Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia.
Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia.
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DOI：
10.1016/j.canlet.2015.05.033
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发表时间：
2015-10-01
期刊：
影响因子：
9.7
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Huang J;Lyu H;Wang J;Liu B
Survivin在包括急性髓系白血病(AML)在内的多种血液系统恶性肿瘤中均有过表达。研究表明，在AML患者中，Survivin的高表达与不良的临床结局相关。目前尚不清楚抑制Survivin是否会改变化疗对AML的疗效。在这里，我们评估了Survivin的特异性敲除对AML细胞化疗敏感性的影响，并探讨了Survivin YM155转录抑制剂单独或与化疗药物联合使用的治疗潜力。我们发现Kasumi-1和HL-60细胞在所有AML细胞系中Survivin的表达水平相对较高。Kasumi-1和HL-60细胞中Survivin的特异性敲除导致：抑制细胞增殖；细胞周期G2/M期停滞；诱导DNA损伤反应和细胞凋亡。Survivin下调增强依托泊苷或阿霉素诱导的AML细胞的抗增殖/抗生存活性。小分子抑制剂YM155以剂量和时间依赖的方式降低Survivin，并触发Kasumi-1和HL-60细胞的凋亡。YM155和化疗药物的联合作用可以是协同的，也可以是拮抗的，这取决于用于联合的药物和正在治疗的AML细胞的类型。综上所述，我们的数据表明Survivin在AML细胞的维持和增殖中发挥着重要作用。虽然Survivin的特异性敲除增强了化疗的敏感性，但YM155与化疗药物联合使用对AML细胞表现出协同或拮抗作用。我们的发现为进一步评估Survivin靶向治疗急性髓细胞白血病患者提供了理论基础。
Overexpression of survivin is observed in various hematological malignancies, including acute myeloid leukemia (AML). Studies show that elevated expression of survivin correlates with a worse clinic outcome in AML patients. It remains unclear whether inhibition of survivin may alter the efficacy of chemotherapy against AML. Here, we evaluate the effects of specific knockdown of survivin on AML cells’ sensitivity to chemotherapy, and investigate the therapeutic potential of the transcription inhibitor of survivin YM155 either alone or in combination with chemotherapeutic agents. We found Kasumi-1 and HL-60 cells had relatively higher expression levels of survivin among all AML cell lines tested. Specific knockdown of survivin in Kasumi-1 and HL-60 cells resulted in: inhibition of cell proliferation; cell cycle G2/M arrest; induction of DNA damage response and apoptosis. Downregulation of survivin enhanced etoposide- or doxorubicin-induced anti-proliferative/anti-survival activity in AML cells. The small molecule inhibitor YM155 reduced survivin in a dose- and time-dependent manner and trigged apoptosis in Kasumi-1 and HL-60 cells. The combinatorial effects of YM155 and chemotherapeutics were either synergetic or antagonistic, depending upon the drugs used for combination and the type of AML cells being treated. Collectively, our data demonstrate that survivin plays an important role in the maintenance and proliferation of AML cells. While specific knockdown of survivin enhances chemosensitivity, the combinations of YM155 and chemotherapeutic agents exhibit synergetic or antagonistic effects on AML cells. Our findings provide a rationale for further assessment of survivin-targeted therapy in the treatment of patients with AML.