■慢性淋巴细胞白血病(CLL)细胞代谢灵活,适应现代抗癌治疗。布鲁顿酪氨酸激酶(BTK)和B细胞淋巴瘤-2(BCL-2)抑制剂已被广泛用于治疗CLL,但随着时间的推移,CLL细胞会对这些治疗产生抗性。CB-839是一种小分子谷氨酰胺酶-1(GLS-1)抑制剂,会损害谷氨酰胺的使用,破坏下游的能量代谢,并阻碍了活性氧的消除。
■为了研究CB-839对CLL细胞的体外作用,我们单独测试了CB-839和ibrutinib的组合,维尼托克,或AZD-5991在HG-3和MEC-1CLL细胞系和原代CLL淋巴细胞上。
■我们发现CB-839引起GLS-1活性和谷胱甘肽合成的剂量依赖性降低。CB-839处理的细胞还显示线粒体超氧化物代谢增加和能量代谢受损,这反映在耗氧率的降低和三磷酸腺苷池的消耗,并导致细胞增殖的抑制。在细胞系中,CB-839联合维奈托克或AZD-5991,但不联合伊布替尼,具有增加的凋亡率和细胞增殖抑制的协同作用。在初级淋巴细胞中,单独使用CB-839或与维奈托克联合使用无明显作用,伊布替尼,或AZD-5991被观察到。
■我们的发现表明,CB-839在CLL治疗中的功效有限,并且与广泛使用的CLL药物联合使用时显示出有限的协同作用。
UNASSIGNED: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.
UNASSIGNED: To investigate the in vitro effects of CB-839 on CLL cells, we tested CB-839 alone and in combination with ibrutinib, venetoclax, or AZD-5991 on the HG-3 and MEC-1 CLL cell lines and on primary CLL lymphocytes.
UNASSIGNED: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed.
UNASSIGNED: Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.