Guopeng Chen1, Wenyan She2, Chaochao Yu3, Tuerxunayi Rouzi1, Xinqi Li1, Linlu Ma1, Nan Zhang1, Hongqiang Jiang1, Xiaoyan Liu1, Jinxian Wu1, Qian Wang1, Hui Shen1, Fuling Zhou4. 1. Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, Hubei, China. 2. College of Chemistry and Molecular Science, Wuhan University, Wuhan, 430072, Hubei, China. 3. Department of Integrated Chinese and Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, Hubei, China. 4. Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, Hubei, China. zhoufuling@whu.edu.cn.
Abstract
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.
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.
Authors: Jon R Christiansen; Adriani Kanellopoulos; May B Lund; Richard Massey; Håvard Dalen; Cecilie E Kiserud; Ellen Ruud; Svend Aakhus Journal: Pediatr Blood Cancer Date: 2015-04-01 Impact factor: 3.167
Authors: B Bhattacharya; S H H Low; C Soh; N Kamal Mustapa; M Beloueche-Babari; K X Koh; J Loh; R Soong Journal: Br J Pharmacol Date: 2014-07 Impact factor: 8.739