MEK抑制剂联合三氧化二砷对髓系白血病细胞凋亡的研究

目的:研究MEK抑制剂PD98059联合三氧化二砷(As2O3)对髓系白血病细胞凋亡的影响及其作用机制。方法:将PD98059、As2O3单独或联合作用于髓系白血病细胞系HL-60、K562细胞,用AnnexinV-FITC法检测细胞凋亡,用流式细胞术检测Bcl-2、Caspapse-3表达。结果:联合组与单用组相比,细胞凋亡率明显增高。Bcl-2在HL-60、K562细胞均高水平表达。As2O3明显抑制HL-60细胞Bcl-2表达,对K562细胞Bcl-2无明显抑制作用。单用PD98059、As2O3及两药合用在诱导HL-60、K562细胞凋亡过程中,活化caspapse-3均明显上升,两药合用较单用PD98059或As2O3活化caspapse-3明显升高。结论:PD98059联合As2O3同时抑制ERK/MAPK和Bcl-2,激活Caspase酶,对HL-60细胞有协同促凋亡效应。两药联合同时靶向作用ERK/MAPK和BCR/ABL,活化Caspase酶,协同诱导K562细胞凋亡。PD98059可增强As2O3对髓系白血病细胞的凋亡诱导作用。

Study on the effects and mechanisms of MEK inhibitor enhancing apoptosis of myeloid leukemia cells induced by As2O3

Objective:To elucidate the effects and mechanisms of MEK inhibitor PD98059 enhancing apoptosis of myeloid leukemia cells induced by As2O3.Methods:HL-60 and K562 cells were examined.Cell apoptosis was determined by annexinV-FITC/PI double-staining.The expression of Bcl-2 and active caspapse-3 were measured by flow cytometry.Results:PD98059 and As2O3 in combination significantly induced apoptosis of HL-60 and K562 cells compared with either PD98059 or As2O3.The expression levels of Bcl-2 were higher in HL-60 and K562 cells.As2O3 decreased Bcl-2 expression in HL-60 cells,but didn′t affect Bcl-2 expression in K562 cells.Either PD98059 or As2O3 alone or PD98059 and As2O3 in combination significantly increased active caspapse-3 expression in HL-60 and K562 cells,the combination group being more significantly increased compared with the other two groups.Conclusion:Combination of PD98059 and As2O3 results in the activities of caspases and the synergistic induction of apoptosis in HL-60 cells by simultaneous targeting of the ERK/MAPK and Bcl-2 pathways.As2O3 interferes with the BCR/ABL protein signal transduction,whereas PD98059 lowers the apoptotic threshold,thereby increasing the activation of caspase-3 and generating the synergistic induction of apoptosis in K562 cells.PD98059 can enhance apoptosis of myeloid leukemia cells induced by As2O3.