Discovery a novel hybrid with resveratrol and hans ester derivatives as activators induce autophagic cell death in tumoral NCI-H460 cells through production of ROS

Abstract Based on the integrated fragment-based drug design, synthesis, and in vivo evaluations, a series of novel resveratrol and hans ester (ReHa) derivatives are discovered as autophagic death inducer. Compound ReHa-2 is the most potent inducer with IC50 values as low as 9.9 mM compare with the molecule (NIP) in autophagic cell death. Compound ReHa-2 lead to autophagic cells death instead of necrosis or apoptosis in human NCI-H460 cells. Mechanistic study uncovers that ReHa-2 is capable of increasing protein LC3-II (a marker of autophagy) and reducing p62 in a time- and dose-dependent manner. Furthermore, ReHa-2 can activate MAPKs and Akt signal pathway. In addition, we identified that ReHa-2 triggered more ROS generation compare with NIP in NCI-H460 cells. Noticeably, the cytotoxicity induced by ReHa-2 against NCI-H460 cells can be significantly revised by pretreatment of the cells with the CAT (a specific scavenger of H2O2) and DTT (a sulfhydrylcontaining nucleophile for quenching ROS), suggesting that the ROS (mainly including H2O2) induced by ReHa-2 is responsible for its cytotoxicity against NCI-H460 cells. Our results suggest that ReHa-2 displays potent activators by inducing autophagic cell death through production of ROS.