Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California-San Diego, La Jolla, California 92093, United States.
J Med Chem. 2012 Dec 13;55(23):10317-27. doi: 10.1021/jm300434z. Epub 2012 Oct 3.
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 and evolved salinosporamide A (marizomib) resistance in bacteria. Resistance mechanisms discussed include the up-regulation of proteasome subunits and mutations of the catalytic β-subunits. Additionally, we explore potential strategies to overcome PI resistance.
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。迄今为止，已有两种 PI 获得 FDA 批准，硼酸肽硼替佐米和最近的环氧酮肽卡非佐米。然而，PI 的内在和获得性耐药性限制了其疗效，但其潜在机制尚不清楚。在这篇观点文章中，我们通过人类细胞系中获得性硼替佐米耐药性和细菌中进化的沙利度胺 A（马立度胺）耐药性来讨论 PI 耐药性的分子理解方面的最新进展。讨论的耐药机制包括蛋白酶体亚基的上调和催化β亚基的突变。此外，我们还探讨了克服 PI 耐药性的潜在策略。
