Aprepitant Sensitizes Acute Myeloid Leukemia Cells to the Cytotoxic Effects of Cytosine Arabinoside in vitro and in vivo
Aprepitant Sensitizes Acute Myeloid Leukemia Cells to the Cytotoxic Effects of Cytosine Arabinoside in vitro and in vivo
复制标题
阿瑞匹坦在体外和体内使急性髓系白血病细胞对阿糖胞苷的细胞毒性作用敏感
DOI：
10.2147/dddt.s244648
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发表时间：
2020-06
期刊：
影响因子：
--
通讯作者：
Caiyun Fu
中科院分区：
文献类型：
--
作者：
Hongzhang Wu;Xurui Cheng;Feiyan Huang;Gang Shao;Yueming Meng;Lingfei Wang;Tao Wang;Xiaoyuan Jia;Tianxin Yang;Xi Wang;Caiyun Fu
目的急性髓系白血病（acute myeloid leukemia，AML）是一种以未成熟髓系前体细胞克隆性增殖为特征的复杂恶性肿瘤。新诊断的AML的标准治疗是由阿糖胞苷（Ara-C）和蒽环类药物组成的化疗，其临床结果令人失望，并且具有严重的不良反应，例如症状性心动过缓、神经毒性。因此，通过联合药物治疗以减少化疗药物的不良反应来治疗AML是有希望的。在我们最近发表的PNAS论文中，我们报道了NK-1 R拮抗剂阿瑞匹坦和SR 140333通过线粒体钙超载诱导氧化应激诱导髓系白血病细胞凋亡。因此，我们验证了Ara-C与NK-1 R拮抗剂联合使用可增强Ara-C疗效的假设。方法MTT法检测细胞增殖情况。流式细胞仪检测细胞周期和坏死情况。采用PI摄取法和LDH释放法检测细胞膜的崩解。建立异种移植瘤模型，观察阿糖胞苷与阿瑞匹坦联合应用的体内效应。结果阿瑞匹坦可使HL 60细胞对阿糖胞苷的细胞毒作用增敏5倍以上，使HL 60细胞G 0/G1期阻滞和坏死增加。坏死性凋亡特异性抑制剂Nec-1可显著恢复细胞增殖活力。吸引人的是，通过原位注射每2天一次的阿糖胞苷（5 mg/kg）和阿瑞匹坦（10 mg/kg）方案使肿瘤体积从媒介物组的2175.0 ± 341.9 mm 3显著减小至组合组的828.4 ± 232.4 mm 3，在人髓性白血病异种移植小鼠中没有明显毒性。结论阿糖胞苷减量联合阿糖胞苷中量阿瑞匹坦治疗急性髓细胞白血病，在消除阿糖胞苷毒副作用的同时，为临床上常规化疗药物阿糖胞苷的小剂量增效减毒提供了新的途径。
Purpose Acute myeloid leukemia (AML) is a complex malignancy characterized by the clonal expansion of immature myeloid precursors. The standard treatment for newly diagnosed AML is chemotherapy consisting of cytosine arabinoside (Ara-C) and anthracyclines with disappointing clinical outcomes and severe adverse effects, such as symptomatic bradycardia, neurotoxicity. Thus, it is promising to treat AML through combination drug therapy to reduce the adverse effects of chemotherapeutics. In our recent published PNAS paper, we reported that NK-1R antagonists, both Aprepitant and SR140333, induce apoptosis of myeloid leukemia cells by inducing oxidative stress through mitochondrial calcium overload. We, therefore, tested the hypothesis of the combination Ara-C with NK-1R antagonist could enhance the efficacy of Ara-C. Methods MTT assay was employed to detect the cell proliferation. Flow cytometry was applied to detect the cell cycle and necrosis. PI uptake and LDH release assay were used to detect the disintegration of the plasma membrane. Xenograft model was constructed to explore the effect of combination Ara-C with Aprepitant in vivo. Results Our results showed that Aprepitant sensitizes HL60 cells to the cytotoxic effects of Ara-C more than 5-fold by enhancing G0/G1 cell cycle arrest and necrosis in vitro. Furthermore, Nec-1, a specific inhibitor of necroptosis, could recover the cell proliferative viability significantly. Attractively, once every 2-days regimen of Ara-C (5 mg/kg) and Aprepitant (10 mg/kg) via in situ injection dramatically reduced the tumor volume from 2175.0 ± 341.9 mm3 in the vehicle group to 828.4 ± 232.4 mm3 in the combination group without obvious toxicity in human myeloid leukemia xenograft mice. Conclusion Taken together, reduced dose of Ara-C combination with moderate Aprepitant provides more effective therapeutical methods for AML treatment in vitro and in vivo with the elimination of the toxicity of Ara-C, which may pay new avenue for the usage of the routine chemotherapy drug Ara-C with low dose to enhance efficacy and reduce toxicity in clinical practice.
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影响因子：
5.1
作者：
Nakka, Venkata Prasuja;Prakash-babu, Phanithi;Vemuganti, Raghu
通讯作者：
Vemuganti, Raghu
DOI：
10.1007/978-3-030-73227-1_13
发表时间：
2021
期刊：
Practical Oncologic Molecular Pathology
影响因子：
--
作者：
Guang Yang;Linsheng Zhang
通讯作者：
Guang Yang;Linsheng Zhang
DOI：
10.2147/dddt.s34271
发表时间：
2012
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Cai Z;Bresell A;Steinberg MH;Silberg DG;Furlong ST
通讯作者：
Furlong ST
影响因子：
2.1
作者：
Yunli Zhou;Duo Zuo;Meng Wang;Yongci Zhang;Man Yu;Jie Yang;Z. Yao
通讯作者：
Yunli Zhou;Duo Zuo;Meng Wang;Yongci Zhang;Man Yu;Jie Yang;Z. Yao
DOI：
10.1136/bmj.323.7318.879
发表时间：
2001-10
期刊：
BMJ : British Medical Journal
影响因子：
--
作者：
R. Kale
通讯作者：
R. Kale