Antitumor activity of bortezomib alone and in combination with trail in human acute myeloid leukemia
Antitumor activity of bortezomib alone and in combination with trail in human acute myeloid leukemia
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DOI：
10.1159/000151511
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发表时间：
2008-01-01
影响因子：
2.4
通讯作者：
Di Raimondo, Francesco
中科院分区：
文献类型：
--
作者：
Conticello, Concetta;Adamo, Luana;Di Raimondo, Francesco
急性髓系白血病（acute myeloid leukemia，AML）是一种以克隆性前体细胞异常增殖为特征的恶性疾病。虽然已经采取了不同的策略来获得完全缓解，但实际上大约60-70%的患者会出现疾病进展。硼替佐米因其抗肿瘤活性而被用于多发性骨髓瘤和其他淋巴系统恶性肿瘤。在这里，我们检查了AML患者（34例患者：25例新诊断，4例复发，5例难治性）的骨髓细胞对硼替佐米单独或与TRAIL联合的敏感性，TRAIL是TNF家族的一员，可诱导肿瘤细胞凋亡，同时保留正常细胞。硼替佐米诱导来自每个患者样品的原始细胞中的细胞死亡。细胞毒性效应是剂量和时间依赖性的（浓度从0.001 μ M到10 μ M，持续24和48小时），并与Bcl-xL和Mcl-1的下调，TRAIL-R1，TRAIL-R2，p21的上调，执行caspase的激活和线粒体膜电位的损失有关。此外，低剂量硼替佐米引发TRAIL抗性AML细胞增强TRAIL介导的杀伤。这些结果表明，蛋白酶体抑制剂和TRAIL的组合可以有效地治疗AML患者，甚至是常规化疗难治的患者。版权所有（C）2008 S. Karger AG，巴塞尔。
Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60-70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose-and time-dependent (concentration from 0.001 to 10 mu M for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy. Copyright (C) 2008 S. Karger AG, Basel.