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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。
Objective: To investigate the effect of MEK inhibitor PD98059 combined with As2O3 on myeloid leukemia cell apoptosis and its mechanism. Methods: PD98059 and As2O3 alone or in combination were applied to HL-60 and K562 cells. Annexin V-FITC method was used to detect apoptosis. Flow cytometry was used to detect the expression of Bcl-2 and Caspapse-3. Results: The apoptosis rate of the combined group was significantly higher than that of the single group. Bcl-2 was highly expressed in HL-60 and K562 cells. As2O3 significantly inhibited the expression of Bcl-2 in HL-60 cells and had no obvious inhibitory effect on Bcl-2 in K562 cells. Activation of caspase-3 by PD98059, As2O3 alone or in combination with both drugs in the induction of apoptosis in HL-60 and K562 cells was significantly increased. Compared with PD98059 or As2O3 alone, caspase-3 activity was significantly increased. CONCLUSION: PD98059 combined with As2O3 can inhibit ERK / MAPK and Bcl-2 simultaneously and activate Caspase, which has a synergistic pro-apoptotic effect on HL-60 cells. The combination of the two drugs simultaneously targets ERK / MAPK and BCR / ABL, activates Caspase, and synergistically induces apoptosis in K562 cells. PD98059 enhances the apoptosis-inducing effect of As2O3 on myeloid leukemia cells.