文章：

HSP70抑制剂氟虫菊酯-μ在急性白血病中的抗白血病活性

Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia

原文发布日期：2011-07-15

DOI: 10.1038/bcj.2011.28

类型: Original Article

开放获取: 是

英文摘要：

Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-μ (PFT-μ), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-μ significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 μM, and was highly active in primary AML blasts with a median IC50 of 8.9 μM (range 5.7–37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT-μ induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-μ also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-μ enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-μ, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-μ in acute leukemias.

摘要翻译： 

热休克蛋白（HSP）70在不同恶性肿瘤中异常表达，已成为抗癌治疗的有前景新靶点。本研究分析了可诱导HSP70抑制剂pifithrin-μ（PFT-μ）在急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）细胞系及原代AML母细胞中的体外抗白血病效应。PFT-μ在所有受试细胞系中以低微摩尔浓度显著抑制细胞活力，IC50值范围为2.5-12.7 μM，在原代AML母细胞中活性极高（中位IC50 8.9 μM，范围5.7-37.2 μM）。重要的是，正常造血细胞显示更高IC50值。在AML和ALL中，PFT-μ以剂量依赖方式诱导凋亡和细胞周期阻滞。该药物还使NALM-6细胞中活化型caspase-3增加，并降低AKT和ERK1/2的胞内浓度。此外，PFT-μ增强了阿糖胞苷、17-烯丙胺基-17-去甲氧基格尔德霉素、辛二酰苯胺异羟肟酸及索拉非尼在NALM-6、TOM-1和KG-1a细胞中的细胞毒性。这是首项证实HSP70抑制剂PFT-μ单药及联合不同抗肿瘤药物在AML和ALL中具有显著抗白血病效应的研究。我们的结果提示PFT-μ在急性白血病中具有潜在治疗作用。

原文链接：

Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia