Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia
Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia
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DOI：
10.1182/blood-2010-12-323022
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发表时间：
2011-07-21
期刊：
影响因子：
20.3
通讯作者：
Gandhi, Varsha
中科院分区：
文献类型：
--
作者：
Chen, Lisa S.;Redkar, Sanjeev;Gandhi, Varsha
Pim激酶是具有影响存活途径的多种底物的Ser/Thr激酶。这些蛋白质在急性髓性白血病（AML）母细胞中过表达，我们假设Pim激酶抑制会影响AML细胞存活。咪唑并[1，2-B]哒嗪化合物SGI-1776抑制Pim-1、Pim-2和Pim-3，并在AML细胞系、异种移植模型和原代母细胞中进行了评价。用SGI-1776处理AML细胞会导致浓度依赖性的细胞凋亡诱导，我们研究了其对Pim激酶功能的影响。传统Pim激酶靶点c-Myc（Ser 62）和4 E-BP 1（Thr 36/Thr 47）的磷酸化在活跃循环的AML细胞系MV-4-11、MOLM-13和OCIAML-3中均降低。抗凋亡蛋白Bcl-2、Bcl-x（L）、XIAP和促凋亡蛋白巴克和Bax的水平没有变化;然而，观察到Mcl-1的显著降低。这与SGI-1776处理后总体RNA和蛋白质合成的抑制以及MCL-1转录物的下降相关。这些数据表明，SGI-1776在AML中的机制涉及Mcl-1蛋白减少。与细胞系数据一致，用携带MV-4-11肿瘤的小鼠进行的异种移植模型研究显示SGI-1776的功效。重要的是，SGI-1776在AML原代细胞中也具有细胞毒性，与FLT 3突变状态无关，并导致Mcl-1蛋白下降。抑制Pim激酶可能成为AML治疗的新策略。（血。2011;118（3）：693-702）
Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b] pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCIAML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-x(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment. (Blood. 2011;118(3):693-702)