Vangapandu Hima V, Alston Brandon, Morse Joshua, Ayres Mary L, Wierda William G, Keating Michael J, Marszalek Joseph R, Gandhi Varsha
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Oncotarget. 2018 May 18;9(38):24980-24991. doi: 10.18632/oncotarget.25166.
Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools. However, glycolysis and glucose uptake were induced as compensatory mechanisms. To mitigate the upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell death. Consistent with these data, low-glucose culture conditions sensitized CLL cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to use a different metabolic pathway when OxPhos is inhibited and that targeting both OxPhos and glycolysis pathways is necessary for biological effect.
慢性淋巴细胞白血病（CLL）患者的血细胞处于复制静止状态，但在转录、翻译和代谢方面具有活性。最近，我们证明氧化磷酸化（OxPhos）是CLL中能量产生的主要途径，并且在基质微环境存在的情况下会进一步增强。重要的是，具有不良预后标志物的患者的CLL细胞显示出OxPhos增加。基于这些数据，我们推测OxPhos可作为治疗CLL的靶点。IACS-010759目前正在进行临床开发，它是一种靶向线粒体复合物I的小分子、口服生物可利用的OxPhos抑制剂。用IACS-010759处理原代CLL细胞可极大地抑制OxPhos，但在24小时和48小时仅引起轻微的细胞死亡。在基质存在的情况下，该药物成功抑制了OxPhos并减少了细胞内核苷酸池。然而，糖酵解和葡萄糖摄取被诱导作为补偿机制。为了减轻上调的糖酵解通量，我们将2-脱氧-D-葡萄糖与IACS-010759联合使用。这种联合降低了OxPhos和糖酵解，并诱导了细胞死亡。与这些数据一致，低葡萄糖培养条件使CLL细胞对IACS-010759敏感。总体而言，这些数据表明，当OxPhos被抑制时，CLL细胞会适应使用不同的代谢途径，并且靶向OxPhos和糖酵解途径对于生物学效应都是必要的。
