Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia
Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia
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DOI：
10.1158/0008-5472.can-19-0515
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发表时间：
2019-10-15
期刊：
影响因子：
11.2
通讯作者：
Sarry, Jean-Emmanuel
中科院分区：
文献类型：
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作者：
Hosseini, Mohsen;Rezvani, Hamid Reza;Sarry, Jean-Emmanuel
化疗改变细胞氧化还原平衡和活性氧（ROS）含量。最近的研究报道，化疗耐药细胞在血液恶性肿瘤中具有增加的氧化状态。在这项研究中，我们证明，与敏感的急性髓系白血病（AML）细胞相比，化疗耐药的急性髓系白血病（AML）细胞对阿糖胞苷（AraC）的反应中线粒体和胞浆活性氧水平较低，并且过表达髓过氧化物酶（MPO），髓过氧化物酶是一种将过氧化氢转化为次氯酸的血红素蛋白（HOCl）。高MPO表达的AML细胞在体外和体内对AraC的敏感性较低。与低MPO表达的AML细胞相比，它们还产生更高水平的HOCl，并表现出线粒体耗氧速率增加。靶向MPO表达或酶活性通过触发氧化损伤和维持氧化应激使AML细胞对AraC治疗敏感，特别是在高MPO表达的AML细胞中。这种致敏作用源于线粒体超氧化物积累，其损害氧化磷酸化和细胞能量平衡，在体外和体内驱动凋亡性死亡和选择性根除耐药AML细胞。总之，这项研究揭示了MPO酶在维持氧化还原平衡和线粒体能量代谢的非经典功能，从而影响下游途径参与AML chemoresistance.Significance：这些研究结果表明髓过氧化物酶的作用，在调节活性氧水平和敏感性的AML细胞阿糖胞苷，一个重要的化疗骨干在AML的治疗。
Chemotherapies alter cellular redox balance and reactive oxygen species (ROS) content. Recent studies have reported that chemoresistant cells have an increased oxidative state in hematologic malignancies. In this study, we demonstrated that chemoresistant acute myeloid leukemia (AML) cells had a lower level of mitochondrial and cytosolic ROS in response to cytarabine (AraC) and overexpressed myeloperoxidase (MPO), a heme protein that converts hydrogen peroxide to hypochlorous acid (HOCl), compared with sensitive AML cells. High MPO-expressing AML cells were less sensitive to AraC in vitro and in vivo. They also produced higher levels of HOCl and exhibited an increased rate of mitochondrial oxygen consumption when compared with low MPO-expressing AML cells. Targeting MPO expression or enzyme activity sensitized AML cells to AraC treatment by triggering oxidative damage and sustaining oxidative stress, particularly in high MPO-expressing AML cells. This sensitization stemmed from mitochondrial superoxide accumulation, which impaired oxidative phosphorylation and cellular energetic balance, driving apoptotic death and selective eradication of chemoresistant AML cells in vitro and in vivo. Altogether, this study uncovers a noncanonical function of MPO enzyme in maintaining redox balance and mitochondrial energetic metabolism, therefore affecting downstream pathways involved in AML chemoresistance.Significance: These findings demonstrate the role of myeloperoxidase in the regulation of ROS levels and sensitivity of AML cells to cytarabine, an essential chemotherapeutic backbone in the therapy of AML.