Eltrombopag Modulates Reactive Oxygen Species and Decreases Acute Myeloid Leukemia Cell Survival
Eltrombopag Modulates Reactive Oxygen Species and Decreases Acute Myeloid Leukemia Cell Survival
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DOI：
10.1371/journal.pone.0126691
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发表时间：
2015-04-27
期刊：
影响因子：
3.7
通讯作者：
Carroll, Martin
中科院分区：
文献类型：
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作者：
Kalota, Anna;Selak, Mary A.;Carroll, Martin
先前的研究表明，小分子血小板生成素（TPO）模拟物艾曲波帕（E）可诱导急性髓系白血病（AML）细胞凋亡。在这里，我们试图明确艾曲波帕抗白血病作用的机制。我们的研究表明，在 2% 血清中浓度为 5 μM E 时，E 可在 2-6 小时内触发 PARP 裂解和 caspase 级联激活，从而诱导白血病细胞凋亡。凋亡酶的诱导很大程度上取决于药物浓度和血清浓度。这种效应与线粒体电位的改变无关，但与活性氧 (ROS) 特别是过氧化氢 (H2O2) 的快速减少有关。有趣的是，E 还降低线粒体最大呼吸能力和备用呼吸能力，这表明诱导的线粒体功能障碍在基础条件下可能并不明显，但只有在压力下才变得明显。用 E 加 Tempol 或 H2O2 共同处理 MOLM14 AML 细胞可部分挽救细胞毒性。柠檬酸铁铵 (FAC) 还可以通过诱导 ROS 水平显着增加来拮抗 E 诱导的毒性。总的来说，我们认为 E 显着降低 ROS 水平，导致 AML 细胞内代谢破坏和细胞快速死亡。
Previous studies have demonstrated that the small molecule thrombopoietin (TPO) mimetic, eltrombopag (E), induces apoptosis in acute myeloid leukemia (AML) cells. Here, we sought to define the mechanism of the anti-leukemic effect of eltrombopag. Our studies demonstrate that, at a concentration of 5 mu M E in 2% serum, E induces apoptosis in leukemia cells by triggering PARP cleavage and activation of caspase cascades within 2-6 hours. The induction of apoptotic enzymes is critically dependent on drug concentration and the concentration of serum. This effect is not associated with an alteration in mitochondrial potential but is associated with a rapid decrease in a reactive oxygen species (ROS) in particular hydrogen peroxide (H2O2). Interestingly, E also decreases mitochondrial maximal and spare respiratory capacities suggesting an induced mitochondrial dysfunction that may not be readily apparent under basal conditions but becomes manifest only under stress. Co-treatment of MOLM14 AML cells with E plus Tempol or H2O2 provides a partial rescue of cell toxicity. Ferric ammonioum citrate (FAC) also antagonized the E induced toxicity, by inducing notable increase in ROS level. Overall, we propose that E dramatically decreases ROS levels leading to a disruption of AML intracellular metabolism and rapid cell death.