The proteasorne inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP
The proteasorne inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP
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DOI：
10.1182/blood-2002-09-2975
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发表时间：
2003-07-01
期刊：
影响因子：
20.3
通讯作者：
Murphy, WJ
中科院分区：
文献类型：
--
作者：
Sayers, TJ;Brooks, AD;Murphy, WJ
由于蛋白酶体在细胞凋亡中起关键作用，该酶的抑制剂，如PS-341，为探索蛋白酶体抑制和其他细胞凋亡诱导剂之间的协同作用提供了很好的机会。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）可选择性诱导肿瘤细胞凋亡。在过夜试验中，PS-341和TRAIL的组合在促进鼠骨髓性白血病C1498和鼠肾癌Renca的细胞凋亡方面比单独使用任何一种药物都有效得多。对于C1498细胞，PS-341的凋亡敏化既不影响核因子κ B（NF-κ B）的活性，也不影响大多数抗凋亡蛋白的水平。然而，在C1498和Renca细胞中观察到抗凋亡蛋白c-FLIP响应PS-341的减少。用PS-341和TRAIL的组合处理与C1498肿瘤细胞混合的正常骨髓18小时导致肿瘤细胞的特异性消耗。在转移到辐射的同基因受体小鼠后，用PS-341加TRAIL组合处理的混合物导致小鼠的长期无肿瘤存活率提高。因此，这些数据支持靶向肿瘤细胞中的凋亡途径，使用协同相互作用以优先促进肿瘤细胞凋亡的药剂如PS-341和TRAIL的组合。(C)2003年，美国血液学会。
Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor kappaB (NF-kappaB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis. (C) 2003 by The American Society of Hematology.