Histology and Embryology Students' Science Association, Department of Histology and Embryology, Faculty of Medicine, Warsaw Medical University, Chalubinskiego 5, 02-004 Warsaw, Poland.
1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
Int J Mol Sci. 2024 Aug 16;25(16):8949. doi: 10.3390/ijms25168949.
Proteasome inhibitors (PIs), bortezomib, carfilzomib, and ixazomib, are the first-line treatment for multiple myeloma (MM). They inhibit cytosolic protein degradation in cells, which leads to the accumulation of misfolded and malfunctioned proteins in the cytosol and endoplasmic reticulum, resulting in cell death. Despite being a breakthrough in MM therapy, malignant cells develop resistance to PIs via different mechanisms. Understanding these mechanisms drives research toward new anticancer agents to overcome PI resistance. In this review, we summarize the mechanism of action of PIs and how MM cells adapt to these drugs to develop resistance. Finally, we explore these mechanisms to present strategies to interfere with PI resistance. The strategies include new inhibitors of the ubiquitin-proteasome system, drug efflux inhibitors, autophagy disruption, targeting stress response mechanisms, affecting survival and cell cycle regulators, bone marrow microenvironment modulation, and immunotherapy. We list potential pharmacological targets examined in in vitro, in vivo, and clinical studies. Some of these strategies have already provided clinicians with new anti-MM medications, such as panobinostat and selinexor. We hope that further exploration of the subject will broaden the range of therapeutic options and improve patient outcomes.
蛋白酶体抑制剂（PI）、硼替佐米、卡非佐米和伊沙佐米是多发性骨髓瘤（MM）的一线治疗药物。它们抑制细胞溶质中的蛋白质降解，导致细胞溶质和内质网中错误折叠和功能失调的蛋白质积累，从而导致细胞死亡。尽管这是 MM 治疗的一个突破，但恶性细胞通过不同的机制对 PI 产生耐药性。了解这些机制推动了针对新的抗癌药物的研究，以克服 PI 耐药性。在这篇综述中，我们总结了 PI 的作用机制以及 MM 细胞如何适应这些药物以产生耐药性。最后，我们探讨了这些机制，提出了干扰 PI 耐药性的策略。这些策略包括泛素-蛋白酶体系统的新抑制剂、药物外排抑制剂、自噬破坏、靶向应激反应机制、影响生存和细胞周期调节剂、骨髓微环境调节和免疫治疗。我们列出了在体外、体内和临床研究中检查的潜在药理靶点。其中一些策略已经为临床医生提供了新的抗 MM 药物，如帕比司他和塞利尼索。我们希望对这一主题的进一步探索将扩大治疗选择的范围，并改善患者的预后。
