Resveratrol Aspirinate Derivatives as Novel Chemopreventive Agents for Colon Canc

描述（由申请人提供）：白藜芦醇阿司匹林衍生物作为结肠癌的新型化学预防剂。本项目的目的是开发白藜芦醇阿司匹林衍生物作为安全而有效的替代阿司匹林预防结肠癌。流行病学研究表明，经常服用阿司匹林的人比不服用阿司匹林的人患CRC的可能性要小得多。然而，使用阿司匹林的主要限制是其副作用，导致胃肠道溃疡和出血。此外，阿司匹林的疗效有限。在过去十年中，为解决这一问题采取了若干创新办法。一氧化氮（NO）-捐赠阿司匹林就是一个例子。不幸的是，NO-阿司匹林用于结肠癌的临床化学预防试验最近由于担心其潜在的遗传毒性而提前终止。因此，迫切需要更安全、更有效的阿司匹林替代品。 我们最近的研究结果表明，白藜芦醇，一种天然的化学预防剂，从葡萄和浆果，及其甲基化衍生物可以与乙酰水杨酰氯反应，形成白藜芦醇阿司匹林酯（RAS）和相关的衍生物。在所有合成的衍生物中，我们发现RAS是活性最强的成分，对人结肠癌细胞（HCT-116和HT-29）的生长抑制作用比白藜芦醇和阿司匹林沿着，以及白藜芦醇和阿司匹林的组合强得多。此外，我们发现，这种类型的化合物可以水解，以再生阿司匹林和相关的芪在小鼠和人类结肠癌细胞。因此，它们可以作为阿司匹林和白藜芦醇及其衍生物的前药。基于我们的初步结果，我们假设RAS作为阿司匹林和白藜芦醇的前药是比阿司匹林和白藜芦醇更有效的结肠癌预防剂。与阿司匹林和白藜芦醇简单联合应用相比，RAS不仅对人结肠癌细胞具有更强的生长抑制作用，而且可以防止阿司匹林与胃粘膜直接接触引起的胃上皮细胞损伤。我们计划在以下具体目标中测试我们的假设：1。在氧化偶氮甲烷处理的小鼠模型中确定白藜芦醇阿司匹林酯（RAS）对异常隐窝病灶（ACF）形成的化学预防功效，以及其长期胃肠道副作用。 2.研究白藜芦醇阿司匹林酯（RAS）在小鼠体内的生物利用度和生物转化。 我们相信，从这个项目的结果将提供基本的信息，这种新的药物对结肠癌的化学预防作用。由于阿司匹林和白藜芦醇都具有不同的药理活性，RAS也将非常有助于预防其他类型的癌症和其他疾病，如炎症，心血管疾病和糖尿病。 公共卫生相关性：白藜芦醇阿司匹林衍生物作为结肠癌的新型化学预防剂。 化学预防是一种积极的癌症预防策略，使用天然或合成的化学试剂来抑制或延迟人类致癌。结直肠癌（CRC）是一个重大的全球健康问题，是全世界男性和女性癌症死亡的第三大原因（WHO统计数据，2009年）。在过去的十五年中，对CRC的化学预防的兴趣显著增加。令人印象深刻的证据支持这样一种观点，即某些膳食植物化学物质和非甾体抗炎药（NSAID）是预防结肠癌的有希望的药物。这项研究的目的是开发一种新的阿司匹林和白藜芦醇的前体药物白藜芦醇阿司匹林酯，作为阿司匹林预防结肠癌的安全有效的替代品。

DESCRIPTION (provided by applicant): Resveratrol Aspirinate Derivatives as Novel Chemopreventive Agents for Colon Cancer . The objective of this project is to develop resveratrol aspirinate derivatives as safe yet effective alternatives to aspirin for colon cancer prevention. Epidemiological studies have demonstrated that regular aspirin users are substantially less likely to develop CRC than non-users. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. In addition, the efficacy of aspirin is limited. Several innovative approaches have been employed in the last decade to address this issue. Nitric oxide (NO)-donating aspirin was one example. Unfortunately, a clinical chemoprevention trial of NO-aspirin for colon cancer was recently terminated prematurely due to concerns about its potential genotoxicity. Therefore, safer and more effective alternatives to aspirin are urgently needed. Our recent results show that resveratrol, a natural chemopreventive agent from grapes and berries, and its methylated derivatives can react with acetylsalicyloyl chloride to form resveratrol aspirinate (RAS) and related derivatives. Among all the synthesized derivatives, we found that RAS is the most active component and have much stronger growth inhibitory effect on human colon cancer cells (HCT-116 and HT-29) than resveratrol and aspirin along, as well as the combination of resveratrol and aspirin. In addition, we found that this type of compounds can be hydrolyzed to regenerate aspirin and related stilbene in mice and in human colon cancer cells. Therefore they may serve as prodrugs of aspirin and resveratrol and its derivatives. Based on our preliminary results, we hypothesize that RAS as a prodrug of aspirin and resveratrol is a more potent colon cancer preventive agent than aspirin and resveratrol. Compared to simply combining aspirin and resveratrol, RAS has not only greater growth inhibitory effects on human colon cancer cells, but also can prevent the damage of gastric epithelial cells caused by direct contact between aspirin and gastric mucosa. We plan to test our hypothesis in the following specific aims: 1. Determine the chemopreventive efficacy of resveratrol aspirinate (RAS) against aberrant crypt foci (ACF) formation in the azoxymethane-treated mouse model, as well as its long-term gastrointestinal side effects. 2. Study the bioavailability and biotransformation of resveratrol aspirinate (RAS) after administration of it to mice. We believe that results from this project will provide basic information on the chemopreventive effect of this novel agent on colon cancer. Since both aspirin and resveratrol have diverse pharmacologic activities, RAS will also be very useful for the prevention of other types of cancer and other diseases, such as inflammation, cardiovascular diseases, and diabetes. PUBLIC HEALTH RELEVANCE: Resveratrol Aspirinate Derivatives as Novel Chemopreventive Agents for Colon Cancer. Chemoprevention is an active cancer preventive strategy to inhibit or delay human carcinogenesis, using naturally occurring or synthetic chemical agents. Colorectal cancer (CRC) is a significant global health concern and is the third leading cause of death from cancer among both men and women worldwide (WHO statistics, 2009). Interest in the chemoprevention of CRC has increased significantly over the past fifteen years. An impressive body of evidence supports the notion that certain dietary phytochemicals and nonsteroidal anti- inflammatory drugs (NSAIDs) are promising agents for colon cancer prevention. The goal of the proposed research is to develop resveratrol aspirinate, a novel prodrug of aspirin and resveratrol, as a safe yet effective alternative to aspirin for colon cancer prevention.