西达本胺对人结肠癌裸鼠皮下移植瘤的抑制作用及机制  

Inhibitory effect and its mechanism of CS055 on human colon carcinoma transplanted tumor

作　　者：刘洋[1] 刘振操 邱少敏[3] 刘琳[2] 

机构地区：[1]东南大学附属中大医院消化内科,南京210009 [2]东南大学附属中大医院临床肿瘤中心,南京210009 [3]南京市肿瘤医院内科

出　　处：《中华实验外科杂志》2015年第2期322-326,共5页Chinese Journal of Experimental Surgery

基　　金：南京市医学科技发展项目（ZKX07005）

摘　　要：目的 观察组蛋白去乙酰化酶抑制剂（HDACi）西达本胺（CS055）对人结肠癌裸鼠皮下移植瘤的抑制作用,并探讨其机制.方法 成功建立人结肠癌裸鼠皮下移植瘤模型,将55只裸鼠随机分成5组,每组11只,分别予以CS055 10.0、5.0、2.5 mg/（kg·d）灌胃和5-氟尿嘧啶（5-Fu）25.0 mg/（kg·d）腹腔注射,以及阴性对照药物0.1 ml/10 g灌胃干预,连续给药21 d.治疗结束后,测量各组瘤体积及瘤重,计算瘤体积抑制率及瘤重抑制率.取瘤组织行苏木素-伊红（HE）染色,通过透射电镜观察肿瘤细胞凋亡,Westem blot检测蛋白去乙酰化酶l（HDACl）、HDAC2、组蛋白-H3（ac-H3）、p21、周期蛋白依赖性激酶4（CDK4）、半胱氨酰天冬氨酸特异性蛋白酶（Caspase）-3的表达.结果 与阴性对照药物比较,高剂量组、中剂量组、低剂量组、5-Fu组抑瘤率分别为15.36％（P＞0.05）、40.27％ （P＜ 0.01）、12.29％ （P＞0.05）、55.63％ （P＜ 0.01）;瘤体积抑制率分别为15.48％ （P＞ 0.05）、40.47％ （P＜0.01）、12.37％ （P＞0.05）、55.74％（P＜0.01）.CS055能抑制HDAC1和HDAC2的表达,提高ac-H3的乙酰化水平;同时诱导p21、Caspase-3的表达,下调CDK4的表达.结论 CS055能抑制人结肠癌裸鼠皮下移植瘤的生长,其机制可能为抑制HDAC1和HDAC2的表达,提高ac-H3的乙酰化水平,通过上调p21的蛋白表达,下调CDK4的蛋白表达,诱导结肠癌细胞周期阻滞;同时上调Caspase-3的蛋白表达,诱导结肠癌细胞凋亡.Objective To explore the inhibitory effect and its mechanism of CS055 [a selective histone deacetylase inhibitor （HDACi）] on human colon carcinoma in nude mice.Methods The xenograft model was established successfully.Fifty-five mice were divided into five groups and eleven blocks by randomized complete-block design.The mice were respectively garaged by CS055 10.0 mg/（kg·d） in the first group,5 mg/（kg·d） in the second group and 2.5 mg/（kg·d） in the third group,while the mice in fourth group were treated by intraperitoneal injection of 5-fluorouracil in a dose of 25.0 mg/（kg·d） and those in the fifth group were gavaged by negative-control-drug 0.1 ml/（10 g·d） as negative control group.After treatment,all nude mice were killed,and all the subcutaneous transplanted tumors were stripped and measured by calipers and scales.Inhibitory rate of tumor weight and tumor volume was calculated.Tissue hematoxylin and eosin （HE） staining and transmission electron microscopy detection were used to detect the tumor cell apoptosis.Western blotting was used to detect the expression of histone deacetylase 1 （HDAC1）,HDAC2,acetylated histone-H3 （ac-H3）,p21,cyclin dependent kinase 4 （CDK4）,and cysteinyl aspartate-specific protease（Caspase）-3.Results Compared to negative control group,the respective inhibition rate of tumor weight in high-dose group,mediate-dose group,low-dose group,and5-fluorouracil group was 15.36% （P〉0.05）,40.27% （P〈0.01）,12.29% （P〉 0.05） and 55.63% （P〈 0.01） respectively,and the respective inhibitory rate of tumor volume was 15.48% （P 〉 0.05）,40.47% （P 〈 0.01）,12.37% （P 〉 0.05） and 55.74% （P 〈 0.01） respectively.CS055 could significantly inhibit the expression of HDAC1 and HDAC2,upregulate the level of acetylation of histonc H3 and the expression of p21,Caspase-3,while downregulate the expression of CDK4 protein.Conclusion CS055 can inhibit the growth of human colon carcinoma xenograft tumor probably by inhibiting the exp

关 键 词：结肠癌 组蛋白去乙酰化酶抑制剂 脱噬作用 裸鼠 

分 类 号：R965[医药卫生—药理学]