文章：

表观遗传学改变作为硼替佐米分子作用的关键方面

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

原文发布日期：23 December 2023

DOI: 10.3390/cancers16010084

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

硼替佐米（BTZ）被广泛应用于多发性骨髓瘤（MM）的治疗，其主要作用机制已得到充分阐明。BTZ能够选择性地、可逆地抑制26S蛋白酶体，更具体地说，它通过与20S蛋白酶体的糜蛋白酶位点相互作用，从而抑制蛋白质的降解。这导致细胞内错误折叠或缺陷蛋白质的积累，进而引发细胞生长抑制和凋亡。除了干扰泛素-蛋白酶体复合物外，BTZ还会引发多种表观遗传学改变，这些改变既参与其细胞毒性效应，也与BTZ耐药性的产生相关。本综述总结了BTZ引起的表观遗传学改变，重点关注了参与其作用机制的修饰、介导耐药性发展的变化以及促进周围神经病变发生的表观遗传学改变。此外，目前已有专门针对表观遗传学改变设计的治疗策略。本文还回顾了可能增强BTZ相关细胞毒性或恢复耐药克隆对BTZ敏感性的表观遗传学药物。最后，我们展望了针对接受BTZ治疗患者靶向表观遗传学改变的未来研究方向。

原文链接：

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action