急性髓性白血病(AML)是一种血液恶性肿瘤,其特征是异常髓样前体的过度增殖伴随着分化阻断和凋亡抑制。抗凋亡MCL-1蛋白的表达增加显示对于AML细胞的持续存活和扩增是关键的。因此,在这里,我们检查了S63845(一种MCL-1的特异性抑制剂)在单一药物治疗中以及与BCL-2/BCL-XL抑制剂联合使用的促凋亡和促分化作用,ABT-737,在两种AML细胞系中:HL-60和ML-1。此外,我们确定MAPK通路的抑制是否影响AML细胞对S63845的敏感性.评估AML细胞凋亡和分化,使用PrestoBlue测定法进行体外研究,库尔特电阻抗法,流式细胞术,光学显微镜和蛋白质印迹技术。S63845导致HL-60和ML-1细胞活力的浓度依赖性降低,并增加了凋亡细胞的百分比。用S63845和ABT-737或MAPK通路抑制剂联合治疗可增强细胞凋亡,但也可诱导受试细胞分化,以及改变MCL-1蛋白的表达。一起来看,我们的数据为进一步研究MCL-1抑制剂与其他促生存蛋白抑制剂联合使用提供了理论基础.
Acute myeloid leukemia (AML) is a hematological malignancy characterized by excessive proliferation of abnormal myeloid precursors accompanied by a differentiation block and inhibition of apoptosis. Increased expression of an anti-apoptotic MCL-1 protein was shown to be critical for the sustained survival and expansion of AML cells. Therefore, herein, we examined the pro-apoptotic and pro-differentiating effects of S63845, a specific inhibitor of MCL-1, in a single-agent treatment and in combination with BCL-2/BCL-XL inhibitor, ABT-737, in two AML cell lines: HL-60 and ML-1. Additionally, we determined whether inhibition of the MAPK pathway had an impact on the sensitivity of AML cells to S63845. To assess AML cells\' apoptosis and differentiation, in vitro studies were performed using PrestoBlue assay, Coulter electrical impedance method, flow cytometry, light microscopy and Western blot techniques. S63845 caused a concentration-dependent decrease in the viability of HL-60 and ML-1 cells and increased the percentage of apoptotic cells. Combined treatment with S63845 and ABT-737 or MAPK pathway inhibitor enhanced apoptosis but also induced differentiation of tested cells, as well as altering the expression of the MCL-1 protein. Taken together, our data provide the rationale for further studies regarding the use of MCL-1 inhibitor in combination with other pro-survival protein inhibitors.