Novel Resveratrol-based Aspirin Prodrugs: Synthesis, Metabolism, and Anticancer Activity, J Med Chem. 2015 J
Zhu Y, Fu J, Shurlknight K, Soroka D, Hu Y, Chen XL, Sang S.
Regular aspirin use has been convincingly shown to reduce the risk of colorectal cancer. However, long-term use of aspirin leads to gastrotoxicity. Herein, we designed and synthesized a novel class of resveratrol-based aspirin prodrugs to simultaneously release aspirin and resveratrol to attenuate the side effects caused by aspirin. Prodrug RAH exerted enhanced anticancer activities which are better than a physical mixture of aspirinand resveratrol as well as each individual. Metabolism of RAH in mice showed that the majority of RAH is decomposed to release resveratrol andaspirin or salicylic acid either in the intestine or after absorption. Mechanistic studies demonstrate RAH inhibits cell cycle arrest through downregulation of cyclins, and induces apoptosis by activation of caspase-3 in cancer cells. These findings highlighted the improved anticancerproperties of resveratrol-based aspirin prodrugs. RAH may represent novel and safe alternatives of aspirin for the purpose of daily use in the future.
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