Distinct molecular mechanisms responsible for bortezomib-induced death of therapy-resistant versus -sensitive B-NHL cells
Distinct molecular mechanisms responsible for bortezomib-induced death of therapy-resistant versus -sensitive B-NHL cells
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DOI：
10.1182/blood-2009-12-259754
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发表时间：
2010-12-16
期刊：
影响因子：
20.3
通讯作者：
Czuczman, Myron S.
中科院分区：
文献类型：
--
作者：
Olejniczak, Scott H.;Blickwedehl, Jennifer;Czuczman, Myron S.
对目前可用的治疗方法的抵抗是成功治疗血液系统恶性肿瘤的主要障碍。在这里，我们使用我们实验室建立的耐药B细胞非霍奇金淋巴瘤(B-NHL)模型和原代B-NHL细胞来研究Bortezomib活性的基本机制。在耐药细胞和原发B-NHL的一个子集中，Bortezomib治疗导致Bak稳定，随后Bak依赖的凋亡激活。与完全通过细胞凋亡而死亡的敏感细胞不同，Bortezomib能够通过激活细胞凋亡或在药物抑制caspase时通过caspase非依赖机制(S)杀死耐药细胞。我们的数据表明，Bortezomib能够通过多种机制杀死B-NHL细胞，而不考虑它们的基础凋亡潜力，并有助于越来越多的证据表明，蛋白酶体抑制剂可以通过调节B细胞淋巴瘤2(Bcl-2)家族蛋白发挥作用。Bortezomib独立于给定B-NHL细胞的固有凋亡阈值发挥作用的能力表明，基于Bortezomib的疗法可能会克服耐药性，并在复发/难治的情况下导致相关的临床活动。(血。2010；116(25)：5605-5614)
Resistance to currently available therapies is a major impediment to the successful treatment of hematological malignancies. Here, we used a model of therapy-resistant B-cell nonHodgkin lymphoma (B-NHL) developed in our laboratory along with primary B-NHL cells to study basic mechanisms of bortezomib activity. In resistant cells and a subset of primary B-NHLs, bortezomib treatment led to stabilization of Bak and subsequent Bak-dependent activation of apoptosis. In contrast to sensitive cells that die strictly by apoptosis, bortezomib was capable of killing resistant cells through activation of apoptosis or caspase-independent mechanism(s) when caspases were pharmacologically inhibited. Our data demonstrate that bortezomib is capable of killing B-NHL cells via multiple mechanisms, regardless of their basal apoptotic potential, and contributes to growing evidence that proteasome inhibitors can act via modulation of B-cell lymphoma 2 (Bcl-2) family proteins. The capacity of bortezomib to act independently of the intrinsic apoptotic threshold of a given B-NHL cell suggests that bortezomib-based therapies could potentially overcome resistance and result in relevant clinical activity in a relapsed/refractory setting. (Blood. 2010; 116(25): 5605-5614)