中文摘要：

目的体外观察组蛋白去乙酰化酶抑制剂TSA、蛋白酶体抑制剂MG-132单独和联合作用致骨髓瘤及淋巴瘤细胞增殖阻滞及凋亡。方法TSA和MG-132以不同浓度单独和联合作用细胞株EL4、WEHI-231、SP2/0、P3NSI,台盼蓝法、AnnexinV/propidium iodide染色、流式细胞仪观察细胞活力、周期和凋亡。Bliss法计算TSA、MG-132对各细胞株的IC_（50）值,Calcuysn软件评价药物协同效应。免疫印迹检测凋亡、周期相关蛋白Bcl-2、Bax、caspase3、CyclinD1、p21的表达,观察转录因子IRF4和c-Myc表达水平。结果TSA和MG-132单独作用均可呈药物浓度依赖性地抑制细胞增殖、诱导细胞凋亡,两药协同效应显著。细胞凋亡相关蛋白caspase-3激活,Bax、Bcl-2表达均相对下调,阻滞于G_0～G_1期的细胞明显增多,CyclinD1表达水平下降,p21水平显著上升。结论TSA和MG-132单独作用细胞株WEHI-231、EL4、SP2/0、P3NSI,呈药物浓度依赖性地抑制细胞增殖、激活caspase-3诱导细胞凋亡,两药合用呈显著协同效应。同时,两药单独或联合作用均能致细胞G_1期阻滞。

英文摘要：

We aimed to investigate the cytotoxicity and proliferation arrest effects of the histone deacetylase（HDAC） inhibitor TSA alone or/and combined with proteasome inhibitor MG-132 against lymphoma and multiple myeloma（MM） cells in vitro.Cell strains EL4,WEHI-231,SP2/0,and P3NSI were treated with TSA and/or MG-132 at different concentrations.Then the cytotoxicity and combination effects on the growth of lymphoma and MM cells were assessed by Trypan Blue assay;apoptosis and cell cycle were measured by flow cytometry,whereas the caspase3 activation,the Bcl-2,Bax,cyclinD1,p21,IRF4 and c-Myc expression were determined by Western blot.In all lymphoma and MM cells,TSA or MG-132 alone induced concentration-dependent cytotoxicity and apoptosis that was associated with prominent G_1 arrest,decreased CyclinD1,increased p21 proteins.While combined TSA/MG-132 treatment resulted in strong synergistic cytotoxicity and apoptosis,Apoptosis induced by TSA/MG-132 alone or combination was shown to involve caspase activation,further,resulted in increased caspase-3 cleavage,decreased Bcl-2 and Bax expression.In MM cells, with high level of IRF4 expression,combined TSA/MG-132 significantly down-regulated IRF4 and c-Myc expression compared with either agent alone;while in lymphoma cells,with low level of IRF4 expression,the level of IRF4 expression was no significant variation and only the level of c-Myc expression was gradually down-regulated by TSA/MG-132 combination.We conclude that TSA/MG- 132 alone or combination results in dose-dependent or synergistic cytotoxicity and apoptosis which involves the activation of caspase and G_1 arrest.Furthermore,the levels of IRF4 and c-Myc expression are alternative in apoptosis of lymphoma and MM.This may have potential therapeutic value in lymphoma and MM.