组蛋白去乙酰化酶抑制剂联合溴结构域蛋白4抑制剂治疗脑胶质瘤的疗效研究

Antitumor Effect of Histone Deacetylase Inhibitor Combined with Bromine Domain Protein 4 In⁃hibitor on Glioblastoma

目的:探讨组蛋白去乙酰化酶(HDAC)抑制剂伏立诺他(SAHA)与溴结构域蛋白4(BRD4)抑制剂JQ1联合用药在动物模型水平治疗脑胶质瘤的疗效。方法:采用MTT法测试SAHA、JQ1及二者联合用药对体外培养的U87、U251、U373MG和C6这4种胶质瘤细胞的抑制活性。选择抑制活性最强的胶质瘤细胞构建皮下荷瘤鼠模型,并将其随机分为空白对照组、SAHA组、JQ1组及SAHA和JQ1联合用药组,连续灌胃给药18 d。每隔2天测量肿瘤体积、小鼠的体质量,计算小鼠体质量变化率;治疗18 d后,取下肿瘤称重,计算各组的抑瘤率。结果:体外抗肿瘤活性表明,联合用药对U87细胞抑制活性最强;选择U87细胞建模并给予相应药物治疗。联合用药能够显著地抑制U87肿瘤体积及重量的增长,优于单一使用SAHA和JQ1治疗;联合用药组的抑瘤率显著高于其他2组。结论:SAHA和JQ1联合用药能够有效的抑制脑胶质瘤的生长,其效果强于单一使用SAHA或JQ1治疗。

Objective:To explore the effect of histone deacetylase inhibitor vorinostat(SAHA)combined with bromine domain protein 4 inhibitor JQ1 against glioblastoma in animal model.Methods:The antiproliferative ac-tivity of SAHA combined with JQ1 on U87,U251,U373MG and C6 was assessed by MTS assay.Subcutaneously,tumor models of U87 were established in nude mice,which were randomly divided into blank control group,SAHA group,JQ1 group and combination treatment group by continuous intragastric administration for 18 days.The tumor volume and body weight of mice were measured every 2 days.After 18 days of treatment,the tumors were removed and weighed to calculate the tumor inhibition rates.Results:In vitro anti-proliferative results sug-gested that the combination of SAHA and JQ1 showed significant anti-proliferative effect on U87,U251,U373MG and C6,especially against U87.In vivo anti-tumor results exhibited that the combination of SAHA and JQ1 could significantly inhibit the growth of U87 tumors in mice,which is better than the single use of SAHA and JQ1 treat-ment.The tumor inhibition rate of the combination group was significantly higher than the other 2 groups.Conclu⁃sion:The combination of SAHA and JQ1 can effectively inhibit the growth of glioblastoma,and its effect is better than that of SAHA or JQ1 alone.