Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve mcl-1 and p21CIP1 down-regulation(Retracted article. See vol.22, pg.4959,2016)
Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve mcl-1 and p21CIP1 down-regulation(Retracted article. See vol.22, pg.4959,2016)
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DOI：
10.1158/1078-0432.ccr-07-0835
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发表时间：
2007-07-15
影响因子：
11.5
通讯作者：
Grant, Steven
中科院分区：
文献类型：
--
作者：
Dasmahapatra, Girija;Yerram, Nitin;Grant, Steven
目的：多激酶抑制剂索拉非尼之间的相互作用在对甲磺酸伊马替尼敏感和耐药的慢性粒细胞白血病（CML）细胞中检查了（Bay 43-9006）和组蛋白脱乙酰酶抑制剂伏立诺他。实验设计：将K562、LAMA 84和原代CML患者来源的CD 34（+）单核细胞暴露于伏立诺他，然后暴露于索拉非尼，之后通过流式细胞术、克隆形成测定和蛋白质印迹法监测对细胞活力和各种存活信号传导途径的影响。实时逆转录-PCR用于监测基因表达，并在用相应构建体转染的细胞中确定p21（CIP 1）和Mcl-1下调的功能贡献。K562和LAMA 84）。在表达活化林恩的甲磺酸伊马替尼耐药细胞以及从CIVIL患者获得的原代CD 34（+）骨髓细胞中获得了类似的结果。该方案还显著抑制CIVIL细胞集落形成。用伏立诺他和索拉非尼组合而非单独处理CIVIL细胞引发了明显的线粒体功能障碍（即，细胞色素c、Smac和AIF释放）、胱天蛋白酶活化、聚（ADP-核糖）聚合酶切割和Mcl-1的下调。索拉非尼还阻断伏立诺他介导的p21（CIP 1）诱导。Mcl-1的下调不依赖于caspase和转录，而p21（CIP 1）的下调部分依赖于caspase和转录。加强表达p21（CIP 1），特别是Mcl-1显着衰减伏立诺他/索拉非尼介导的lethality.Conclusions：这些研究结果表明，联合治疗伏立诺他和索拉非尼协同诱导CIVIL细胞凋亡，通过一个过程，涉及Mcl-1下调和抑制p21（CIP 1）诱导。
Purpose: Interactions between the multikinase inhibitor sorafenib (Bay 43-9006) and the histone deacetylase inhibitor vorinostat were examined in chronic myelogenous leukemia (CML) cells sensitive and resistant to imatinib mesylate.Experimental Design: K562, LAMA 84, and primary CML patient-derived CD34(+) mononuclear cells were exposed to vorinostat followed by sorafenib, after which effects on cell viability and various survival signaling pathways were monitored by flow cytometry, clonogenic assays, and Western blotting. Real-time reverse transcription-PCR was used to monitor gene expression, and the functional contribution of p21(CIP1) and Mcl-1 down-regulation were determined in cells transfected with corresponding constructs.Results: Pretreatment (24 h) with vorinostat followed by sorafenib optimally induced mitochondrial injury and cell death in Bcr/Abl(+) cells (e.g., K562 and LAMA 84). Similar results were obtained in imatinib mesylate-resistant cells expressing activated Lyn as well as in primary CD34(+) bone marrow cells obtained from CIVIL patients. This regimen also markedly inhibited CIVIL cell colony formation. Combined but not individual treatment of CIVIL cells with vorinostat and sorafenib triggered pronounced mitochondrial dysfunction (i.e., cytochrome c, Smac, and AIF release), caspase activation, poly (ADP-ribose) polymerase cleavage, and down-regulation of Mcl-1. Sorafenib also blocked vorinostat-mediated induction of p21(CIP1). Down-regulation of Mcl-1 was caspase and transcription independent, whereas p21(CIP1) down-regulation was partially caspase and transcription dependent. Enforced expression of p21(CIP1) and particularly Mcl-1 significantly attenuated vorinostat/sorafenib-mediated lethality.Conclusions: These findings suggest that combined treatment with vorinostat and sorafenib synergistically induces apoptosis in CIVIL cells through a process that involves Mcl-1 down-regulation and inhibition of p21(CIP1) induction.