西达本胺联合吗替麦考酚酯抑制继发性急性髓系白血病细胞增殖  

Chidamide combined with mycophenolate mofetil suppress proliferation of secondary acute myeloid leukemia cells

作　　者：蔡铎 梁思敏[1] 周巧[1] 王利[1] CAI Duo;LIANG Simin;ZHOU Qiao;WANG Li(Department of Hematology,the First Affiliated Hospital of Chongqing Medical University,Chongqing,400016,China;Key Laboratory of Translational Medicine for Major Metabolic Diseases,the First Affiliated Hospital of Chongqing Medical University,Chongqing,400016,China)

机构地区：[1]重庆医科大学附属第一医院血液内科,重庆400016 [2]重庆医科大学附属第一医院重大代谢性疾病转化医学重点实验室,重庆400016

出　　处：《陆军军医大学学报》2022年第13期1338-1348,共11页Journal of Army Medical University

基　　金：重庆市科卫联合医学科研项目重点项目(2018ZDXM001)。

摘　　要：目的探讨西达本胺(chidamide,CDM)和吗替麦考酚酯(mycophenolate mofetil,MMF)联合应用对继发性急性髓系白血病细胞增殖的影响。方法慢性髓系白血病急变期细胞株K562及MDS转白细胞株SKM-1,分别按照不同浓度的CDM单药组(0.25、0.5、1、2、4μmol/L),MMF单药组(0.5、1、2、4、8μmol/L)及联合用药组(CDM∶MMF=1∶2)干预24、48、72 h后,CCK-8实验检测细胞增殖抑制率。基于最佳联合干预浓度干预72 h后,流式细胞学检测细胞周期及凋亡率的变化,并通过网络药理学探讨其作用机制。结果CCK-8结果显示,联合组(1μmol/L CDM+2μmol/L MMF)在K562和SKM-1细胞中的联合指数分别为0.38944和0.63098。与CDM及MMF单药组比较,联合用药能显著提高对K562和SKM-1细胞增殖抑制率(P<0.01),并促进K562细胞凋亡率增高(P<0.05)。相较单药MMF组,联合组显著诱导K562、SKM-1细胞G_(0)/G_(1)期阻滞,但较CDM单药无统计学差异。其后网络药理学构建出66个节点、222条边的药物-疾病靶点PPI网络,并根据拓扑学筛选出CDK1、CDK2、CDK4、CDK6、CDK9、SYK、BTK、KDR、PIK3CB等9个核心靶点,富集分析主要涉及蛋白质磷酸化、细胞增殖、凋亡调控等多种生物进程,及PI3K-AKT、FOXO等信号通路。结论CDM联合MMF可显著抑制继发性急性髓系白血病细胞生长。ObjectiveTo investigate the effects of combined application of chidamide(CDM)and mycophenolate mofetil(MMF)on the proliferation of secondary acute myeloid leukemia(sAML)cells.MethodsChronic myeloid leukemia blast-phase cell line K562 and myelodysplastic syndromes(MDS)-transformed leukocyte line SKM-1 were employed in the study.The cells were divided into groups according to different concentrations of intervention drugs:CDM alone groups(0.25,0.5,1,2 and 4μmol/L),MMF alone groups(0.5,1,2,4 and 8μmol/L)and combined drug groups(CDM∶MMF=1∶2),respectively.The inhibitory rate of cell proliferation was detected by CCK-8 assay after treatment for 24,48 and 72 h,respectively.Moreover,the changes of cell cycle and apoptotic rate were determined by flow cytometry after 72 h of intervention under the optimal combined drug concentration,and its mechanism was analyzed by network pharmacology.ResultsCCK-8 assay showed that the combination index of the combined drug group(1μmol/L CDM+2μmol/L MMF)was 0.38944 in K562 cells and 0.63098 in SKM-1 cells.When compared with the CDM and MMF monotherapy groups,the combined treatment significantly enhanced the inhibitory effect on the proliferation of both K562 and SKM-1 cells(P<0.01),and increased the apoptotic rate of K562 cells(P<0.05).As compared with the MMF alone group,the combination group remarkably arrested the cell cycle at the G_(0)/G_(1) phase,though which had no statistical difference with CDM alone.Subsequently,a drug-disease target protein-protein interaction(PPI)network including 66 nodes and 222 edges was constructed through network pharmacology,and 9 core targets including CDK1,CDK2,CDK4,CDK6,CDK9,SYK,BTK,KDR,and PIK3CB were screened out according to topology.Enrichment analysis indicated that various biological processes such as protein phosphorylation,cell proliferation,and apoptosis regulation were mainly involved,as well as PI3K-AKT,FOXO and other signaling pathways.ConclusionCDM combined with MMF significantly inhibits the growth of sAML cells.

关 键 词：西达本胺 麦考酚酸 继发性急性髓系白血病 网络药理学 

分 类 号：R733.7[医药卫生—肿瘤] R965[医药卫生—临床医学] R979.1