Combined Inhibition of ALK and HDAC Induces Synergistic Cytotoxicity in Neuroblastoma Cell Lines
Combined Inhibition of ALK and HDAC Induces Synergistic Cytotoxicity in Neuroblastoma Cell Lines
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DOI：
10.21873/anticanres.13504
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发表时间：
2019-07-01
影响因子：
2
通讯作者：
Nagai, Hirokazu
中科院分区：
文献类型：
--
作者：
Hagiwara, Kazumi;Tokunaga, Takashi;Nagai, Hirokazu
背景/目的：神经母细胞瘤（Neuroblastoma， NB）是儿童最常见的颅外实体瘤；NB需要更有效的治疗，特别是晚期病例。本研究旨在评估间变性淋巴瘤激酶（ALK）抑制剂alectinib和组蛋白去乙酰化酶抑制剂vorinostat对携带野生型或突变ALK的NB细胞系的联合作用。材料和方法：采用3-（4,5-二甲基噻唑-2-基）-2,5二苯基溴化四唑测定法检测细胞毒性。western blotting分析蛋白表达。结果：阿勒替尼与伏立诺他联合用药对ALK R1275Q突变NB细胞株的生长抑制具有协同作用。caspase-3和多聚（adp -核糖）聚合酶的切割增加，表明caspase依赖性细胞凋亡增强。此外，这种组合降低了MYCN原癌基因和核因子kappa B的蛋白水平，这两种基因对NB肿瘤的发生和发展都很重要。结论：alectinib和vorinostat联合治疗ALK R1275Q突变NB可能是一种新的治疗选择。
Background/Aim: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK. Materials and Methods: Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting. Results: Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN protooncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression. Conclusion: Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.