Nan Wu , Yue Zhang , Xiongjie Yin , Peng Du , Yan Piao , Jiuzhen Zhao , Jing Zhu , Zheshan Quan , Cheng-Zhu Wu , Lili Jin , Changhao Zhang
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引用次数: 0
Abstract
Curcumin (CUR) is a natural product isolated from Curcuma longa L., which has become a research hotspot due to its significant anti-tumor activity by inducing tumor cell apoptosis and inhibiting proliferation. This study designed and synthesized 20 CUR derivatives containing 1,2,3-triazoles and heterocycles by modifying the methylene group between two carboxyl groups of CUR and hybridizing with aldehyde containing fragments. Among them, compound A4 showed significant in vitro anti proliferative activity against 4T1 and MDA-MB-231, and could dose dependently induce early and late apoptosis in 4T1 cells. Further research has found that A4 induces ferroptosis in 4T1 cells by regulating the levels of reactive oxygen species (ROS), ferrous ions (Fe2+), lipid peroxidation (LPO), and glutathione (GSH), as well as disrupting the integrity and homeostasis of mitochondrial membranes. In addition, A4 significantly inhibits the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), while promoting the expression of p53 protein. Gene knockout test confirmed that A4 may induce cell ferroptosis through p53/SLC7A11/GPX4 signaling pathway and play an anti breast cancer role. These findings indicate that CUR derivative A4 is a new type of ferroptosis inducer. It can induce apoptosis of cells by regulating multiple targets in cells to achieve the purpose of anti breast cancer, which is helpful for cancer treatment and overcoming the further development of drug resistance.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.