Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, Hubei, China.
College of Chemistry and Molecular Science, Wuhan University, Wuhan, 430072, Hubei, China.
J Cancer Res Clin Oncol. 2023 Jul;149(8):4225-4242. doi: 10.1007/s00432-022-04333-2. Epub 2022 Sep 3.
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.
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.
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.
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.
急性髓系白血病（AML）是成人中最常见的肿瘤之一，常规药物治疗效果难以令人满意。本研究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。
采用平均 1 分钟全质谱分析对 MZ2 进行了表征。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了 MZ2 诱导死亡的方式和机制。通过构建患者来源的异种移植（PDX）AML 模型评估了 MZ2 的体内疗效。
与前体有机砷 Z2 不同，MZ2 能有效降低有氧糖酵解水平。我们深入研究发现，MZ2 呈剂量依赖性抑制 PDK2 的表达，而不影响糖酵解途径的另一个关键酶 LDHA 的表达。MZ2 重建了能量代谢，诱导线粒体 ROS（mtROS）的产生，进而触发内在凋亡途径。我们还评估了 MZ2 是否产生自噬，结果表明 MZ2 能诱导 AML 细胞自噬，这可能与前体有机砷药物有关。在体内，MZ2 能有效抑制小鼠白血病的进展，免疫组化结果提示其具有 PDK2 抑制作用。
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一种潜在策略。
