title: Novel Resveratrol-Based Aspirin Prodrugs: Synthesis, Metabolism, and Anticancer Activity.
abstract: 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 aspirin and resveratrol as well as each individually. Metabolism of RAH in mice showed that the majority of RAH is decomposed to release resveratrol and aspirin 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 anticancer properties of resveratrol-based aspirin prodrugs. RAH may represent novel and safe alternatives of aspirin for the purpose of daily use in the future.
authors.affiliation: Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University , North Carolina Research Campus, 500 Laureate Way, Kannapolis, North Carolina 28081, United States.
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University , North Carolina Research Campus, 500 Laureate Way, Kannapolis, North Carolina 28081, United States.|College of Life Sciences, Fujian Agriculture and Forestry University , No. 15 Shangxiadian Road, Cangshan District, Fuzhou, Fujian Province 350002, P. R. China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Fu
authors.affiliation: Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University , North Carolina Research Campus, 500 Laureate Way, Kannapolis, North Carolina 28081, United States.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Shurlknight
authors.affiliation: Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University , North Carolina Research Campus, 500 Laureate Way, Kannapolis, North Carolina 28081, United States.
authors.forename: Dominique N
authors.initials: DN
authors.lastname: Soroka
authors.affiliation: Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University , 700 George Street, Durham, North Carolina 27707, United States.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University , 700 George Street, Durham, North Carolina 27707, United States.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University , North Carolina Research Campus, 500 Laureate Way, Kannapolis, North Carolina 28081, United States.
authors.forename: Shengmin
authors.initials: S
authors.lastname: Sang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016213:Cyclins / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016213:Cyclins; D011355:Prodrugs; D013267:Stilbenes; D053148:Caspase 3; D000077185:Resveratrol; D001241:Aspirin