A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway
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-La...
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Elsevier
2025-02-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383524004623 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ying Hou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cfc751c60df541f9a89ee02987d65621 |
| institution | DOAJ |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-cfc751c60df541f9a89ee02987d656212025-08-20T02:47:37ZengElsevierActa Pharmaceutica Sinica B2211-38352025-02-01152991100610.1016/j.apsb.2024.12.005A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathwayYing Hou0Bingling Zhong1Lin Zhao2Heng Wang3Yanyan Zhu4Xianzhe Wang5Haoyi Zheng6Jie Yu7Guokai Liu8Xin Wang9Jose M. Martin-Garcia10Xiuping Chen11State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, ChinaSchool of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, ChinaFaculty of Biology, Medicine and Health, the University of Manchester, Manchester M13 9PT, UKDepartment of Crystallography & Structural Biology, Institute of Physical Chemistry Blas Cabrera, Spanish National Research Council (CSIC), Madrid 28006, SpainState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao 999078, China; GMU-GIBH Joint School of Life Sciences, the Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou 510005, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2211383524004623NQO1CryptotanshinoneIronFerroptosisNAD+ depletionCalcium |
| spellingShingle | 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 A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway Acta Pharmaceutica Sinica B NQO1 Cryptotanshinone Iron Ferroptosis NAD+ depletion Calcium |
| title | A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway |
| title_full | A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway |
| title_fullStr | A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway |
| title_full_unstemmed | A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway |
| title_short | A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway |
| title_sort | small molecule cryptotanshinone induces non enzymatic nqo1 dependent necrosis in cancer cells through the jnk1 2 iron parp calcium pathway |
| topic | NQO1 Cryptotanshinone Iron Ferroptosis NAD+ depletion Calcium |
| url | http://www.sciencedirect.com/science/article/pii/S2211383524004623 |
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