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组蛋白去乙酰化酶抑制剂LBH589逆转多发性骨髓瘤细胞耐药机制的体外研究 被引量：4

Study on histone deacetylase inhibitor LBH589 reversal of multiple myeloma cells drug resistance mechanism in vitro
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摘要 目的探讨新一代组蛋白去乙酰化酶抑制剂LBH589作用于多发性骨髓瘤（MM）耐药细胞产生的相关基因表达变化，分析其逆转MM细胞耐药的机制。方法采用Westernblot法分析LBH589单药（0、20、50nmol／L）及50nmol／LLBH589联合5Ixmol／L地塞米松作用MM1R细胞24h后组蛋白H4乙酰化的表达程度及bcl-X基因的表达变化。采用实时荧光定量PCR分析LBH589（0、20、50nmol／L）及50nmol／LLBH589联合5μmol／L地塞米松分别作用MM1R细胞24、48h后TOSO基因的表达变化。结果Westernblot分析显示不同浓度LBH589单药及联合地塞米松作用MM1R细胞24h后随着药物浓度的升高，组蛋白H4乙酰化的程度逐渐上调[（0．205±0．008）％、（0．346±0．009）％，（0．580±0．053）％、（0．986±0．012）％，F=992．957，P=0．032】；bcl—X基因的表达则逐渐下调[（1．210±0．160）％、（0．930±0．036）％、（0．730±0．017）％、（0．488±0．029）％，F=56．432，P=0．0281，变化呈剂量依赖性，且联合组的作用效果强于单药组（均P〈0．05）。实时荧光定量PCR分析显示不同浓度LBH589单药及联合地塞米松作用MM1R细胞24、48h后随着药物浓度的增加和时问的延长，TOSO基因的表达逐渐下调[24h：（1．00±0．00）％、（0．55±0．01）％、（0．47±0．01）％、（0．38±0．01）％，F=1006．344，P=0．040；48h：（1．00±0．00）％、（0．39±0．04）％、（0．05±0．01）％、（0．03±0．00）％，F=2383．977，P=0．0451，变化呈剂量-时间依赖I生，且联合组的作用效果强于单药组（均P〈0．05）。结论组蛋白去乙酰化酶抑制剂LBH589通过影响bel—x及TOSO基因的表达，恢复MM1R对地塞米松的敏感性，促进组蛋白乙酰化，诱导细胞凋亡，达到治疗肿瘤的目的。 Objective To study on a new generation of histone deacetylase inhibitor LBH589 on multiple myeloma （MM） resistant cells associated with changes in gene expression, and the mechanism of LBH589 reversal of MM cells drug resistance. Methods By Western blot analysis, LBH589 （0, 20, 50 nmol/L） and 50 nmol/L LBH589 combined respectively with dexamethasone of 5 μmol/L at 24 h, expression of histone H4 acetylation and bcl-X gene on MMIR cells were detected. By real-time fluorescence quantitative PCR analysis, LBH589 （ 0, 20, 50 nmol/L ） and 50 nmol/L LBH589 combined respectively with dexamethasone of 5 μmol/L at 24 h and 48 h, expression of TOSO on MM1R cells were detected. Results Western blot analysis showed that single LBH589 and combined with dexamethasone showed at 24 h the up-regulation on expression of the histone H4 acetylation[（0.205±0.008） %, （0.346±0.009） %, （0.580±0.053） %, （0.986±0.012） %, F = 992.957, P = 0.032], while down-regulation on expression of the bcl-X in MM1R ceils in a dose-dependent manner[（1.210±0.160） %, （0.930±0.036） %, （0.730±0.017） %, （0.488±0.029） %, F = 56.432, P = 0.028]. However, the group of single LBH589 was less effective than the combined group （all P 〈 0.05）. Real-time fluorescence quantitative PCR analysis showed single LBH589 and that combined with dexamethasone showed at 24 h and 48 h, the down-regulation on expression of the TOSO in MM1R cells in a dose-dependent manner, 24 h specific numerical were （1.00±0.00） %, （0.55±0.01） %, （0.47±0.01） %, （0.38±0.01） % （F = 1006.344, P = 0.041）, 48 h specific numerical were （1.00±0.00） %, （0.39_＋0.04） %, （0.05±0.01） %, （0.03±0.00） % （F = 2383.977, P = 0.045）, however, the group of single LBH589 was less effective than the combined group （all P 〈 0.05）. Conclusion Histone deacetylase inhibitor LBH589 can recover dexamethasone sensitivity of MM1R through effect the gene expression of bcl-X and TOSO, promot histone aeetylation, and inducing cell apoptosis to treat tumor.
作者 张灵 马艳萍 贾谷
机构地区 山西医科大学第二医院血液科
出处 《白血病．淋巴瘤》 CAS 2013年第1期50-52,56,共4页 Journal of Leukemia & Lymphoma
基金 基金项目：山西省国际科技合作计划（2010081064）
关键词 多发性骨髓瘤 组蛋白去乙酰化酶 LBH589 MM1R细胞 耐药 Multiple myeloma Histone deacetylase LBH589 MM1R cells Drug resistance
分类号 R733.3 [医药卫生—肿瘤]
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参考文献17

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共引文献20

同被引文献36

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白血病．淋巴瘤
2013年 第1期

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