Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma.
Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma.
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DOI：
10.1158/1535-7163.mct-11-0433
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发表时间：
2011-11
影响因子：
5.7
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Hideshima T;Richardson PG;Anderson KC
在过去的十年中，包括蛋白酶体抑制剂Bortezomib在内的新药物显著改善了多发性骨髓瘤(MM)患者的反应和生存。尽管有这些进展，许多患者复发或没有受益于目前可用的治疗方法；因此，多发性骨髓瘤仍然是一种不治之症。脱乙酰酶抑制剂(DACI)，包括潘诺比妥和伏立恒，是最近出现的治疗MM的新药物。脱乙酰酶是一组作用于多种细胞内蛋白质的酶，包括组蛋白、转录因子和分子伴侣。虽然Daci作为单一药物抑制MM细胞的生长并诱导其凋亡，但当它们与Bortezomib联合使用时，观察到了协同作用。协同作用的机制基础是多因素的，包括破坏蛋白质降解和抑制MM细胞与肿瘤微环境的相互作用。本文综述了蛋白酶体抑制剂和DACI在多发性骨髓瘤中作用机制的研究进展，并探讨了它们协同作用的生物学基础。本文总结的研究数据已被用作在复发和难治性MM中单独和联合应用DACI的II期和III期临床试验的基础。
Novel agents, including the proteasome inhibitor bortezomib, have significantly improved the response and survival of patients with multiple myeloma (MM) over the last decade. Despite these advances, many patients relapse or do not benefit from the currently available therapies; thus, MM remains an incurable disease. Deacetylase inhibitors (DACi), including panobinostat and vorinostat, have recently emerged as novel agents being evaluated in the treatment of MM. Deacetylases are a group of enzymes with effects on various intracellular proteins including histones, transcription factors, and molecular chaperones. Although DACi inhibit cell growth and induce apoptosis in MM cells as a single agent, synergistic activity has been observed when they were used in combination with bortezomib. The mechanistic basis of synergy is multifactorial and includes disruption of protein degradation and inhibition of the interaction of MM cells with the tumor microenvironment. This review summarizes recent advancements in the understanding of the mechanism of action of proteasome inhibitors and DACi in MM and examines the biological basis of their synergistic effects. Data from the studies summarized here have been used as the rationale for the implementation of phase II and III clinical trials of DACi, alone and combined with bortezomib, in relapsed and refractory MM.