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

• 批准号: 10319568
• 负责人: Lorne J Hofseth
• 金额: $ 33.4万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 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/10319568
• 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' 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; Inflammatory; Inflammatory Bowel Diseases; Intestines; Knowledge; Lead; Life Style; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Nature; North America; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Plants; Prevalence; Property; Research; Resveratrol; SIRT1 gene; Sepsis; Signal Pathway; Signal Transduction; Source; Standardization; TNF gene; TP53 gene; Testing; Toxic effect; Treatment outcome; Treatment-related toxicity; Ulcerative Colitis; anti-cancer; anticancer activity; base; 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; macrophage; microbiota; murine colitis; novel; p53 Signaling Pathway; replication stress; response; sex; side effect; single molecule; small molecule; sound; treatment strategy

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.

项目摘要 影响到北美和欧洲的400多万人，经济负担为30美元- 450亿美元，炎症性肠病（IBD）使人衰弱，严重影响生活方式，并携带高 结肠癌风险。由于传统的治疗结果是温和的危险的副作用，大约一半 的IBD患者转向补充和替代药物（CAM）。尽管CAM已经被用于 几千年来，我们对支持其有效性的机制的了解存在差距。 了解这些机制将导致IBD的标准化治疗，而不是FDA批准的毒性治疗。 毒品这将降低他们患结肠癌的风险。在过去的十年里，我们已经证明，西洋参（AG） 抑制结肠炎并预防小鼠结肠癌。使用科学严谨的生物测定指导 通过分级分离，我们分离出一种具有抗炎、抗癌作用的聚乙炔化合物panaxynol（PA） 特性. PA（与正在测试的其他100种CAM相比）来自天然来源，并且是单一的 成分，允许它被标准化本身，或在鸡尾酒。是什么让这种分子 有趣且创新的是其机制--它是从AG中提取的单个分子，具有独特的能力 靶向巨噬细胞（mΦ）进行细胞凋亡。我们的长期目标是确定AG的主要组成部分 负责我们在过去几年中观察到的AG强大的抗炎和化学预防特性 过去十年;并确定其作用机制。本申请的总体目标是获得 更深入地了解：（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化动物模型）;和（B）结肠炎和结肠癌的生物工程化动物模型背后的潜在机制。 观察到PA靶向mΦ进行凋亡。我们在这里集中在DNA损伤独立的p53信号转导 途径作为朝向mΦ凋亡的机制。这项研究的科学前提是 健壮。比较九种FDA批准的药物，小分子和CAM，PA是最有效的， 在DSS小鼠模型中抑制结肠炎。我们的中心假设是，PA，经过十年的严格隔离， 生物测定引导的分离，在结肠中具有抗炎和抗癌活性，因为它激活 p53介导的浸润性MΦ中的细胞凋亡;减轻结肠炎;以及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- 类似于mΦ中的信号应答，其独立于可检测的DNA损伤。为了解决这个问题，我们 将在三种结肠炎小鼠模型和基因工程小鼠中测试PA的功效。因为它 PA似乎利用了mΦ中独特的p53机制，我们将在p53小鼠中测试PA 在结肠MΦ中条件性敲除。探索了一种不依赖于DNA损伤的机制。结果 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，可以迅速在临床上实施。