• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Drug Design, Development and Therapy >Aprepitant Sensitizes Acute Myeloid Leukemia Cells to the Cytotoxic Effects of Cytosine Arabinoside in vitro and in vivo
【24h】

Aprepitant Sensitizes Acute Myeloid Leukemia Cells to the Cytotoxic Effects of Cytosine Arabinoside in vitro and in vivo

机译：当前剂量敏感急性髓性白血病细胞对体外和体内胞嘧啶阿拉伯苷的细胞毒性作用

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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 mmsup3/sup in the vehicle group to 828.4 ± 232.4 mmsup3/sup 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.
机译：目的：急性髓性白血病（AML）是一种复杂的恶性肿瘤，其特征在于未成熟髓样前体的克隆膨胀。新诊断的AML的标准治疗是由胞嘧啶阿拉伯苷（ARA-C）和蒽环类的化疗，令人失望的临床结果和严重的不良反应，如症状性心动过缓，神经毒性。因此，通过组合药物治疗来治疗AML以降低化学治疗剂的不良反应。在我们最近发表的PNA纸中，我们报道了NK-1R拮抗剂，既通过线粒体钙过载诱导氧化胁迫诱导骨髓白血病细胞凋亡。因此，我们测试了NK-1R拮抗剂的组合ARA-C的假设可以增强ARA-C的功效。方法：采用MTT测定检测细胞增殖。施用流式细胞术以检测细胞周期和坏死。 PI吸收和LDH释放测定用于检测血浆膜的崩解。构建异种移植模型以探讨组合ARA-C与共体内的组合效果。结果：我们的研究结果表明，通过增强G0 / G1细胞循环骤停和体外坏死，Aprepitant通过增强G0 / G1细胞循环骤停和坏死，将HL60细胞敏感到ARA-C的细胞毒性效应超过5倍。此外，NEC-1是一种肮脏的抑制剂，可以显着恢复细胞增殖活力。吸引力地，一旦ARA-C（5mg / kg）和4- kg的每两天方案（5 mg / kg）通过原位注射率显着降低了2175.0±341.9 mm 3 的肿瘤体积在组合组中，载体组至828.4±232.4 mm 3 ，无明显毒性在人髓性白血病异种移植小鼠中。结论：连合起来，减少了与中度的ARA-C组合的剂量为体外和体内的AML治疗提供了更有效的治疗方法，并消除了ARA-C的毒性，这可能为常规支付新的途径。化疗药物ARA-C具有低剂量，以提高疗效和减少临床实践中的毒性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号