State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao Special Administrative Region of China; School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao Special Administrative Region of China.
Drug Resist Updat. 2023 Sep;70:100977. doi: 10.1016/j.drup.2023.100977. Epub 2023 Jun 2.
Drug resistance is a major challenge in cancer treatment. The substrates of NAD(P)H:quinone oxidoreductase 1 (NQO1) show a promising anticancer effect in clinical trials. We previously identified a natural NQO1 substrate 2-methoxy-6-acetyl-7-methyljuglone (MAM) with a potent anticancer effect. The present study was designed to explore the efficacy of MAM in fighting against drug-resistant non-small cell lung cancer (NSCLC). The anticancer effect of MAM was evaluated in cisplatin-resistant A549 and AZD9291-resistant H1975 cells. The interaction of MAM with NQO1 was measured by cellular thermal shift assay and drug affinity responsive target stability assay. The NQO1 activity and expression were measured using NQO1 recombinant protein, Western blotting, and immunofluorescence staining assay. The roles of NQO1 were examined by NQO1 inhibitor, small interfering RNA (siRNA), and short hairpin RNA (shRNA). The roles of reactive oxygen species (ROS), labile iron pool (LIP), and lipid peroxidation were determined. MAM induced significant cell death in drug-resistant cells with similar potency to that of parental cells, which were completely abolished by NQO1 inhibitor, NQO1 siRNA, and iron chelators. MAM activates and binds to NQO1, which triggers ROS generation, LIP increase, and lipid peroxidation. MAM significantly suppressed tumor growth in the tumor xenograft zebrafish model. These results showed that MAM induced ferroptosis by targeting NQO1 in drug-resistant NSCLC cells. Our findings provided a novel therapeutic strategy for fighting against drug resistance by induction of NQO1-mediated ferroptosis.
耐药性是癌症治疗的主要挑战。烟酰胺腺嘌呤二核苷酸（NAD(P)H）：醌氧化还原酶 1（NQO1）的底物在临床试验中显示出有希望的抗癌作用。我们之前鉴定了一种天然的 NQO1 底物 2-甲氧基-6-乙酰-7-甲基胡桃醌（MAM），具有很强的抗癌作用。本研究旨在探讨 MAM 对抗耐药性非小细胞肺癌（NSCLC）的疗效。在顺铂耐药的 A549 和 AZD9291 耐药的 H1975 细胞中评估了 MAM 的抗癌作用。通过细胞热转移测定和药物亲和反应靶稳定性测定来测量 MAM 与 NQO1 的相互作用。使用 NQO1 重组蛋白、Western 印迹和免疫荧光染色测定来测量 NQO1 的活性和表达。通过 NQO1 抑制剂、小干扰 RNA（siRNA）和短发夹 RNA（shRNA）来检查 NQO1 的作用。确定了活性氧（ROS）、不稳定铁池（LIP）和脂质过氧化的作用。MAM 诱导耐药细胞发生显著的细胞死亡，其效力与亲本细胞相似，这完全被 NQO1 抑制剂、NQO1 siRNA 和铁螯合剂所消除。MAM 激活并与 NQO1 结合，触发 ROS 生成、LIP 增加和脂质过氧化。MAM 显著抑制了肿瘤异种移植斑马鱼模型中的肿瘤生长。这些结果表明，MAM 通过靶向耐药性 NSCLC 细胞中的 NQO1 诱导铁死亡。我们的研究结果为通过诱导 NQO1 介导的铁死亡来对抗耐药性提供了一种新的治疗策略。
