The heat shock protein 90 inhibitor IPI-504 induces apoptosis of AKT-dependent diffuse large B-cell lymphomas.
The heat shock protein 90 inhibitor IPI-504 induces apoptosis of AKT-dependent diffuse large B-cell lymphomas.
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DOI：
10.1111/j.1365-2141.2008.07484.x
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发表时间：
2009-02
影响因子：
6.5
通讯作者：
Shipp MA
中科院分区：
文献类型：
--
作者：
Abramson JS;Chen W;Juszczynski P;Takahashi H;Neuberg D;Kutok JL;Takeyama K;Shipp MA
热休克蛋白90（HSP 90）是一种分子伴侣，在多种癌症中稳定关键客户蛋白。在此，我们评估的作用，热休克蛋白90和可能的客户蛋白在弥漫性大B细胞淋巴瘤（DLBCL）的发病机制，并评估活动的热休克蛋白90抑制剂在这种疾病。我们利用基因表达谱来表征先前定义的原代人DLBCL亚群中HSP 90 α和β亚型的表达。此后，我们评估了新的HSP 90抑制剂IPI-504在DLBCL细胞系中作为单一疗法和合理组合的活性，并鉴定了负责药物活性的可能的客户蛋白。HSP 90 α和β亚型在原代“BCR”和“OxPhos”DLBCL中差异表达。IPI-504与两种HSP 90亚型中保守的ATP结合位点相互作用，在低微摩尔浓度下抑制大多数DLBCL细胞系的增殖并诱导凋亡。IPI-504敏感的细胞系表达高水平的HSP 90客户蛋白pAKT，并且在IPI-504处理后表现出pAKT水平的剂量依赖性降低，并且在AKT RNAi后显著降低增殖。低剂量（<1 μM）IPI-504和AKT/Pi 3 K通路抑制剂LY 24009的组合在IPI-504敏感性DLBCL细胞系中具有协同作用。低剂量IPI-504也与化疗剂多柔比星协同。增加剂量的IPI-504，单独和与多柔比星组合，诱导HSP 70的表达，这是对HSP 90抑制剂的抗性的已知机制。HSP 90抑制剂IPI-504需要在DLBCL中单独和与合理的靶向抑制剂组合进行进一步研究。
Heat Shock Protein 90 (HSP90) is a molecular chaperone which stabilizes critical client proteins in multiple cancers. Herein, we assess the role of HSP90 and likely client proteins in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), and evaluate the activity of HSP90 inhibitors in this disease. We utilized gene expression profiling to characterize HSP90 α and β isoform expression in previously defined subsets of primary human DLBCLs. Thereafter, we assessed the activity of the novel HSP90 inhibitor, IPI-504, in DLBCL cell lines as monotherapy and in rational combinations, and identified likely client proteins responsible for drug activity. HSP90 α and β isoforms were differentially expressed in primary “BCR” and “OxPhos” DLBCLs. IPI-504, which interacts with the conserved ATP-binding site in both HSP90 isoforms, inhibited proliferation and induced apoptosis in the majority of DLBCL cell lines at low micromolar concentrations. IPI-504-sensitive cell lines expressed high levels of the HSP90 client protein, pAKT, and exhibited dose-dependent decreases in pAKT levels following IPI-504 treatment and significantly reduced proliferation following AKT RNAi. The combination of low-dose (<1 µM) IPI-504 and the AKT/Pi3K pathway inhibitor, LY24009, was synergistic in IPI-504-sensitive DLBCL cell lines. Low-dose IPI-504 was also synergistic with the chemotherapeutic agent, doxorubicin. Increasing doses of IPI-504, alone and in combination with doxorubicin, induced expression of HSP70, a known mechanism of resistance to HSP90 inhibitors. The HSP90 inhibitor IPI-504 warrants further investigation in DLBCL alone and in combination with rational target inhibitors.
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影响因子：
7.3
作者：
Jeon, Y. K.;Park, C. H.;Kim, Y-N
通讯作者：
Kim, Y-N
影响因子：
45.3
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Grem, JL;Morrison, G;Wilson, RH
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Isaacs, JS;Xu, WP;Neckers, L
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Neckers, L
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