Purpose

Acute myeloid leukemia (AML) is one of the most common neoplasms in adults, and it is difficult to achieve satisfactory results with conventional drugs. Here, we synthesized a novel organic arsenic derivative MZ2 and evaluated its ability to remodel energy metabolism to achieve anti-leukemia.

Methods

MZ2 was characterized by the average 1-min full mass spectra analysis. Biological methods such as Western blot, qPCR, flow cytometry and confocal microscopy were used to assess the mode and mechanism of MZ2-induced death. The in vivo efficacy of MZ2 was assessed by constructing a patient-derived xenograft (PDX) AML model.

Results

Unlike the precursor organic arsenical Z2, MZ2 can effectively reduce the level of aerobic glycolysis. Our in-depth found that MZ2 inhibited the expression of PDK2 in a dose-dependent manner and did not affect the expression of LDHA, another key enzyme of the glycolytic pathway. MZ2 reconstituted energy metabolism to induce the generation of mitochondrial ROS (mtROS) and then triggerd intrinsic apoptosis pathway. We also assessed whether MZ2 generates autophagy and results showed that MZ2 can induce autophagy of AML cells, which may be associated with the precursor organic arsenic drug. In vivo, MZ2 effectively attenuated leukemia progression in mice, and immunohistochemical results suggested its PDK2 inhibitory effect.

Conclusion

In summary, the novel organic arsine derivative MZ2 exhibited excellent anti-tumor effects in acute myeloid leukemia, which may provide a potential strategy for the treatment of acute myeloid leukemia.

中文翻译：

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一种新型有机砷衍生物 MZ2 重塑急性髓系白血病的代谢并触发 mtROS 介导的细胞凋亡

目的

急性髓系白血病（AML）是成人最常见的肿瘤之一，常规药物很难取得满意的疗效。在这里，我们合成了一种新型有机砷衍生物MZ2，并评估了其重塑能量代谢以实现抗白血病的能力。

方法

MZ2 通过平均 1 分钟全质谱分析进行表征。采用Western blot、qPCR、流式细胞术和共聚焦显微镜等生物学方法评估MZ2诱导死亡的模式和机制。通过构建患者来源的异种移植（PDX）AML 模型来评估 MZ2 的体内功效。

结果

与前体有机砷Z2不同，MZ2可以有效降低有氧糖酵解水平。我们深入发现MZ2以剂量依赖的方式抑制PDK2的表达，并且不影响糖酵解途径的另一个关键酶LDHA的表达。MZ2重建能量代谢以诱导线粒体ROS（mtROS）的产生，然后触发内在的凋亡途径。我们还评估了MZ2是否产生自噬，结果表明MZ2可以诱导AML细胞自噬，这可能与前体有机砷药物有关。在体内，MZ2 有效减弱小鼠白血病的进展，免疫组织化学结果表明其具有 PDK2 抑制作用。

结论

综上所述，新型有机胂衍生物MZ2在急性髓系白血病中表现出优异的抗肿瘤作用，可能为急性髓系白血病的治疗提供潜在的策略。