AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines
AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines
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DOI：
10.1182/blood-2008-02-137737
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发表时间：
2009-02-19
期刊：
影响因子：
20.3
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
Levy, Dana S.;Kahana, Jason A.;Kumar, Rakesh
PI 3 K/AKT信号传导在各种血液恶性肿瘤中被激活。我们评估了一种新的泛AKT激酶抑制剂GSK 690693对代表不同血液肿瘤的112种细胞系增殖的影响。所有检测的细胞系中有55%对AKT抑制剂敏感（EC 50 < 1 μ M），急性淋巴细胞白血病（ALL）、非霍奇金淋巴瘤和伯基特淋巴瘤对GSK 690693的敏感性分别为89%、73%和67%。GSK 690693的抗增殖作用对恶性细胞具有选择性，因为GSK 690693不抑制正常人CD 4（+）外周T淋巴细胞以及小鼠胸腺细胞的增殖。在用GSK 690693处理的敏感和不敏感细胞系中，AKT下游底物的磷酸化均降低，这表明耐药的原因与缺乏AKT激酶抑制无关。与AKT在细胞存活中的作用一致，GSK 690693也诱导敏感ALL细胞系的凋亡。总的来说，我们的数据为AKT信号在各种血液恶性肿瘤，特别是ALL和一些淋巴瘤中的作用提供了直接证据。（血。2009; 113：1723-1729）
The PI3K/AKT signaling is activated in various hematologic malignancies. We evaluated the effect of a novel, pan-AKT kinase inhibitor, GSK690693, on the proliferation of 112 cell lines representing different hematologic neoplasia. Fifty-five percent of all cell lines tested were sensitive to AKT inhibitor (EC50 < 1 mu M), with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, and Burkitt lymphoma showing 89%, 73%, and 67% sensitivity to GSK690693, respectively. The antiproliferative effect was selective for the malignant cells, as GSK690693 did not inhibit the proliferation of normal human CD4(+) peripheral T lymphocytes as well as mouse thymocytes. Phosphorylation of downstream substrates of AKT was reduced in both sensitive and insensitive cell lines on treatment with GSK690693, suggesting that the cause of resistance was not related to the lack of AKT kinase inhibition. Consistent with the role of AKT in cell survival, GSK690693 also induced apoptosis in sensitive ALL cell lines. Overall, our data provide direct evidence for the role of AKT signaling in various hematologic malignancies, especially ALL and some lymphomas. (Blood. 2009; 113: 1723-1729)