吗啉衍生物 N-(4-吗啉亚甲基)乙磺酰胺通过靶向 NRF2 诱导肿瘤细胞的铁变态反应。

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Biological & pharmaceutical bulletin Pub Date : 2024-02-14 Epub Date: 2024-01-30 DOI:10.1248/bpb.b23-00544
Bingchun Sun, Ligang Zhang, Binhua Wu, Xiping Luo
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引用次数: 0

摘要

含有吗啉基分子的小分子药物已成为肿瘤靶向治疗策略的重要候选药物,但这些药物导致肿瘤细胞死亡的具体分子机制还需要进一步研究。我们利用吗啉衍生物N-(4-吗啉亚甲基)乙磺酰胺(MESA)刺激前列腺癌和卵巢癌细胞,重点研究了MESA的铁突变效应,包括其介导的靶分子和信号通路。结果表明,MESA能诱导铁突变,导致肿瘤细胞增殖抑制和凋亡。此外,MESA还能显著增加肿瘤细胞内MDA、ROS和Fe2+的水平,并介导铁氧化相关分子GPX4、NRF2、ACSL4、SLC7A11和P62-KEAP1-NRF2-ARE信号通路的动态变化。此外,NRF2的过表达可减少肿瘤细胞的死亡和暴露于MESA的ROS水平。最重要的是,通过分子对接和热稳定性实验证实,MESA能与NRF2蛋白结合,NRF2是MESA诱导肿瘤细胞铁变态反应的靶分子。综上所述,我们的研究结果表明了吗啉衍生物MESA在前列腺癌和卵巢癌细胞中的铁突变效应及其作用机制,包括靶向分子和信号通路,这将有助于开发MESA作为基于细胞铁突变的肿瘤治疗小分子药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Morpholine Derivative N-(4-Morpholinomethylene)ethanesulfonamide Induces Ferroptosis in Tumor Cells by Targeting NRF2.

Small molecule drugs containing morpholine-based moieties have become crucial candidates in the tumor targeted therapy strategies, but the specific molecular mechanisms of these drugs causing tumor cell death require further investigation. The morpholine derivative N-(4-morpholinomethylene)ethanesulfonamide (MESA) was used to stimulate prostate and ovarian cancer cells and we focused on the ferroptosis effects, including the target molecule and signal pathways mediated by MESA. The results showed that MESA could induce ferroptosis to cause the proliferation inhibition and apoptosis effects of tumor cells according to the identification of ferroptosis inhibitor fer-1 and other cell death inhibitors. Further MESA could significantly increase the intracellular malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+ levels in tumor cells and mediate the dynamic changes of ferroptosis-relative molecules GPX4, nuclear factor erythroid2-related factor 2 (NRF2), ACSL4, SLC7A11 and P62-Kelch-like ECH-associated protein 1 (KEAP1)-NRF2-antioxidant response element (ARE) signal pathways. Further, NRF2 overexpression could reduce the tumor cell death and ROS levels exposure to MESA. Most importantly, it was confirmed that MESA could bind to NRF2 protein through molecular docking and thermal stability assays and NRF2 was a target molecule of MESA for inducing ferroptosis effects in tumor cells. Collectively, our findings indicated the ferroptosis effects of the morpholine derivative MESA in prostate and ovarian cancer cells and its function mechanism including targeted molecule and signal pathways, which would be helpful for developing MESA as a prospective small molecule drug for cancer therapy based on cell ferroptosis.

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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
247
审稿时长
2 months
期刊介绍: Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012. The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.
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