Harnessing the power of p53 with Panaxynol from American Ginseng to suppress colitis and prevent colon cancer

利用 p53 与西洋参中的人参醇 (Panaxynol) 的功效抑制结肠炎并预防结肠癌

基本信息

批准号：
10737737
负责人：
Lorne J Hofseth
金额：
$ 15.79万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10737737
关键词：
Ablation Address Affect American Animal Model Animals Anti-Inflammatory Agents Apoptosis Area Autoimmune Diseases Biological Assay Biomedical Engineering Cells Chemicals Chemoprevention Chemopreventive Agent Clinical Clinical Trials Coculture Techniques Colitis Colon Colon Carcinoma Combined Modality Therapy Complementary and alternative medicine Crohn&apos s disease DNA DNA Damage Dangerousness Disease Dose Drug Kinetics Economic Burden Effectiveness Europe Exposure to FDA approved Fractionation Functional disorder Genetically Engineered Mouse Genome Ginseng Preparation Goals Immune Induction of Apoptosis Infiltration Inflammatory Inflammatory Bowel Diseases Intestines Knowledge Lead Life Style LoxP-flanked allele Macrophage Malignant Neoplasms Mediating Modeling Molecular Mus Myeloid Cells Natural Compound Natural Source Nature North America Pathway interactions Patients Persons Pharmaceutical Preparations Plants Prevalence Property Research Resveratrol SIRT1 gene Sepsis Signal Pathway Signal Transduction Standardization TNF gene TP53 gene Testing Toxic effect Treatment outcome Ulcerative Colitis anti-cancer anticancer activity cancer chemoprevention cell type cellular targeting colon cancer prevention colon cancer risk conditional knockout conventional therapy cost dextran sulfate sodium induced colitis efficacy testing experimental study improved in vivo innovation microbiota murine colitis novel p53 Signaling Pathway pharmacologic replication stress response sex side effect single molecule small molecule sound treatment strategy

项目摘要

PROJECT SUMMARY Affecting upwards of 4 million people in North America and Europe, with an economic burden of $30 - $45 billion, Inflammatory Bowel Diseases (IBDs) are debilitating, significantly affect life-style, and carry a high colon cancer risk. Because conventional treatment outcomes are modest with dangerous side effects, about half of IBD patients turn to complementary and alternative medicines (CAMs). Although CAMs have been used for thousands of years, there is a gap in our knowledge of the mechanisms supporting their effectiveness. Understanding these mechanisms will lead to standardized treatment for IBD outside of toxic FDA-approved drugs. This will lower their colon cancer risk. Over the past decade, we have shown that American Ginseng (AG) suppresses colitis and prevents colon cancer in mice. Using scientifically rigorous Bioassay-Guided Fractionation, we have isolated a polyacetylene called panaxynol (PA) that has anti-inflammatory and anti-cancer properties. PA (compared to the100's of other CAMs being tested) comes from a natural source, and is a single ingredient, allowing it to be standardized on its own, or in a cocktail. What makes this molecule particularly interesting and innovative is the mechanism - it is a single molecule extracted from AG, with a unique capacity to target macrophages (mΦ) for apoptosis. Our long-term goal is to identify the primary component(s) of AG responsible for the robust anti-inflammatory and chemopreventive properties of AG we have observed over the past decade; and to determine their mechanism of action. The overall objective of this application is to gain a deeper understanding of both: (a) the broad treatment potential of PA (i.e. multiple pharmacologic and bioengineered animal models of colitis and colon cancer); and (b) the underlying mechanism(s) behind the observation that PA targets mΦ for apoptosis. We focus here on a DNA-damage independent p53 signaling pathway as a mechanism toward mΦ apoptosis. The scientific premise underlying the proposed research is robust. Comparing nine FDA-approved drugs, small molecules, and CAMs, PA is the most efficacious at suppressing colitis in a DSS mouse model. Our central hypothesis is that PA, isolated after a decade of rigorous bioassay-guided fractionation, has anti-inflammatory and anti-cancer activity in the colon because it activates p53- mediated apoptosis in infiltrating mΦ; mitigating colitis; and preventing colon cancer associated with colitis. Furthermore, PA acts as an anti-inflammatory in these models because it induces p53 through a DNA damage- like signaling response in mΦ that is independent of detectable DNA damage. To address this hypothesis, we will test the efficacy of PA in three mouse models of colitis and in genetically engineered mice. Because it appears that PA is taking advantage of a unique p53 mechanism in mΦ, we will test PA in mice with p53 conditionally knocked out in colonic mΦ. A DNA damage-independent mechanism is explored. Results consistent with our hypothesis would identify an innovative, low cost, safe, specific, and natural compound with anti-inflammatory and cancer chemopreventive properties that could quickly be implemented clinically.

项目概要影响北美和欧洲超过 400 万人，造成 30 美元的经济负担 - 炎症性肠病 (IBD) 造成 450 亿美元的损失，使人衰弱，严重影响生活方式，并带来高风险因为传统的治疗结果有限，并且有危险的副作用，大约有一半的风险。的 IBD 患者转向补充和替代药物 (CAM)，尽管 CAM 已用于治疗。几千年来，我们对支持其有效性的机制的了解存在差距。了解这些机制将有助于在 FDA 批准的有毒物质之外实现 IBD 的标准化治疗这将降低他们患结肠癌的风险在过去的十年中，我们已经证明西洋参 (AG)。使用科学严格的生物测定引导抑制结肠炎并预防结肠癌。分馏，我们分离出了一种叫做人参醇（PA）的聚乙炔，具有抗炎、抗癌作用 PA（与正在测试的数百种其他 CAM 相比）来自天然来源，并且是单一的。成分，使其能够单独标准化，或在鸡尾酒中标准化。是什么让这种分子特别如此。有趣且创新的是其机制 - 它是从 AG 中提取的单分子，具有独特的能力我们的长期目标是确定 AG 的主要成分。我们观察到，AG 具有强大的抗炎和化学预防特性过去十年；并确定其作用机制。该应用的总体目标是获得对两者有更深入的了解：(a) PA 的广泛治疗潜力（即多种药理学和结肠炎和结肠癌的生物工程动物模型）；以及（b）背后的潜在机制观察到 PA 针对 mΦ 进行细胞凋亡，我们在此关注 DNA 损伤独立的 p53 信号传导。作为 mΦ 细胞凋亡机制的途径本研究的科学前提是与 FDA 批准的九种药物、小分子和 CAM 相比，PA 是最有效的。我们的中心假设是，经过十年严格的研究，PA 被分离出来。生物测定引导的分级分离，在结肠中具有抗炎和抗癌活性，因为它激活 p53 介导的细胞凋亡可减轻浸润性结肠炎；并预防与结肠炎相关的结肠癌。此外，PA 在这些模型中起到抗炎作用，因为它通过 DNA 损伤诱导 p53 - mΦ 中的信号反应与可检测到的 DNA 损伤无关。将测试 PA 在三种结肠炎小鼠模型和基因工程小鼠中的功效。看来 PA 正在利用 mΦ 中独特的 p53 机制，我们将在具有 p53 的小鼠中测试 PA 探索了结肠 mΦ 中的 DNA 损伤无关机制。与我们的假设一致，将确定一种创新的、低成本的、安全的、特异性的和天然的化合物抗炎和癌症化学预防特性可以快速应用于临床。