Conticello Concetta, Adamo Luana, Vicari Luisa, Giuffrida Raffaella, Iannolo Gioacchin, Anastasi Gabriele, Caruso Laura, Moschetti Gaetano, Cupri Alessandra, Palumbo Giuseppe Antonio, Gulisano Massimo, De Maria Ruggero, Giustolisi Rosario, Di Raimondo Francesco
Department of Biomedical Sciences, Hematology Section, University of Catania, Catania, Italy.
Acta Haematol. 2008;120(1):19-30. doi: 10.1159/000151511. Epub 2008 Aug 21.
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 microM 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.
急性髓系白血病（AML）是一种以克隆前体细胞异常增殖为特征的恶性疾病。尽管已采用不同策略来实现完全缓解，但实际上约60 - 70%的患者病情仍会进展。硼替佐米因其抗肿瘤活性已被用于多发性骨髓瘤和其他淋巴系统恶性肿瘤。在此，我们检测了AML患者（34例患者：25例新诊断患者、4例复发患者、5例难治性患者）的骨髓细胞对单独使用硼替佐米或与肿瘤坏死因子（TNF）家族成员TRAIL联合使用的敏感性，TRAIL可诱导肿瘤细胞凋亡而不损伤正常细胞。硼替佐米可诱导每个患者样本中的原始细胞死亡。细胞毒性作用具有剂量和时间依赖性（浓度为0.001至10微摩尔，作用24小时和48小时），并与Bcl - xL和Mcl - 1的下调、TRAIL - R1、TRAIL - R2、p21的上调、执行性半胱天冬酶的激活以及线粒体膜电位的丧失有关。此外，低剂量的硼替佐米可使对TRAIL耐药的AML细胞对TRAIL介导的杀伤作用更敏感。这些结果表明，蛋白酶体抑制剂与TRAIL联合使用可能对治疗AML患者有效，即使是对传统化疗难治的患者。
