一种新型口服活性蛋白酶体抑制剂通过不同于硼替佐米的机制诱导多发性骨髓瘤细胞凋亡。

A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.

作者信息

Chauhan Dharminder, Catley Laurence, Li Guilan, Podar Klaus, Hideshima Teru, Velankar Mugdha, Mitsiades Constantine, Mitsiades Nicolas, Yasui Hiroshi, Letai Anthony, Ovaa Huib, Berkers Celia, Nicholson Benjamin, Chao Ta-Hsiang, Neuteboom Saskia T C, Richardson Paul, Palladino Michael A, Anderson Kenneth C

机构信息

The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

出版信息

Cancer Cell. 2005 Nov;8(5):407-19. doi: 10.1016/j.ccr.2005.10.013.

DOI:10.1016/j.ccr.2005.10.013

PMID:16286248

Abstract

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.

摘要

硼替佐米治疗已被证明对复发和/或难治性多发性骨髓瘤（MM）的治疗有效；然而，长期治疗会产生毒性并导致耐药性的产生。在此，我们表明新型蛋白酶体抑制剂NPI-0052可诱导对传统疗法和硼替佐米治疗耐药的MM细胞发生凋亡。NPI-0052在化学结构、对蛋白酶体活性的影响、作用机制以及对正常细胞的毒性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耐受性良好且可延长生存期，显著降低肿瘤复发率。联合使用NPI-0052和硼替佐米可诱导协同抗MM活性。因此，我们的研究为评估单独使用NPI-0052以及将其与硼替佐米联合使用以改善MM患者预后的临床方案提供了理论依据。