Abstract 4658: Resveratrol aspirinate derivatives as novel chemopreventive agents for colon cancer

Abstract

Abstract In more than a century of use, the benefits of aspirin have been exploited in different therapeutic areas, from inflammation to cardiovascular diseases and cancer prevention. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. The present study found 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 RAS can be hydrolyzed to regenerate resveratrol and aspirin in mice and in human colon cancer cells. Therefore they serve as prodrugs of aspirin and resveratrol and its derivatives. 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. Further mechanistic studies found that RAS inhibited cell growth through regulating cell cycle arrest via down-regulation of cyclins D1 and E, and inducing cancer cell apoptosis via mitochondrial pathway. In addition, two stable RAS analogues, for the first time, were successfully synthesized to demonstrate the importance of the scaffold composed of resveratrol and aspirin in the anti-cancer activity of RAS. Our results demonstrated for the first time that resveratrol based aspirin derivatives represent a brand-new, safer and improved alternative to aspirin in anti-cancer and anti-inflammatory therapies. Note: This abstract was not presented at the meeting. Citation Format: Shengmin Sang, Yingdong Zhu, Junsheng Fu, Kelly Shurlknight. Resveratrol aspirinate derivatives as novel chemopreventive agents for colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4658. doi:10.1158/1538-7445.AM2015-4658