Targeting NOX2 and glycolytic metabolism as a therapeutic strategy in acute myeloid leukaemia.

IF 9.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Carla Ijurko, Marta Romo-González, Rodrigo Prieto-Bermejo, María Díez-Campelo, María-Belén Vidriales, Sandra Muntión, Fermín Sánchez-Guijo, Jesús Sánchez-Yagüe, Ángel Hernández-Hernández
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Abstract

Acute myeloid leukaemia (AML) is a highly heterogeneous malignancy, with a poor 5-year overall survival rate of approximately 30%. Consequently, the search for novel therapeutic strategies is ongoing, and the identification of new vulnerabilities could accelerate progress. Oxidative stress and metabolic rewiring are established hallmarks of cancer, and recent evidence suggests that NADPH oxidases may regulate metabolism, potentially linking these two processes. Increasing research highlights the importance of NOX2 in AML, particularly its role in metabolic regulation. In this study, we investigated the effects of simultaneously inhibiting NOX2 and glycolysis in AML cells. Dual inhibition of NOX2 and glycolysis-by targeting hexokinase or lactate dehydrogenase (LDH)-significantly reduced cell proliferation, markedly impaired clonogenic potential, and induced extensive cell death in a broad panel of AML cell lines. Importantly, these findings were further validated in primary bone marrow samples derived from AML patients, where combined inhibition triggered similar potent anti-leukemic effects. Furthermore, the combined inhibition of NOX2 and LDH enhanced the efficacy of cytarabine (AraC), suggesting this approach could boost the effectiveness of conventional therapies. In an in vivo AML model, targeting NOX2 and LDH in myeloid progenitor cells delayed the onset of leukaemia and extended survival. In conclusion, our findings propose a novel therapeutic strategy for AML through the dual targeting of NOX2 and glycolysis.

将 NOX2 和糖代谢作为急性髓性白血病的治疗策略。
急性髓性白血病(AML)是一种高度异质性的恶性肿瘤,5 年总生存率约为 30%。因此,人们一直在寻找新的治疗策略,而找出新的薄弱环节可以加快治疗进程。氧化应激和新陈代谢重构是癌症的既定特征,最近的证据表明,NADPH 氧化酶可调节新陈代谢,可能将这两个过程联系起来。越来越多的研究强调了NOX2在急性髓细胞白血病中的重要性,尤其是它在代谢调节中的作用。在这项研究中,我们探讨了同时抑制NOX2和糖酵解对AML细胞的影响。通过靶向己糖激酶或乳酸脱氢酶(LDH)对 NOX2 和糖酵解进行双重抑制,显著降低了细胞增殖,明显损害了细胞的克隆潜力,并诱导了大量急性髓细胞白血病细胞系的细胞死亡。重要的是,这些发现在来自急性髓细胞白血病患者的原发性骨髓样本中得到了进一步验证,联合抑制可引发类似的强效抗白血病作用。此外,联合抑制NOX2和LDH还能增强阿糖胞苷(AraC)的疗效,表明这种方法能提高传统疗法的疗效。在活体急性髓细胞性白血病模型中,靶向髓系祖细胞中的 NOX2 和 LDH 可延缓白血病的发生并延长存活期。总之,我们的研究结果提出了一种通过NOX2和糖酵解双重靶向治疗急性髓细胞性白血病的新疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biomarker Research
Biomarker Research Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
15.80
自引率
1.80%
发文量
80
审稿时长
10 weeks
期刊介绍: Biomarker Research, an open-access, peer-reviewed journal, covers all aspects of biomarker investigation. It seeks to publish original discoveries, novel concepts, commentaries, and reviews across various biomedical disciplines. The field of biomarker research has progressed significantly with the rise of personalized medicine and individual health. Biomarkers play a crucial role in drug discovery and development, as well as in disease diagnosis, treatment, prognosis, and prevention, particularly in the genome era.
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