A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway.
10.1016/j.apsb.2024.12.005
- Author:
Ying HOU
1
;
Bingling ZHONG
1
;
Lin ZHAO
1
;
Heng WANG
1
;
Yanyan ZHU
1
;
Xianzhe WANG
1
;
Haoyi ZHENG
1
;
Jie YU
1
;
Guokai LIU
2
;
Xin WANG
3
;
Jose M MARTIN-GARCIA
4
;
Xiuping CHEN
1
Author Information
1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 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 M13 9PT, UK.
4. Department of Crystallography & Structural Biology, Institute of Physical Chemistry Blas Cabrera, Spanish National Research Council (CSIC), Madrid 28006, Spain.
- Publication Type:Journal Article
- Keywords:
Calcium;
Cancer;
Cryptotanshinone;
Ferroptosis;
Iron;
NAD+ depletion;
NQO1;
Targeted therapy
- From:
Acta Pharmaceutica Sinica B
2025;15(2):991-1006
- CountryChina
- Language:English
-
Abstract:
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 as β-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 Ca2+, 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+/Ca2+ 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.
