组蛋白去乙酰化酶抑制剂甲磺酸普依司他对套细胞淋巴瘤的体内外抗肿瘤药效学评价  

Antitumor pharmacodynamic evaluation of histone deacetylase inhibitor purinostat mesylate in vitro and in vivo for mantle cell lymphoma

作　　者：陶雅丽 裴和颖 王方 白鹏 陈俐娟[4] 牛挺[1] Tao Yali;Pei Heyin;Wang Fang;Bai Peng;Chen Lijuan;Niu Ting(Department of Hematology,West China Hospital,Sichuan University,Chengdu 610041,Sichuan Province,China;Collaborative Innovation Center for Biotherapy,West China Hospital,West China Medical School,Sichuan University,Chengdu 610041,Sichuan Province,China;Center for Nursing Innovation and Research,West China Hospital,Sichuan University,Chengdu 610041,Sichuan Province,China;State Key Laboratory of Biotherapy and Cancer Center,Sichuan University,Chengdu 610041,Sichuan Province,China)

机构地区：[1]四川大学华西医院血液内科,成都610041 [2]四川大学华西医院生物治疗研究中心,成都610041 [3]四川大学华西医院护理创新研究中心,成都610041 [4]四川大学生物治疗国家重点实验室,成都610041

出　　处：《国际输血及血液学杂志》2023年第1期51-59,共9页International Journal of Blood Transfusion and Hematology

基　　金：国家自然科学基金青年项目(82003799);四川大学华西医院临床研究孵化项目(19HXFH030);四川大学华西医院成果转化项目(CGZH21001);四川大学华西医院学科卓越发展1.3.5工程项目(ZYJC21007)。

摘　　要：目的探讨组蛋白去乙酰化酶抑制剂(HDACi)甲磺酸普依司他(PM)对套细胞淋巴瘤(MCL)细胞系的抗增殖活性,以及对MCL皮下移植瘤小鼠模型的抗肿瘤效果。方法选择MCL细胞系Jeko-1和Granta-519,以及非肥胖糖尿病/重度联合免疫缺陷(NOD/SCID)小鼠为研究对象,采用不同浓度梯度PM原料药(PMF,终浓度分别为0.1、0.3、0.5、1.0、2.0、4.0 nmol/L)和同浓度帕比司他(LBH589)分别处理Jeko-1,采用不同浓度梯度PMF(终浓度分别为0.4、0.8、1.6、3.1、6.3、12.5 nmol/L)和同浓度LBH589分别处理Granta-519。加药孵育120 h后,采用细胞计数试剂盒(CCK)-8法检测细胞增殖活性并计算半数抑制浓度(IC50)值。建立Jeko-1 NOD/SCID小鼠皮下移植瘤模型,按照给药种类和剂量将其分为PM 2.5 mg/kg组(n=7)、PM 5 mg/kg组(n=7)、PM 10 mg/kg组(n=7)、LBH58910 mg/kg组(n=6)和溶剂对照组(n=7)。于给药第21天时,观察各组小鼠的相对肿瘤抑制率(T/C)、瘤重及肿瘤生长抑制率。不同组别间瘤重比较,采用单因素方差分析。同浓度PMF和LBH589的细胞增殖抑制率比较,采用双因素方差分析。动物实验方案的设计获得了四川大学华西医院动物实验中心伦理委员会的批准,符合国际通行的实验动物使用规范。结果①加药孵育120 h后,PMF和LBH589以剂量依赖性方式抑制Jeko-1和Granta-519的细胞增殖。除终浓度为0.1、0.3 nmol/L的PMF与同浓度LBH589相比外,其余各终浓度PMF对Jeko-1的细胞增殖抑制率均高于同浓度LBH589,并且差异有统计学意义(终浓度为0.5、1.0、2.0、4.0 nmol/L PMF比同浓度LBH589:F=311.4、39470.4、1232.7、4575.4,P=0.03、<0.0001、=0.001、<0.0001)。Jeko-1中PMF的IC50值为(366.8±3.4)pmol/L,低于LBH589的(1570.0±51.6)pmol/L,并且差异有统计学意义(F=2367.4,P<0.0001)。不同终浓度PMF对Granta-519的细胞增殖抑制率均高于同浓度LBH589,并且差异均有统计学意义(终浓度为0.4、0.8、1.6、3.1、6.3、12.5 nmol/L PMF比同�Objective To explore the antiproliferative activity of histone deacetylase inhibitor(HDACi)purinostat mesylate(PM)on mantle cell lymphoma(MCL)cell lines and its anti-tumor effect on a mouse model of subcutaneously transplanted MCL tumor.Methods MCL cell lines Jeko-1 and Granta-519,as well as non-obese diabetic/severe combined immunodeficiency(NOD/SCID)mouse were selected as research subjects.Jeko-1 were treated with escalating final concentrations(0.1,0.3,0.5,1.0,2.0,4.0 nmol/L)of PM formulation(PMF)and LBH589 singly.Granta-519 were treated with escalating final concentrations(0.4,0.8,1.6,3.1,6.3,12.5 nmol/L)of PMF and LBH589 singly.After incubating cells for 120 h,cytotoxicity was assessed using the cell counting kit(CCK)-8 assay.And inhibitory concentration 50(IC50)value was calculated.Jeko-1 NOD/SCID mouse subcutaneous transplant tumor model was constructed to evaluate the anti-tumor effects of PM and LBH589 in vivo.According to the type and dose of administration,they were divided into PM 2.5 mg/kg group(n=7),PM 5 mg/kg group(n=7),PM 10 mg/kg group(n=7),LBH58910 mg/kg group(n=6)and vehicle control group(n=7).On the 21st day of administration,the relative tumor inhibition rate(T/C),tumor weight and tumor growth inhibition rate of each group were observed.Single factor analysis of variance was used to compare tumor weight among different groups,and double factor analysis of variance was used to compare the inhibition rate of cell proliferation between PMF and LBH589 at the same concentration.The design of the experimental protocol was approved by the Ethics Committee of the West China Hospital,Sichuan University,and was in accordance with international standards for the use of laboratory animals.Results①After incubating cells for 120 h,PMF and LBH589 showed concentration-dependent anti-proliferative activity on Jeko-1 and Grantan-519.Except for the final concentration of 0.1 and 0.3 nmol/L compared to LBH589 with the same concentration,the cell proliferation inhibition rates of Jeko-1 in the other final conce

关 键 词：淋巴瘤 膜细胞 组蛋白脱乙酰基酶类 疾病模型 动物 甲磺酸普依司他 帕比司他 

分 类 号：R965[医药卫生—药理学]