A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib
A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib
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DOI：
10.1016/j.ccr.2005.10.013
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发表时间：
2005-11-01
期刊：
影响因子：
50.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Chauhan, D;Catley, L;Anderson, KC
硼替佐米治疗已被证明成功治疗复发性和/或难治性多发性骨髓瘤（MM）;然而，长期治疗与毒性和耐药性的发展相关。在这里，我们表明，新的蛋白酶体抑制剂NPI-0052诱导细胞凋亡的MM细胞耐常规和硼替佐米治疗。NPI-0052在其化学结构、对蛋白酶体活性的影响、作用机制和对正常细胞的毒性特征方面与硼替佐米不同。此外，NPI-0052具有口服生物活性。在动物肿瘤模型研究中，NPI-0052具有良好的耐受性和延长的存活率，并且显著降低了肿瘤复发。组合NPI-0052和硼替佐米诱导协同抗MM活性。因此，我们的研究为临床方案提供了评价NPI-0052单独使用和与硼替佐米一起使用以改善MM患者结局的基本原理。
Bortezomib therapy has proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM); however, prolonged treatment is associated with toxicity and development of drug resistance. Here, we show that the novel proteasome inhibitor NPI-0052 induces apoptosis in MM cells resistant to conventional and Bortezomib therapies. NPI-0052 is distinct from Bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, and toxicity profile against normal cells. Moreover, NPI-0052 is orally bioactive. In animal tumor model studies, NPI-0052 is well tolerated and prolongs survival, with significantly reduced tumor recurrence. Combining NPI-0052 and Bortezomib induces synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating NPI-0052, alone and together with Bortezomib, to improve patient outcome in MM.