of colon cancer by hydroxylated polymethoxyflavones

描述(由申请人提供)：通过合理选择有效的生物活性饮食成分组合来加强癌症化学预防是一个有吸引力的策略，因为这些成分之间可能存在协同作用。然而，由于目前对饮食成分相互作用的了解很差，这种方法的使用受到了极大的限制。为了探索这一有希望的方法，本项目旨在确定两种羟基聚甲氧基黄酮(OH-PMF，从橘皮中提取)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涉及的分子机制。长期目标是开发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)联合使用不仅在抑制培养的结肠癌细胞生长方面有很强的协同作用，而且在抑制偶氮甲烷(AOM)处理的大鼠的异常隐窝灶(ACF)形成方面也有很强的协同作用。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而增强对结肠癌发生的抑制作用。我们的理论基础是，该项目的成功完成可能会导致开发一种新的策略，通过使用从橙皮中提取的5HPMF和5HHMF的优化组合来预防结肠癌。这一假说将通过两个特定的目标来验证：1)在AOM诱导的大鼠结肠癌模型中，确定5HPMF、5HHMF及其组合的抑制作用；2)阐明5HPMF、5HHMF及其组合抑制结肠癌发生的分子机制。该项目的创新之处在于：1)将从橙皮中研究两种尚未被研究用于预防结肠癌的新型黄酮类化合物；2)重点是开发这两种化合物之间的协同作用，以实现其最大限度的有效性，而不是单一分离化合物的活性。从拟议的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。 公共卫生相关性：拟议的研究重点是生物活性饮食成分之间的潜在协同作用，这是癌症预防的一个重要而未被研究的领域。我们在这个项目中的贡献有望是详细了解两种未开发的羟基聚甲氧基黄酮(OH-PMF，从橙皮中提取)在抑制结肠癌发生中的相互作用模式。这一贡献意义重大，因为它将提供所需的知识，利用羟基PMF的组合开发一种新的结肠癌化学预防策略，以实现其最大限度的有效性，这可能对公众健康产生巨大的积极影响。

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.