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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

基本信息

批准号：
8098904
负责人：
Hang Xiao
金额：
$ 16.72万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098904
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 Health 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

项目摘要

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组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，因为这些组分之间可能存在协同相互作用。然而，这种方法的使用受到了很大的限制，目前对膳食成分相互作用的认识不足。为了探索这种有前途的方法，本项目旨在确定两种羟基化多甲氧基黄酮（OH-PMFs，从橙子皮）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。长期目标是制定基于饮食的结肠癌预防策略。我们的初步结果表明，5 HPMF和5 HHMF（两个主要的OH-PMF）的组合产生了很强的协同作用，不仅在抑制结肠癌细胞的生长在培养中，而且在抑制异常隐窝病灶（ACF）的形成在氧化偶氮甲烷（AOM）处理的大鼠。基于这些结果，我们的中心假设是，5 HPMF和5 HHMF协同作用，并通过协同下调EGFR和K-Ras对结肠癌发生产生增强的抑制作用。我们的理由是，该项目的成功完成可能会导致开发一种新的策略，通过使用优化的组合，从橙子皮的5 HPMF和5 HHMF结肠癌预防。将通过追求两个特定目标来检验该假设：1）确定5 HPMF、5 HHMF及其组合在AOM诱导的大鼠结肠癌发生模型中的抑制作用;以及2）阐明5 HPMF、5 HHMF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）它将研究来自橙子皮的两种新型黄酮类化合物，这两种化合物尚未被研究用于结肠癌预防; 2）重点是开发两种化合物之间的协同相互作用，以实现其最大化的有效性，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新的策略，使用5 HPMF和5 HHMF联合预防结肠癌。公共卫生相关性：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和未充分研究的领域。我们在这个项目中的贡献，预计将是一个详细的了解两个未开发的羟基化多甲氧基黄酮（OH-PMFs，从橙子皮）之间的相互作用模式，在抑制结肠癌的发生。这一贡献是重要的，因为它将提供开发一种新的结肠癌化学预防策略所需的知识，使用OH-PMF的组合以实现其最大化的有效性，这可能对公共卫生产生巨大的积极影响。