Synergistic chemoprevention of colon cancer by hydroxylated polymethoxyflavones

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加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很大的限制。为了探索这一有前景的方法，本项目旨在确定两种羟基化多甲氧基黄酮（OH-PMFs，来自橘子皮）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。长期目标是制定以饮食为基础的结肠癌预防策略。我们的初步结果表明，5HPMF和5HHMF（两种主要的oh - pmf）联合使用不仅可以抑制培养的结肠癌细胞生长，而且可以抑制偶氮氧甲烷（AOM）处理大鼠异常隐窝灶（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，这个项目的成功完成可能会导致一种新的策略的发展，通过使用橙子皮中的5HPMF和5HHMF的优化组合来预防结肠癌。该假设将通过两个具体目标进行验证：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及其联合抑制结肠癌发生的分子机制。本项目的创新之处在于：1)将研究从橘子皮中提取的两种新的类黄酮化合物，这两种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，以最大限度地发挥其功效，而不是单个分离化合物的活性。从拟议的研究中获得的信息将促进使用5HPMF和5HHMF联合预防结肠癌的新策略的发展。

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.