Synthetic lethality of combined AT-101 with idarubicin in acute myeloid leukemia via blockade of DNA repair and activation of intrinsic apoptotic pathway
Synthetic lethality of combined AT-101 with idarubicin in acute myeloid leukemia via blockade of DNA repair and activation of intrinsic apoptotic pathway
复制标题
AT-101 联合伊达比星通过阻断 DNA 修复和激活内在凋亡途径对急性髓系白血病的综合致死率
DOI：
10.1016/j.canlet.2019.07.003
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发表时间：
2019
期刊：
影响因子：
9.7
通讯作者：
Xu Bing
中科院分区：
文献类型：
--
作者：
Yang Qianying;Chen Kai;Zhang Leisi;Feng Liying;Fu Guofeng;Jiang Shan;Bi Silei;Lin Chunjie;Zhou Yong;Zhao Haijun;Chen Xiao Lei;Fu Guo;Xu Bing
白血病干细胞（LSC）被认为是急性髓细胞白血病（AML）治疗失败的主要原因。常规化疗药物不能根除白血病干细胞，成为耐药和疾病复发的根源。因此，靶向LSC的新治疗策略对于AML患者至关重要。在此，我们报告了Bcl-2抑制剂AT-101和化疗药物伊达比星（IDA）的组合导致从KG-1α和Kasumi-1 AML细胞系中分选出的CD 34 + CD 38 −白血病干细胞样细胞和原代CD 34 +AML细胞体外协同致死，而正常对照细胞则不受影响。此外，组合治疗还显著抑制由FLT 3-ITDmutAML患者体内产生的患者来源的异种移植物（PDX）小鼠模型的生长。从机制上讲，AT-101与IDA诱导细胞死亡的协同作用与DNA损伤修复的阻断密切相关，从而激活内在的凋亡途径。总之，这些发现表明，AT-101和IDA的组合治疗选择性地消除体外和体内的白血病干细胞样细胞，代表了用于治疗复发性和难治性AML患者的有效和替代的挽救治疗。
Leukemia stem cells (LSCs) are deemed to the mainspring for treatment failure in acute myeloid leukemia (AML). Conventional chemotherapeutic drugs fail to eradicate leukemia stem cells, which becomes the root of drug resistance and disease recurrence. Hence, new therapeutic strategies targeting LSCs are supposed to be critical for patients with AML. Here we report that combination of Bcl-2 inhibitor AT-101 and chemotherapeutic drug idarubicin (IDA) results in synergistic lethality in CD34+CD38−leukemia stem-like cells sorted from KG-1α and Kasumi-1 AML cell lines and primary CD34+AML cellsin vitrowhile sparing the normal counterparts. In addition, combinatorial treatment also significantly inhibits the growth of patient-derived xenograft (PDX) mouse models generated from FLT3-ITDmutAML patientin vivo. Mechanistically, the synergistic effects of AT-101 with IDA to induce cell death are closely associated with blockage of DNA damage repair and thus activates the intrinsic apoptotic pathway. In summary, these findings suggest that combinatorial therapy with AT-101 and IDA selectively eliminates leukemia stem-like cells bothin vitroandin vivo, representing a potent and alternative salvage therapy for the treatment of relapsed and refractory patients with AML.