Objective: To investigate the antileukemia activity of phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 on human leukemia cell line U937.
Methods: MTT, soft agar assay, flow cytometric analysis and western blot were used to detect the effect of ZSTK474 on U937 cell proliferation, tumorigenicity, cell cycle, cell apoptosis and phosphorylation levels of the key factor of PI3K/AKT pathway. Chou-Talalay method was used to evaluate the combination of ZSTK474 with Cytarabine or Homoharringtonine.
Results: PI3K inhibitor ZSTK474 could inhibit the proliferation and tumorigenicity of U937 cell, induce G1 cell cycle arrest and promote cell apoptosis, and enhance intracellular ROS production and decrease MMP, downregulate Cyclin D1, p-Rb, BCL-2 and upregulate p27, caspase-9, caspase-3, PARP and BAX. Furthermore, the phosphorylation of PDK1, GSK-3β, AKT and mTOR could be downregulated by ZSTK474. The combination of ZSTK474 with Homoharringtonine was synergistic.
Conclusion: ZSTK474 can inhibit the pathway of PI3K/AKT, ZSTK474 alone or in combination with Homoharringtonine shows potential antileukemia activity on U937 cells.
题目: ZSTK474对U937细胞抗白血病活性的研究.
目的: 探讨PI3K抑制剂ZSTK474对人白血病细胞U937抗白血病的活性。.
方法: 采用MTT、软琼脂克隆形成、流式细胞术、Western blot检测ZSTK474对U937细胞增殖、致瘤性、周期分布、凋亡、PI3K/AKT信号通路中重要因子磷酸化水平的影响; 采用Chou-Talalay法检测ZSTK474与Cytarabine或Homoharringtonine药物联合的作用。.
结果: ZSTK474能抑制U937细胞增殖和致瘤性，诱导细胞G1期阻滞及凋亡，引起胞内活性氧的产生、线粒体膜电位下降，下调蛋白Cyclin D1、p-Rb、BCL-2，上调p27、caspase-9、caspase-3、PARP、BAX，此外，还可下调p-PDK1、p-AKT、p-GSK-3β和p-mTOR。ZSTK474与Homoharringtonine联用具有协同作用。.
结论: ZSTK474能够抑制PI3K/AKT通路，单用或与Homoharringtonine联用对U937细胞具有潜在的抗白血病活性。.