Small Molecule TH-39 Potentially Targets Hecl/Nek2 Interaction and Exhibits Antitumor Efficacy in K562 Cells via G0/G1 Cell Cycle Arrest and Apoptosis Induction
Small Molecule TH-39 Potentially Targets Hecl/Nek2 Interaction and Exhibits Antitumor Efficacy in K562 Cells via G0/G1 Cell Cycle Arrest and Apoptosis Induction
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DOI：
10.1159/000452546
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发表时间：
2016-01-01
影响因子：
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通讯作者：
Yu, Luoting
中科院分区：
文献类型：
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作者：
Zhu, Yongxia;Wei, Wei;Yu, Luoting
背景：癌症仍然是世界范围内主要的公共卫生问题，迫切需要具有抗肿瘤活性的新疗法。方法：采用免疫印迹法、共免疫沉淀法、MTT法和流式细胞术检测TH-39对K562细胞具有较强的抗增殖活性，IC50为0.78 μ M。结果：TH-39可能破坏K562细胞中Hecl和Nek2的相互作用。此外，TH-39通过影响K562细胞形态和诱导G0/G1期阻滞，以浓度和时间依赖的方式抑制细胞增殖。G0/G1期阻滞与CDK2-cyclin E复合物和CDK4/6-cyclin D复合物活性下调有关。TH-39还能诱导细胞凋亡，其机制与caspase-3激活、Bcl-2表达下调、Bax表达上调有关。TH-39还能降低K562细胞线粒体膜电位（δ psi m），增加活性氧（ROS）的积累。结果表明TH-39可能通过ros -线粒体凋亡途径诱导细胞凋亡。结论：本研究突出了抗癌化合物TH-39在治疗耐药慢性髓系白血病中的潜在疗效。(C) 2016，作者：s kager AG，巴塞尔出版
Background: Cancer is still a major public health issue worldwide, and new therapeutics with anti-tumor activity are still urgently needed. Methods: The anti-tumor activity of TH-39, which shows potent anti-proliferative activity against K562 cells with an IC50 of 0.78 mu M, was investigated using immunoblot, co-immunoprecipitation, the MTT assay, and flow cytometry. Results: Mechanistically, TH-39 may disrupt the interaction between Hecl and Nek2 in K562 cells. Moreover, TH-39 inhibited cell proliferation in a concentration- and time dependent manner by influencing the morphology of K562 cells and inducing G0/G1 phase arrest. G0/G1 phase arrest was associated with down-regulation of CDK2-cyclin E complex and CDK4/6-cyclin D complex activities. Furthermore, TH-39 also induced cell apoptosis, which was associated with activation of caspase-3, down-regulation of Bcl-2 expression and up regulation of Bax. TH-39 could also decrease mitochondrial membrane potential (Delta psi m) and increase reactive oxygen species (ROS) accumulation in K562 cells. The results indicated that TH-39 might induce apoptosis via the ROS-mitochondrial apoptotic pathway. Conclusion: This study highlights the potential therapeutic efficacy of the anti-cancer compound TH-39 in treatment-resistant chronic myeloid leukemia. (C) 2016 The Author(s) Published by S Karger AG, Basel