Kulig Piotr, Łuczkowska Karolina, Bakinowska Estera, Baumert Bartłomiej, Machaliński Bogusław
Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Department of Hematology and Transplantology, Pomeranian Medical University, 71-252 Szczecin, Poland.
Cancers (Basel). 2023 Dec 23;16(1):84. doi: 10.3390/cancers16010084.
Bortezomib (BTZ) is widely implemented in the treatment of multiple myeloma (MM). Its main mechanism of action is very well established. BTZ selectively and reversibly inhibits the 26S proteasome. More precisely, it interacts with the chymotryptic site of the 20S proteasome and therefore inhibits the degradation of proteins. This results in the intracellular accumulation of misfolded or otherwise defective proteins leading to growth inhibition and apoptosis. As well as interfering with the ubiquitin-proteasome complex, BTZ elicits various epigenetic alterations which contribute to its cytotoxic effects as well as to the development of BTZ resistance. In this review, we summarized the epigenetic alterations elicited by BTZ. We focused on modifications contributing to the mechanism of action, those mediating drug-resistance development, and epigenetic changes promoting the occurrence of peripheral neuropathy. In addition, there are therapeutic strategies which are specifically designed to target epigenetic changes. Herein, we also reviewed epigenetic agents which might enhance BTZ-related cytotoxicity or restore the sensitivity to BTZ of resistant clones. Finally, we highlighted putative future perspectives regarding the role of targeting epigenetic changes in patients exposed to BTZ.
硼替佐米（BTZ）广泛应用于多发性骨髓瘤（MM）的治疗。其主要作用机制已明确。BTZ选择性且可逆地抑制26S蛋白酶体。更确切地说，它与20S蛋白酶体的糜蛋白酶活性位点相互作用，从而抑制蛋白质降解。这导致错误折叠或有其他缺陷的蛋白质在细胞内积累，进而导致生长抑制和细胞凋亡。除了干扰泛素-蛋白酶体复合物外，BTZ还引发各种表观遗传改变，这些改变有助于其细胞毒性作用以及BTZ耐药性的产生。在本综述中，我们总结了BTZ引发的表观遗传改变。我们重点关注了有助于作用机制的修饰、介导耐药性产生的修饰以及促进周围神经病变发生的表观遗传变化。此外，还有专门针对表观遗传变化设计的治疗策略。在此，我们还综述了可能增强BTZ相关细胞毒性或恢复耐药克隆对BTZ敏感性的表观遗传药物。最后，我们强调了关于在接受BTZ治疗的患者中靶向表观遗传变化作用的未来推测性观点。
