Hou Ying, Zhong Bingling, Zhao Lin, Wang Heng, Zhu Yanyan, Wang Xianzhe, Zheng Haoyi, Yu Jie, Liu Guokai, Wang Xin, Martin-Garcia Jose M, Chen Xiuping
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
Acta Pharm Sin B. 2025 Feb;15(2):991-1006. doi: 10.1016/j.apsb.2024.12.005. Epub 2024 Dec 9.
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 -lapachone (-lap), are currently in clinical trials for the treatment of cancer. -Lap selectively kills NQO1-positive (NQO1) cancer cells by inducing reactive oxygen species (ROS) 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, 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 the JNK1/2/iron/PARP/NAD/Ca 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.
人NAD(P)H：醌氧化还原酶1（NQO1）是一种黄素酶，在多种实体瘤中高表达，这使其成为抗癌药物的一个有吸引力的靶点。靶向NQO1的可生物活化药物，如β-拉帕醌（β-lap），目前正处于癌症治疗的临床试验阶段。β-拉帕醌通过诱导活性氧（ROS）和NQO1的催化活化选择性杀死NQO1阳性（NQO1+）癌细胞。在本研究中，我们证明了隐丹参酮（CTS），一种天然存在的化合物，可诱导NQO1依赖性坏死而不影响NQO1活性。CTS通过诱导NQO1依赖性坏死选择性杀死NQO1+癌细胞。有趣的是，CTS直接与NQO1结合但不激活其催化活性。此外，CTS可激活JNK1/2和PARP，促进铁和钙的积累，并消耗ATP和NAD。此外，CTS在NQO1异种移植模型中选择性抑制肿瘤生长，NQO1抑制剂和NQO1 shRNA可逆转这种抑制作用。总之，CTS通过JNK1/2/铁/PARP/NAD/钙信号通路诱导NQO1依赖性坏死。本研究证明了NQO1在诱导细胞死亡中的非酶功能，并为设计和开发靶向NQO1的抗癌药物提供了新途径。
