Molecular mechanisms of acquired proteasome inhibitor resistance.

Molecular mechanisms of acquired proteasome inhibitor resistance.
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DOI:
10.1021/jm300434z
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发表时间:
2012-12-13
影响因子:
7.3
通讯作者:
Moore, Bradley S.
Moore, Bradley S.
中科院分区:
医学1区
文献类型:
--
作者:
Kale, Andrew J.;Moore, Bradley S.

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蛋白酶体抑制剂(PI)的发展改变了多发性骨髓瘤和套细胞淋巴瘤的治疗方法。到目前为止,已经有两种PI获得FDA批准,一种是硼酸盐肽Bortezomib,另一种是环氧酮多肽carfilzomib。然而,对PI的内在和获得性耐药,其潜在机制尚不清楚,可能会限制其疗效。从这一角度出发,我们讨论了人类细胞系对天然进化的盐孢子胺A(Marizomib)抗性的获得性Bortezomib抗性的分子研究进展。讨论的抗性机制包括蛋白酶体亚基上调和催化β亚基突变。此外,我们还探索了克服PI抗性的潜在策略。
The development of proteasome inhibitors (PIs) has transformed the treatment of multiple myeloma and mantle cell lymphoma. To date, two PIs have been FDA approved, the boronate peptide bortezomib and, most recently, the epoxyketone peptide carfilzomib. However, intrinsic and acquired resistance to PIs, for which the underlying mechanisms are poorly understood, may limit their efficacy. In this perspective, we discuss recent advances in the molecular understanding of PI resistance through acquired bortezomib resistance in human cell lines to evolved saliniosporamide A (marizomib) resistance in nature. Resistance mechanisms discussed include the upregulation of proteasome subunits and mutations of the catalytic β-subunits. Additionally, we explore potential strategies to overcome PI resistance.
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