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

项目总结 北美和欧洲有400多万人受到影响，经济负担达30美元- 450亿美元，炎症性肠病(IBD)使人虚弱，显著影响生活方式，并具有很高的 结肠癌风险。因为常规治疗的结果是温和的，有大约一半的危险副作用 的IBD患者转向补充和替代药物(CAM)。尽管凸轮已经被用于 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在FDA批准的有毒物质之外对IBD进行标准化治疗 毒品。这将降低他们患结肠癌的风险。在过去的十年里，我们已经证明了西洋参(AG) 抑制小鼠结肠炎和预防结肠癌。使用科学严谨的生物测定指导 通过分级分离，我们分离出了一种名为人参醇(PA)的聚乙炔，它具有抗炎和抗癌作用 属性。PA(与其他正在测试的100英寸S相比)来自天然来源，是一种单一的 成分，允许它自己标准化，或在鸡尾酒中。是什么让这种分子特别 有趣和创新的是机制-它是从AG中提取的单个分子，具有独特的能力 以巨噬细胞(m-Φ)为靶细胞进行细胞凋亡。我们的长期目标是确定股份公司的主要组成部分(S) 对我们观察到的AG强大的抗炎和化学预防作用负责 过去十年；并确定它们的行动机制。这个应用程序的总体目标是获得 加深对两者的了解：(A)PA的广泛治疗潜力(即多种药理和 (B)结肠炎和结肠癌的生物工程动物模型)；和(B) 观察PA靶向m-Φ诱导细胞凋亡。我们在这里集中在DNA损伤独立的P53信号 作为m-Φ细胞凋亡机制的途径。这项拟议研究的科学前提是 很健壮。比较FDA批准的9种药物、小分子药物和CAM，PA在以下方面最有效 抑制DSS小鼠模型中的结肠炎。我们的中心假设是，在经过十年的严格审查后被孤立的PA 生物测定引导的分级，在结肠中具有抗炎和抗癌活性，因为它激活了 P53介导的细胞凋亡在浸润性mΦ中的作用；减轻结肠炎；以及预防结肠癌与结肠炎相关。 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- 就像mΦ中独立于可检测到的dna损伤的信号反应。为了解决这一假设，我们 将在三种结肠炎小鼠模型和基因工程小鼠身上测试PA的疗效。因为它 似乎PA正在利用mΦ中独特的P53机制，我们将在携带P53的小鼠身上测试PA 有条件地在结肠mΦ中被击倒。探索了一种与DNA损伤无关的机制。结果 符合我们的假设将确定一种创新的、低成本、安全、特定和天然的化合物 可迅速用于临床的抗炎和癌症化学预防特性。

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.