Resveratrol Aspirinate Derivatives as Novel Chemopreventive Agents for Colon Canc

白藜芦醇阿司匹林衍生物作为结肠癌的新型化学预防剂

• 批准号: 8534724
• 负责人: Shengmin Sang
• 金额: $ 6.7万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534724
• 关键词: Aberrant crypt foci; Address; Adverse effects; Affect; Aspirin; Azoxymethane; Berry; Biological Availability; Biological Products; Blood; Cardiovascular Diseases; Cause of Death; Cell Proliferation; Chemical Agents; Chemoprevention; Chemopreventive Agent; Chloride Ion; Chlorides; Clinical Chemoprevention; Colon; Colon Carcinoma; Colorectal Cancer; Diabetes Mellitus; Diet; Dietary Phytochemical; Disease; Drug Kinetics; Epidemiologic Studies; Epithelial Cells; Feces; France; Future; Gastric mucosa; Gastrointestinal tract structure; Ginger; Goals; Grapes; Green tea; Growth; HT29 Cells; Hemorrhage; Human; Induction of Apoptosis; Inflammation; Inhibition of Cell Proliferation; Malignant Neoplasms; Metabolic; Metabolic Biotransformation; Methods; Mus; Natural regeneration; Nitric Oxide; Non-Steroidal Anti-Inflammatory Agents; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Prevention; Prevention strategy; Preventive; Prodrugs; Research; Resveratrol; Sampling; Stilbenes; Stomach; Testing; Tissues; Toxic effect; Ulcer; Urine; Woman; base; cancer cell; cancer prevention; cancer type; carcinogenesis; gallocatechol; gastrointestinal; genotoxicity; global health; in vivo; innovation; interest; liquid chromatography mass spectrometry; men; mouse model; novel; novel strategies; prevent; shogaol; statistics

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.

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。该项目的目标是开发白藜芦醇阿司匹林衍生物，作为阿司匹林的安全有效替代品，用于预防结肠癌。流行病学研究表明，经常服用阿司匹林的人患结直肠癌的可能性比不服用阿司匹林的人要低得多。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，阿司匹林的功效也是有限的。在过去的十年中，已经采用了几种创新方法来解决这个问题。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-阿司匹林治疗结肠癌的临床化学预防试验最近提前终止。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（一种来自葡萄和浆果的天然化学预防剂）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酯（RAS）和相关衍生物。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以及白藜芦醇和阿司匹林的组合强得多。阿司匹林。此外，我们发现此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二苯乙烯。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。根据我们的初步结果，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。与单纯联合阿司匹林和白藜芦醇相比，RAS不仅对人结肠癌细胞具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造成的胃上皮细胞损伤。我们计划在以下具体目标中检验我们的假设： 1. 确定白藜芦醇阿司匹酯 (RAS) 对氧化偶氮甲烷处理的小鼠模型中异常隐窝病灶 (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酯(RAS)给小鼠给药后的生物利用度和生物转化。 我们相信该项目的结果将为这种新型药物对结肠癌的化学预防作用提供基本信息。由于阿司匹林和白藜芦醇都具有不同的药理活性，RAS对于预防其他类型的癌症和其他疾病（例如炎症、心血管疾病和糖尿病）也非常有用。

项目成果

Novel Resveratrol-Based Aspirin Prodrugs: Synthesis, Metabolism, and Anticancer Activity.

基于白藜芦醇的新型阿司匹林前药：合成、代谢和抗癌活性。

• DOI: 10.1021/acs.jmedchem.5b00536
• 发表时间: 2015-08-05
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Yingdong Zhu;Junsheng Fu;Kelly L. Shurlknight;Dominique N. Soroka;Yuhui Hu;Xiaoxin Chen;S. Sang
• 通讯作者: S. Sang

Gastroprotective [6]-Gingerol Aspirinate as a Novel Chemopreventive Prodrug of Aspirin for Colon Cancer.

胃保护性 [6]-姜酚阿司匹林酯作为阿司匹林的新型化学预防前药，用于治疗结肠癌。

• 发表时间: 2017-01-09
• 影响因子: 4.6
• 作者: Zhu, Yingdong;Wang, Fang;Zhao, Yantao;Wang, Pei;Sang, Shengmin
• 通讯作者: Sang, Shengmin