Gregory Mark A, Nemkov Travis, Park Hae J, Zaberezhnyy Vadym, Gehrke Sarah, Adane Biniam, Jordan Craig T, Hansen Kirk C, D'Alessandro Angelo, DeGregori James
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Clin Cancer Res. 2019 Jul 1;25(13):4079-4090. doi: 10.1158/1078-0432.CCR-18-3223. Epub 2019 Apr 2.
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.
AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.
We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating ALL cells and .
Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.
急性髓系白血病（AML）是一种血液系统恶性肿瘤，其特征为未成熟髓系前体细胞的积累。AML对传统化疗反应不佳，通常被诊断为致命疾病。迫切需要更有效且毒性更小的治疗形式。已知AML细胞的存活高度依赖于氨基酸谷氨酰胺。这些研究旨在确定谷氨酰胺酶抑制对AML代谢的影响，并识别可用于治疗的普遍弱点。
使用了AML癌细胞系、原发性AML细胞以及AML和急性淋巴细胞白血病（ALL）的小鼠模型。
我们发现，通过使用谷氨酰胺酶抑制剂（CB - 839）阻断谷氨酰胺代谢，会显著损害多种类型AML中抗氧化剂谷胱甘肽的产生，导致线粒体活性氧（mitoROS）积聚和凋亡性细胞死亡。此外，谷氨酰胺酶抑制使AML细胞对进一步扰乱线粒体氧化还原状态的辅助药物敏感，如三氧化二砷（ATO）和高三尖杉酯碱（HHT）。实际上，ATO或HHT与CB - 839联合使用会加剧mitoROS和凋亡，并导致AML细胞系、原发性AML患者样本以及AML小鼠模型中细胞死亡更彻底。此外，这些针对氧化还原的联合疗法在根除ALL细胞方面也有效。
靶向谷氨酰胺代谢并联合扰乱线粒体氧化还原状态的药物，代表了一种治疗多种类型白血病的有效且可能广泛适用的治疗策略。
