Chemotherapy: Open Access
Open Access

Abstract

Discovery of Novel Hybrid with Resveratrol and Hantzsch Ester Derivatives as Activators Induce Autophagic Cell Death in Tumoral NCI-H460 Cells through Production of ROS

Yu-Ting Du*, Hong-Liang Wang, San-Hu Zhao and Xiao-Juan Zhang

Based on the integrated fragment-based drug design, synthesis, and in vivo evaluations, a series of novel resveratrol and hantzsch 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 Nitrendipine (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 sulfhydryl containing 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.

Published Date: 2022-10-04; Received Date: 2022-09-01