Therapeutic strategies of targeting nonapoptotic regulated cell death (RCD) with smallmolecule compounds in cancer  

作　　者：Xin Jin Wenke Jin Linlin Tong Jia Zhao Lan Zhang Na Lin 

机构地区：[1]Department of Ultrasound,Department of Medical Oncology and Department of Hematology,the First Hospital of China Medical University,China Medical University,Shenyang 110001,China [2]Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs,School of Life Science and Engineering,Southwest Jiaotong University,Chengdu 610031,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期2815-2853,共39页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant No.22277102).

摘　　要：Regulated cell death(RCD)is a controlled form of cell death orchestrated by one or more cascading signaling pathways,making it amenable to pharmacological intervention.RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis,facilitating development,and modulating immunity.Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival.Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse,comparable to apoptosis.Moreover,they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs.With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines,a growing number of small-molecule compounds targeting single or multiple pathways have been discovered,providing novel strategies for current cancer therapy.In this review,we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines,mainly including autophagy-dependent cell death,ferroptosis,cuproptosis,disulfidptosis,necroptosis,pyroptosis,alkaliptosis,oxeiptosis,parthanatos,mitochondrial permeability transition(MPT)-driven necrosis,entotic cell death,NETotic cell death,lysosome-dependent cell death,and immunogenic cell death(ICD).Furthermore,we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds.In brief,these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines,ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.

关 键 词：Regulated cell death(RCD) Non-apoptotic RCD subroutine Autophagy Ferroptosis NECROPTOSIS Regulatory mechanism Small-molecule compound Cancer therapy 

分 类 号：R730.5[医药卫生—肿瘤]