文章：

新型NF-κB抑制剂IMD-0354诱导慢性淋巴细胞白血病细胞凋亡

The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia

原文发布日期：2011-03-25

DOI: 10.1038/bcj.2011.9

类型: Original Article

开放获取: 是

英文摘要：

Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.

摘要翻译： 

核因子κB（NF-κB）是细胞存活的重要调节因子，已被证实在慢性淋巴细胞白血病（CLL）细胞中持续激活。近期研究发现，新型NF-κB抑制剂IMD-0354（N-（3,5-双三氟甲基苯基）-5-氯-2-羟基苯甲酰胺）能特异性抑制IκB激酶对IκBα的磷酸化，从而阻止NF-κB释放。本研究通过膜联蛋白V染色、荧光微培养细胞毒性检测及电泳迁移率变动分析，分别观察IMD-0354在体外对CLL细胞凋亡增长率、药物敏感性及NF-κB DNA结合活性的影响，并进一步探讨该药物对凋亡相关基因表达的影响。结果显示：IMD-0354能诱导CLL细胞凋亡（均值26%，范围8-48%），且该作用与免疫球蛋白重链可变区（IGHV）基因突变状态无关；该药物同时呈现剂量依赖性细胞毒效应，显著降低CLL细胞中NF-κB的DNA结合活性。此外，我们发现IMD-0354处理后促凋亡与抗凋亡基因表达水平存在差异。本研究首次证实IMD-0354可诱导CLL细胞凋亡，值得作为抗肿瘤药物开展进一步体内研究。

原文链接：

The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia