新型组蛋白去乙酰化酶抑制剂FK228对人结肠癌细胞HCT-116的体内外抑制作用  

Inhibitory effect of a novel histone deacetylases inhibitor FK228 on human colon cancer HCT-116 cells in vitro and in vivo

作　　者：徐东波[1] 望运玲 岳源[1] 武双婵[1] 丁虹[1] 

机构地区：[1]武汉大学药学院药理实验室,430072 [2]湖北省宜昌市第二人民医院药剂科

出　　处：《中华肿瘤杂志》2013年第11期814-818,共5页Chinese Journal of Oncology

基　　金：基金项目：国家中小企业创新基金（09C2621421479）

摘　　要：目的探讨新型组蛋白去乙酰化酶抑制剂FK228对人结肠癌细胞HCT-116的体内外抑制作用。方法采用不同浓度的FK228和氟尿嘧啶（5-Fu）处理HCT-116细胞24、48、72h，采用CCK．8法观察比较FK228对结肠癌HCT-116细胞的生长抑制作用。体内实验构建BALB／c裸鼠皮下移植瘤模型，腹腔注射FK228（5mg／kg）和5-Fu（50mg／kg），比较FK228对HCT-116裸鼠移植瘤的生长抑制作用及血液、肝、。肾毒性。结果FK228对结肠癌细胞HCT-116具有明显的生长抑制作用，且具有时间和剂量依赖性，其48h的IC50为12．05ng／ml，而5-Fu的IC50仅为18．92μg/ml。给药20d后，FK228组裸鼠肿瘤体积为（139．71±44．54）mm^3，显著低于5-Fu组[（282．28±58．81）mm^3，P〈0．01]和模型组[（520．65±39．73）mm^3，P〈0．01]；FK228组裸鼠肿瘤重量为（0．07±0．02）g，显著低于5-Fu组[（0．20±0．08）g，P〈0．01]。5-Fu组和FK228组的肿瘤抑制率分别为45．8％和73．2％（P〈0．01）。5-Fu组和FK228组的丙氨酸转氨酶（ALT）水平显著高于模型组和空白组（均P〈0．01），而FK228组的血尿素氮（BUN）水平与空白组、模型组的差异无统计学意义（均P〉0．05），5-Fu组的BUN水平明显高于模型组和空白组（均P〈0．01）。5-Fu组裸鼠的白细胞（WBC）、红细胞（RBC）、血红蛋白（Hb）和血小板（PLT）水平显著低于模型组（均P〈0．05），而FK228组裸鼠仅WBC水平与模型组差异有统计学意义（P〈0．05）。HE染色结果显示，FK228组肝细胞局部出现纤维变性，并伴有血细胞和炎性细胞浸润；肾脏出现了轻微肾小管水肿，其他形态正常。5-Fu组肝细胞出现了局部大量坏死、变形，一部分肝细胞水肿变形；肾脏出现了明显的肾小球和肾小管变形、坏死，管壁变薄。结论与5-Fu比较，FK228可在体内外明显抑制HCT-116细胞的生长，对肾和血液系统的毒性不明显，具有较�Objective To investigate the inhibitory effects of a novel histone deacetylases inhibitor FK228 on human colon cancer HCT-116 cells in vitro and in vivo, and evaluate its toxicity and side effects. Methods The in vitro growth inhibitions of HCT-116 cells by different concentrations of FK228 and 5-Fu for 24, 48 and 72 h were assessed by CCK-8 assay. BALB/c nude mouse models of tumor xenografts were prepared by subcutaneous implantation of tumor tissue, and 4 mg/kg FK228 and 50 mg/kg 5-Fu were i. p. injected, respectively. The inhibitory effects on tumor growth, hematology, and liver and kidney function were evaluated. Results CCK-8 assay indicated that FK228 had an obvious growth inhibitory effect on HCT-116 cells in a doseand time-dependent manner. The ICs0 of FK228 in HCT-116 cells was 12.05 ng/ml for 48 h, while the ICs0 of 5-Fu was 18.92 μg/ml. At 20 days after FK228 and 5-Fu treatment, the tumor volume of the FK228 group was （ 139.71 ±44.54） mm3 , significantly lower than that of the 5-Fu group [ （282.28 ± 58.81 ） mm3 ] and that of the model group [ （520.65 ± 39.73 ） mm3, P 〈 0.01 for both ]. The average tumor weight was （0.07 ± 0.02 ） g in the FK228 group, significantly lower than that of the 5-Fu group [（0.20 ± 0. 08） g, P 〈 0. 01 ]. The tumor growth inhibition rate of the FK228 group was 73.2%,significantly higher than that of the 5-Fu group （45.8%, P 〈0.01 ）. The ALT levels of the FK228 and 5- Fu groups were significantly higher than that of the model group （ P 〈 0.01 ）. The BUN of 5-Fu group was significantly higher than that of the model group （ P 〈 0. 01 ）, but the BUN of FK228 group was not significantly different from that of the blank and control groups （ P 〉 0.05 for both）. Routine blood test showed that WBC, RBC, Hb and PLT of the 5-Fu group were significantly lower than those of the model group （P 〈0.05 for all）, but only WBC of the FK228 group was significantly lower than that of the model group （ P 〈 0.05 ）. The pathological exa

关 键 词：结肠肿瘤 HCT-116 FK228 药理作用 药物毒性 

分 类 号：R735.3[医药卫生—肿瘤]