ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress.
ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress.
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DOI：
10.1158/1078-0432.ccr-11-2113
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发表时间：
2012-04-01
期刊：
影响因子：
--
通讯作者：
Wiestner A
中科院分区：
文献类型：
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作者：
Chapman CM;Sun X;Roschewski M;Aue G;Farooqui M;Stennett L;Gibellini F;Arthur D;Pérez-Galán P;Wiestner A
慢性淋巴细胞白血病（CLL）是一种成熟B细胞的恶性肿瘤，化疗无法治愈。来自微环境的信号支持白血病细胞存活和增殖，并可能赋予化疗抗性。ON 01910.Na（Rigosertib）是一种多激酶PI 3 K抑制剂，正在进入骨髓增生异常综合征的III期试验。我们的目的是分析ON 01910.Na对CLL细胞的体外疗效，并研究该药物对肿瘤生物学的分子效应。使用Annexin V和CD 19染色的细胞的流式细胞术在体外测定ON 01910.Na对来自34名患者的CLL细胞的细胞毒性。使用Affyssin微阵列、流式细胞术、蛋白质印迹和与基质细胞共培养的整体基因表达谱来描绘ON 01910.Na的作用机制。ON 01910.Na诱导CLL B细胞凋亡，对T细胞或正常B细胞没有显著毒性。ON 01910.Na对与更侵袭性病程（IGHV未突变，不良细胞遗传学）相关的白血病细胞的活性与对无这些特征的细胞的活性相同。基因表达谱分析揭示了两种主要的作用机制：PI 3 K/AKT抑制和ROS诱导，通过激活蛋白1（AP-1）、c-Jun NH 2-末端激酶和ATF 3导致氧化应激反应，最终导致NOXA上调。ROS清除剂和shRNA介导的ATF 3和NOXA敲低保护细胞免于药物诱导的凋亡。ON 01910.Na还消除了滤泡树突状细胞对CLL细胞的促存活作用，并减少了SDF-1诱导的白血病细胞迁移。这些数据支持ON 01910.Na在CLL中的临床开发。
Chronic Lymphocytic Leukemia (CLL), a malignancy of mature B-cells, is incurable with chemotherapy. Signals from the microenvironment support leukemic cell survival and proliferation, and may confer chemotherapy resistance. ON 01910.Na (Rigosertib) a multikinase PI3K inhibitor is entering phase III trials for myelodysplastic syndrome. Our aim was to analyze the efficacy of ON 01910.Na against CLL cells in vitro and investigate the molecular effects of this drug on tumor biology. Cytotoxicity of ON 01910.Na against CLL cells from 34 patients was determined in vitro using flow cytometry of cells stained with Annexin V and CD19. Global gene expression profiling on Affymetrix microarrays, flow cytometry, western blotting, and co-cultures with stroma cells were used to delineate ON 01910.Na mechanism of action. ON 01910.Na induced apoptosis in CLL B-cells without significant toxicity against T-cells or normal B-cells. ON 01910.Na was equally active against leukemic cells associated with a more aggressive disease course (IGHV unmutated, adverse cytogenetics) than against cells without these features. Gene expression profiling revealed two main mechanisms of action: PI3K/AKT inhibition and induction of ROS that resulted in an oxidative stress response through activating protein 1 (AP-1), c-Jun NH2-terminal kinase, and ATF3 culminating in the upregulation of NOXA. ROS scavengers and shRNA mediated knockdown of ATF3 and NOXA protected cells from drug induced apoptosis. ON 01910.Na also abrogated the pro-survival effect of follicular dendritic cells on CLL cells and reduced SDF-1-induced migration of leukemic cells. These data support the clinical development of ON 01910.Na in CLL.