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首页> 外文期刊>Biochemistry >Antitumor Effect of Non-steroid Glucocorticoid Receptor Ligand CpdA on Leukemia Cell Lines CEM and K562
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Antitumor Effect of Non-steroid Glucocorticoid Receptor Ligand CpdA on Leukemia Cell Lines CEM and K562

机译：非甾体糖皮质激素受体配体CpdA对白血病细胞株CEM和K562的抗肿瘤作用

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摘要

Glucocorticoids (GCs) are widely used in chemotherapy of hematological malignancies, particularly leukemia. Their effect is mediated by glucocorticoid receptor (GR), a well-known transcription factor. Besides their therapeutic impact, GCs may cause a number of side effects leading to various metabolic complications. The goal of immediate interest is testing glucocorticoid analogs capable of induction/enhancement of GR transrepression, but preventing GR dimer-ization and transactivation leading to side effects. in this work we have investigated effects of a promising new selective GR agonist, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylarnrnonium chloride (CpdA), on CEM and K562 leukemia cells. Both cell lines express functional GR. CpdA compared with the glucocorticoid fluocinolone acetonide (FA) exerted more prominent cytostatic and apoptotic effects on the cells. Both cell lines exhibited sensitivity to CpdA, demonstrating a good correlation with the effects of FA on cell growth and viability. in contrast to FA, CpdA did not induce GR transactivation evaluated by no obvious increase in expression of GR target (and dependent) gene FKBP51. At the same time, luciferase assay showed that CpdA efficiently activated transrepression of NF-κB and AP-1 factors. We also evaluated the effect of combined action of CpdA and the proteasome inhibitor Bortezomib. The latter induced a caspase-dependent apoptosis in both T-cell leukemia cell lines. By treatment of CEM cells with different CpdA/GC and Bortezomib doses, we have designed a protocol where CpdA shows potentiating effect on Bortezomib cytotoxic activity. Generally, the present work characterizes a novel non-steroid GR ligand, CpdA, as a promising compound for possible application in leukemia chemotherapy.
机译：糖皮质激素（GCs）被广泛用于血液系统恶性肿瘤，尤其是白血病的化学疗法。它们的作用由众所周知的转录因子糖皮质激素受体（GR）介导。除了具有治疗作用外，GC还可能引起许多副作用，导致各种代谢并发症。迫在眉睫的目标是测试能够诱导/增强GR反式抑制但防止GR二聚化和反式激活导致副作用的糖皮质激素类似物。在这项工作中，我们研究了一种有前途的新型选择性GR激动剂2-（4-乙酰氧基苯基）-2-氯-N-甲基乙基甲基氯化铵（CpdA）对CEM和K562白血病细胞的作用。两种细胞系均表达功能性GR。与糖皮质激素丙酮酸氟轻松（FA）相比，CpdA对细胞具有更显着的细胞抑制和凋亡作用。两种细胞系均表现出对CpdA的敏感性，表明与FA对细胞生长和活力的影响具有良好的相关性。与FA相反，CpdA不会诱导GR反式激活，因为GR靶标（和依赖基因）FKBP51的表达没有明显增加。同时，萤光素酶检测显示CpdA有效激活了NF-κB和AP-1因子的反式表达。我们还评估了CpdA和蛋白酶体抑制剂Bortezomib联合作用的效果。后者在两种T细胞白血病细胞系中均诱导了caspase依赖性凋亡。通过用不同的CpdA / GC和Bortezomib剂量处理CEM细胞，我们设计了一个方案，其中CpdA对Bortezomib的细胞毒活性显示出增强作用。通常，本工作将新型非类固醇GR配体CpdA表征为有望用于白血病化学治疗的化合物。

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