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。该项目的目的是开发白藜芦醇阿斯匹林衍生物，作为预防结肠癌的阿司匹林的安全有效的替代品。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结直肠癌的可能性要小得多。然而，阿司匹林使用的主要限制是它的副作用，引起胃肠道溃疡和出血。此外，阿司匹林的疗效有限。在过去十年中，已经采用了几种创新方法来解决这一问题。提供一氧化氮（NO）的阿司匹林就是一个例子。不幸的是，由于担心其潜在的遗传毒性，no -阿司匹林用于结肠癌的临床化学预防试验最近过早终止。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，葡萄和浆果中的天然化学预防剂白藜芦醇及其甲基化衍生物可以与乙酰水杨酰氯反应生成阿司匹林白藜芦醇（RAS）及其衍生物。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）的生长抑制作用明显强于白藜芦醇和阿司匹林单用以及白藜芦醇和阿司匹林合用。此外，我们发现这类化合物可以在小鼠和人类结肠癌细胞中水解再生阿司匹林和相关的苯乙烯。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。与阿司匹林与白藜芦醇单纯联合使用相比，RAS不仅对人结肠癌细胞有更大的生长抑制作用，而且可以防止阿司匹林与胃粘膜直接接触对胃上皮细胞的损伤。我们计划在以下几个具体目标中检验我们的假设：1。测定白藜芦醇阿司匹林（RAS）对偶氮甲烷处理小鼠模型异常隐窝灶（ACF）形成的化学预防作用及其长期胃肠道副作用。2. 研究小鼠给药后白藜芦醇的生物利用度和生物转化。我们相信本项目的研究结果将为该新型药物对结肠癌的化学预防作用提供基础信息。由于阿司匹林和白藜芦醇都有不同的药理活性，RAS对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也非常有用。

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.