双氢青蒿素触发多药耐药白血病细胞的脱铁作用。

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xueyan Zhang, Ziying Ai, Zhewen Zhang, Rui Dong, Lina Wang, Suya Jin, Hulai Wei
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引用次数: 7

摘要

铁下垂在肿瘤耐药中的分子机制和作用尚不清楚。在本研究中,我们发现多药耐药(MDR) K562/阿霉素(ADM)白血病细胞的谷胱甘肽(GSH)水平和铁调节蛋白2 (IRP2)、转铁蛋白受体、铁蛋白重链1 (FTH1)和过氧化物酶4 (GPX4)的表达高于亲本药物敏感的K562白血病细胞。这些升高可能增加了K562/ADM细胞的抗氧化能力,并赋予它们对铁紊乱的缓冲能力,保护它们免受铁凋亡,并有利于耐药。然而,双氢青蒿素(DHA)抑制MDR K562/ADM细胞活力,增强对ADM的敏感性,其机制是通过下调GSH水平和GPX4、IRP2和FTH表达,上调活性氧(ROS)水平,进而抑制总丝氨酸/苏氨酸激酶(AKT)、雷帕霉素总靶蛋白(t-mTOR)、磷酸化mTOR (p-mTOR)和p-mTOR/t-mTOR水平而引起的铁死亡。此外,与K562细胞相比,MDR K562/ADM细胞由于FTH1、GPX4、p-mTOR和p-mTOR/t-mTOR的进一步抑制,在铁沉抑制剂处理后,表现出更大的ROS增加、GSH减少和活力恢复。总的来说,氧化损伤的增加和抗氧化防御的阻断形成了DHA诱导的铁凋亡,这是MDR白血病细胞对DHA敏感的原因。调节铁稳态/ROS/AKT/mTOR可能是使耐药白血病增敏的潜在化疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dihydroartemisinin Triggers Ferroptosis in Multidrug-Resistant Leukemia Cells.
The molecular mechanisms and role of ferroptosis in tumor drug resistance remain unclear. In this study, we found that multidrug-resistant (MDR) K562/adriamycin (ADM) leukemia cells possessed higher glutathione (GSH) levels and iron-regulatory protein 2 (IRP2), transferrin receptor, ferritin heavy chain 1 (FTH1), and peroxidase-4 (GPX4) expression than parental drug-sensitive K562 leukemia cells. These elevations might have increased the antioxidant ability of K562/ADM cells and granted them increased buffering capacity against iron disorder, protecting them from ferroptosis and favoring drug resistance. However, dihydroartemisinin (DHA) restrained MDR K562/ADM cell viability and enhanced the sensitivity to ADM by strengthening ferroptosis induced by downregulation of GSH levels and GPX4, IRP2, and FTH expression, upregulation of reactive oxygen species (ROS) levels, and the consequent suppression of total serine/threonine kinase (AKT), total mammalian target of rapamycin (t-mTOR), phosphorylated mTOR (p-mTOR), and p-mTOR/t-mTOR levels. Moreover, compared with K562 cells, MDR K562/ADM cells exhibited greater ROS increases, GSH decreases, and viability rescue after ferroptosis inhibitor treatment owing to further suppression of FTH1, GPX4, p-mTOR, and p-mTOR/t-mTOR. Collectively, the increase in oxidative damage and the blockade of antioxidant defence shaped DHA-induced ferroptosis, which was responsible for the sensitivity of MDR leukemia cells to DHA. Regulating iron homeostasis/ROS/AKT/mTOR might be a potential chemotherapeutic strategy for sensitizing drug-resistant leukemia.
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来源期刊
DNA and cell biology
DNA and cell biology 生物-生化与分子生物学
CiteScore
6.60
自引率
0.00%
发文量
93
审稿时长
1.5 months
期刊介绍: DNA and Cell Biology delivers authoritative, peer-reviewed research on all aspects of molecular and cellular biology, with a unique focus on combining mechanistic and clinical studies to drive the field forward. DNA and Cell Biology coverage includes: Gene Structure, Function, and Regulation Gene regulation Molecular mechanisms of cell activation Mechanisms of transcriptional, translational, or epigenetic control of gene expression Molecular Medicine Molecular pathogenesis Genetic approaches to cancer and autoimmune diseases Translational studies in cell and molecular biology Cellular Organelles Autophagy Apoptosis P bodies Peroxisosomes Protein Biosynthesis and Degradation Regulation of protein synthesis Post-translational modifications Control of degradation Cell-Autonomous Inflammation and Host Cell Response to Infection Responses to cytokines and other physiological mediators Evasive pathways of pathogens.
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