Emodin and Its Combination with Cytarabine Induce Apoptosis in Resistant Acute Myeloid Leukemia Cells in Vitro and in Vivo
Emodin and Its Combination with Cytarabine Induce Apoptosis in Resistant Acute Myeloid Leukemia Cells in Vitro and in Vivo
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大黄素及其与阿糖胞苷的组合在体外和体内诱导耐药急性髓系白血病细胞凋亡
DOI：
10.1159/000492544
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Hu, Jianda
中科院分区：
文献类型：
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作者：
Chen, Yingyu;Gan, Donghui;Hu, Jianda
背景/目标：急性髓系白血病（acute myeloid leukemia，AML）是一种生存率低、复发率高的恶性血液病，其主要原因是多药耐药（multidrug resistance，MDR）的产生。鉴定新的药物以改善治疗策略成为AML治疗的重要优先事项。大黄素对多种恶性肿瘤均有治疗作用。在这项研究中，我们研究了大黄素单独使用或与阿糖胞苷（Ara-C）联合使用对多药耐药AML HL-60/ADR细胞以及人高致瘤性AML HL-60/H3细胞的小鼠异种移植模型的抗白血病作用。还讨论了潜在的机制。方法：MTT法检测细胞活力。采用DNA片段化试验、Annexin V-PE/7-AAD、AO/EB染色和电子显微镜观察来评估细胞凋亡诱导作用。蛋白质印迹法测定Akt和ERK信号通路中蛋白质表达的变化。本研究进一步分析了对HL-60/H3异种移植模型的体内抗白血病作用和总体小鼠生存结局。结果如下：大黄素剂量依赖性地诱导耐药HL-60/ADR细胞体外生长抑制和凋亡作用，以及在HL-60/H3异种移植模型体内。此外，大黄素显着增强AML细胞对Ara-C的化疗敏感性，抑制白血病细胞生长，并提高AML小鼠异种移植模型的存活率。Akt和ERK信号通路的双重靶点可能有助于在体外和体内对AML细胞的抗白血病作用。结论：大黄素及其联合阿糖胞苷治疗急性髓性白血病是一种有前景的治疗方法，值得进一步研究。(C)2018作者（S）由S发布。Karger AG，巴塞尔。
Background/Aims: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor survival and a high risk of relapse, which is mainly caused by the emergence of multidrug resistance (MDR). The identification of novel agents to improve therapeutic strategies becomes important priority for AML treatment. It has been shown that emodin has therapeutic effects on many kinds of human malignant tumors. In this study, we investigated the anti-leukemia effects of emodin alone or in combination with cytarabine (Ara-C) on multidrug-resistant AML HL-60/ADR cells and in a mouse xenograft model of human highly tumorigenic AML HL-60/H3 cells. The underlying mechanism was also addressed. Methods: Cell viability after treatment was measured by MTT assay. The DNA fragmentation assay, Annexin V-PE/7-AAD, AO/EB staining, and electron microscopy were introduced to assess the apoptotic induction effects. Changes in protein expression in the Akt and ERK signaling pathways were determined by western blotting. In vivo antileukemia effects on HL-60/H3 xenograft model and overall mouse survival outcomes were further analyzed in this study. Results: Emodin dose-dependently induced growth inhibition and apoptotic effects in resistant HL-60/ADR cells in vitro as well as in the HL-60/H3 xenograft models in vivo. Moreover, emodin significantly enhanced chemosensitivity of AML cells to Ara-C, inhibited leukemic cell growth, and improved survival in the mouse xenograft model of AML. Dual targeting of Akt and ERK signaling pathways might contribute to the anti-leukemia effects on AML cells in vitro and in vivo. Conclusion: Emodin and its combination with Ara-C may be considered a promising therapeutic approach in AML and worthy of further investigation. (C) 2018 The Author(s) Published by S. Karger AG, Basel.