The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications
The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications
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DOI：
10.1182/blood-2002-06-1768
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发表时间：
2003-03-15
期刊：
影响因子：
20.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Mitsiades, N;Mitsiades, CS;Anderson, KC
蛋白酶体抑制剂PS-341抑制核因子-κ B在这项研究中，我们发现亚毒性浓度的PS-341有效地使MM细胞系和患者细胞对DNA损伤化疗剂如阿霉素和美法仑敏感，包括对这些药物具有抗性的细胞和从PS-341单一疗法后复发的患者中分离的那些细胞。此外，PS-341消除细胞粘附介导的耐药性。使用基因表达谱和蛋白质组学分析，我们证明，PS-341，在其其他促凋亡作用，下调参与细胞对遗传毒性应激反应的几个效应子的表达。这些数据表明，除了下调细胞凋亡抑制剂的表达，PS-341抑制遗传毒性应激反应途径，从而恢复对DNA损伤化疗药物的敏感性。因此，这些研究为临床使用这种药物与常规化疗联合提供了框架。
The proteasome inhibitor PS-341 inhibits nuclear factor-kappaB (NF-kappaB) activation, induces apoptosis in cancer cells, including multiple myeloma (MM) cells, and has marked clinical activity as a monotherapy for MM. In this study, we found that subtoxic concentrations of PS-341 potently sensitized MM cell lines and patient cells to DNA-damaging chemotherapeutic agents such as doxorubicin and melphalan, including cells resistant to these drugs and those isolated from a patient who had relapsed after PS-341 monotherapy. Moreover, PS-341 abolished cell adhesion-mediated drug resistance. Using gene expression profiling and proteomic analysis, we demonstrate that PS-341, among its other proapoptotic effects, down-regulates the expression of several effectors involved in the cellular response to genotoxic stress. These data suggest that, in addition to down-regulating the expression of apoptosis inhibitors, PS-341 inhibits genotoxic stress response pathways and thereby restores sensitivity to DNA-damaging chemotherapeutic agents. These studies, therefore, provide the framework for clinical use of this agent in combination with conventional chemotherapy.