Chen Ting, Zhou Qian-Xiang, Qiu Yu-Ling, Kong De-Xin
School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
School of Pharmacy, Tianjin Medical University, Tianjin 300070, China E-mail:
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021 Feb;29(1):17-25. doi: 10.19746/j.cnki.issn.1009-2137.2021.01.003.
To investigate the antileukemia activity of phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 on human leukemia cell line U937.
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.
PI3K inhibitor ZSTK474 could inhibit the proliferation and tumorigenicity of U937 cell, induce G 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.
ZSTK474 can inhibit the pathway of PI3K/AKT, ZSTK474 alone or in combination with Homoharringtonine shows potential antileukemia activity on U937 cells.
研究磷脂酰肌醇-3激酶（PI3K）抑制剂ZSTK474对人白血病细胞系U937的抗白血病活性。
采用MTT法、软琼脂试验、流式细胞术分析和蛋白质免疫印迹法检测ZSTK474对U937细胞增殖、致瘤性、细胞周期、细胞凋亡及PI3K/AKT通路关键因子磷酸化水平的影响。采用Chou-Talalay法评估ZSTK474与阿糖胞苷或高三尖杉酯碱的联合作用。
PI3K抑制剂ZSTK474可抑制U937细胞的增殖和致瘤性，诱导G期细胞周期阻滞并促进细胞凋亡，增强细胞内活性氧生成并降低线粒体膜电位，下调细胞周期蛋白D1、磷酸化视网膜母细胞瘤蛋白、B细胞淋巴瘤-2蛋白，并上调p27蛋白、半胱天冬酶-9、半胱天冬酶-3、聚（ADP-核糖）聚合酶和Bax蛋白。此外，ZSTK474可下调3-磷酸肌醇依赖性蛋白激酶-1、糖原合成酶激酶-3β、蛋白激酶B和哺乳动物雷帕霉素靶蛋白的磷酸化水平。ZSTK474与高三尖杉酯碱联合具有协同作用。
ZSTK474可抑制PI3K/AKT通路，ZSTK474单独或与高三尖杉酯碱联合对U937细胞显示出潜在的抗白血病活性。
