Novel cinnamaldehyde-based aspirin derivatives for the treatment of colorectal cancer

摘要

Colorectal cancer (CRC) is a leading cause of mortality worldwide. Current treatments of CRC involve anti-cancer agents with relatively good efficacy but unselectively target both cancer and non-cancer cells. Thus, there is a need to discover and develop novel CRC therapeutics that have potent anti-cancer effects, but show reduced off-target cell effects. Here, a novel series of cinnamaldehyde-based aspirin derivatives were designed and synthesized. Biological evaluation indicated that the most active compound1fexhibited more than 10-fold increase in the anti-proliferation efficacy in HCT-8 cells compared to the parent compounds. Its effects were similarly reproduced in another CRC cell line, DLD-1, but with 7- to 11-fold less inhibitory activity in non-tumorigenic colon cells. Flow cytometry analysis showed that1finduced cell cycle arrest and apoptosis, which was further validated with immunoblot analysis of the relative protein levels of cleaved caspase 3 and PARP as well as the ROS production in CRC cells. More so,1fsignificantly inhibited the growth of implanted CRCin vivoin mouse xenograft model. Taken together, our results show that cinnamaldehyde-based aspirin derivatives such as1fshow promise as novel anti-CRC agent for further pharmaceutical development.