Moreno-Martínez Daniel, Nomdedeu Meritxell, Lara-Castillo María Carmen, Etxabe Amaia, Pratcorona Marta, Tesi Niccolò, Díaz-Beyá Marina, Rozman María, Montserrat Emili, Urbano-Ispizua Alvaro, Esteve Jordi, Risueño Ruth M
Josep Carreras Leukaemia Research Institute. Barcelona, Spain.
Oncotarget. 2014 Jun 30;5(12):4337-46. doi: 10.18632/oncotarget.2016.
Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials.
急性髓系白血病（AML）是一种肿瘤，其特征为骨髓中未成熟髓系母细胞迅速增殖，预后不良且频繁复发。因此，需要新的治疗方法来诱导缓解和预防复发。由于分化程度较高的AML母细胞化疗敏感性更高且寿命有限，基于分化的疗法是一种有前景的治疗方法。基于公开的基因表达谱，一种髓系特异性分化相关基因表达模式被定义为治疗靶点。在一项计算机筛选中，为寻找能诱导相似基因表达调控的小分子，鉴定出一种XIAP抑制剂（氯化去甲喹啉，DQA）。与恩贝林（另一种XIAP抑制剂）类似，用DQA处理可诱导AML细胞产生细胞毒性并使其分化。XIAP抑制以不同方式损害最原始AML母细胞的细胞活力，并降低AML细胞的克隆形成能力，而对健康成熟血液和造血干细胞没有影响。综上所述，这些结果表明XIAP是AML治疗的一个潜在靶点，并支持在临床试验中对XIAP抑制剂进行评估。
