A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway  

作　　者：Ying Hou Bingling Zhong Lin Zhao Heng Wang Yanyan Zhu Xianzhe Wang Haoyi Zheng Jie Yu Guokai Liu Xin Wang Jose M.Martin-Garcia Xiuping Chen 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao 999078,China [2]School of Pharmaceutical Sciences,Shenzhen University Medical School,Shenzhen University,Shenzhen 518055,China [3]Faculty of Biology,Medicine and Health,the University of Manchester,Manchester M139PT,UK [4]Department of Crystallography&Structural Biology,Institute of Physical Chemistry Blas Cabrera,Spanish National Research Council(CSIC),Madrid 28006,Spain [5]MoE Frontiers Science Center for Precision Oncology,University of Macao,Macao 999078,China [6]GMU-GIBH Joint School of Life Sciences,the Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases,Guangzhou Medical University,Guangzhou 510005,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第2期991-1006,共16页药学学报(英文版)

基　　金：supported by the Science and Technology Development Fund,Macao S.A.R(FDCT)(0070/2022/A2,005/2023/SKL,China);the National Natural Science Foundation of China(82173848);the Research Fund of University of Macao(MYRG2020-00053-ICMS,MYRG-GRG2023-00072-ICMS-UMDF,China);the Ministry of Education Frontiers Science Centre for Precision Oncology,University of Macao(SP2023-00001-FSCPO,China).

摘　　要：Human NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavoenzyme expressed at high levels in multiple solid tumors,making it an attractive target for anticancer drugs.Bioactivatable drugs targeting NQO1,such asβ-lapachone(β-lap),are currently in clinical trials for the treatment of cancer.β-Lap selectively kills NQO1-positive(NQO1^(+))cancer cells by inducing reactive oxygen species(ROS)via catalytic activation of NQO1.In this study,we demonstrated that cryptotanshinone(CTS),a naturally occurring compound,induces NQO1-dependent necrosis without affecting NQO1 activity.CTS selectively kills NQO1^(+)cancer cells by inducing NQO1-dependent necrosis.Interestingly,CTS directly binds to NQO1 but does not activate its catalytic activity.In addition,CTS enables activation of JNK1/2 and PARP,accumulation of iron and Ca^(2+),and depletion of ATP and NAD^(+).Furthermore,CTS selectively suppressed tumor growth in the NQO1^(+)xenograft models,which was reversed by NQO1 inhibitor and NQO1 shRNA.In conclusion,CTS induces NQO1-dependent necrosis via the JNK1/2/iron/PARP/NAD^(+)/Ca^(2+)signaling pathway.This study demonstrates the non-enzymatic function of NQO1 in inducing cell death and provides new avenues for the design and development of NQO1-targeted anticancer drugs.

关 键 词：NQO1 CRYPTOTANSHINONE Iron Ferroptosis NADþdepletion CALCIUM Targeted therapy Cancer 

分 类 号：R285[医药卫生—中药学]