新型组蛋白去乙酰化酶抑制剂对结肠癌细胞的增殖抑制作用
신형조단백거을선화매억제제대결장암세포적증식억제작용
A novel histone deacetylase inhibitor induces proliferation inhibition of human colon cancer cells
  • 万方数据
    军事医学 군사의학
    BULLETIN OF THE ACADEMY OF MILITARY MEDICAL SCIENCES
    2014年 9期 708-713 ,共6页

    蒋琛琛%乔志新%张淑贞%任素萍%王春燕%李伟静%王璇琳%贺敏%郐启源%丁雪洁%王艳冰%王钰%杨丽华%王福梅%朱长进%尉承泽%于群

    장침침%교지신%장숙정%임소평%왕춘연%리위정%왕선림%하민%회계원%정설길%왕염빙%왕옥%양려화%왕복매%주장진%위승택%우군

    结肠肿瘤%组蛋白去乙酰化酶抑制剂%JZ004%细胞凋亡%膜电位,线粒体 結腸腫瘤%組蛋白去乙酰化酶抑製劑%JZ004%細胞凋亡%膜電位,線粒體
    결장종류%조단백거을선화매억제제%JZ004%세포조망%막전위,선립체
    colon neoplasms%histone deacetylase inhibitor%JZ004%apoptosis%membrane potential,mitochondrial
    目的：观察组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor， HDACi）JZ004对结肠癌细胞系HCT-8和HT-29细胞增殖的影响，并初步探讨其抗癌机制。方法用不同浓度JZ004分别处理HCT-8和HT-29细胞， MTT法检测细胞的增殖情况；流式细胞仪检测细胞周期停滞、细胞凋亡；若丹明（rhodamine）123和二氯二氢荧光素二乙酸酯（ DCFH-DA）测定细胞线粒体跨膜电位及活性氧（ reactive oxygen species ，ROS）产生的变化；免疫印迹法检测细胞内乙酰化组蛋白H3、p21、细胞周期蛋白依赖激酶（CDK）4、Bcl-2、Mcl-1、Bax等相关蛋白的表达水平。结果MTT结果显示，JZ004对结肠癌细胞系的增殖有明显抑制作用，其抑制效果与时间、剂量呈正相关；流式分析结果显示，细胞凋亡率随JZ004浓度提高而增加；JZ004处理72 h后，p21表达水平上调，CDK4蛋白表达下调，细胞周期停滞于G0／G1期而抑制细胞的生长，细胞内ROS产生增多，且线粒体跨膜电位显著下降，促凋亡蛋白Bax的表达呈上调趋势，而抑凋亡蛋白Bcl-2、Mcl-1表达则受到抑制。结论 JZ004作为一种新型的HDACi对结肠癌细胞具有明显的抑制生长和诱导凋亡作用，凋亡诱导机制可能与Bcl-2家族蛋白表达水平变化有关。提示JZ004具有成为结肠癌临床化疗药物的潜能。
    목적：관찰조단백거을선화매억제제（histone deacetylase inhibitor， HDACi）JZ004대결장암세포계HCT-8화HT-29세포증식적영향，병초보탐토기항암궤제。방법용불동농도JZ004분별처리HCT-8화HT-29세포， MTT법검측세포적증식정황；류식세포의검측세포주기정체、세포조망；약단명（rhodamine）123화이록이경형광소이을산지（ DCFH-DA）측정세포선립체과막전위급활성양（ reactive oxygen species ，ROS）산생적변화；면역인적법검측세포내을선화조단백H3、p21、세포주기단백의뢰격매（CDK）4、Bcl-2、Mcl-1、Bax등상관단백적표체수평。결과MTT결과현시，JZ004대결장암세포계적증식유명현억제작용，기억제효과여시간、제량정정상관；류식분석결과현시，세포조망솔수JZ004농도제고이증가；JZ004처리72 h후，p21표체수평상조，CDK4단백표체하조，세포주기정체우G0／G1기이억제세포적생장，세포내ROS산생증다，차선립체과막전위현저하강，촉조망단백Bax적표체정상조추세，이억조망단백Bcl-2、Mcl-1표체칙수도억제。결론 JZ004작위일충신형적HDACi대결장암세포구유명현적억제생장화유도조망작용，조망유도궤제가능여Bcl-2가족단백표체수평변화유관。제시JZ004구유성위결장암림상화료약물적잠능。
    Objective To examine the anticancer effect of a novel histone deacetylase inhibitor (HDACi), JZ004, on colon cancer cells HCT-8 and HT-29, and to investigate the molecular mechanisms of proliferation inhibition and apoptosis induction of cancer cells treated by JZ 004.Methods Colon cancer cells were treated with a series of concentrations of JZ004 .MTT assay was used to detect the proliferation of cancer cells .The cell cycle distribution and apoptosis were deter-mined by flow cytometry .Rhodamine 123 and DCFH-DA were applied to detect the mitochondrial membrane potential (ΔΨm) and reactive oxygen species ( ROS) production.The protein expressions of acetyl-histone H3, p21, cyclin-dependent kinase(CDK)4, Bcl-2, Mcl-1 and Bax were assayed by Western blotting .Results JZ004 was found to inhibit proliferation and induce apoptosis of colon cancer cells in a time-and dose-dependent manner , accompanied by a dose-dependent hyperacetylation of histone H3.JZ004 induced the cancer cell arrest in G 0/G1 phase by increasing the expres-sion level of p21 while CDK4 was downregulated .JZ004 also increased cellular ROS production and reduced ΔΨm by regu-lating the expressions of Bcl-2 family proteins .Conclusion As a novel HDACi , JZ004 effectively inhibits proliferation and increases ROS production to induce apoptosis of colon cancer cells .The results indicate that JZ004 is a potential compound to be developed as an anti-colon cancer agent for clinic application .
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