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Review
. 2023 Dec 23;16(1):84.
doi: 10.3390/cancers16010084.

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

Piotr Kulig  1 , Karolina Łuczkowska  1 , Estera Bakinowska  1 , Bartłomiej Baumert  2 , Bogusław Machaliński  1   2
Affiliations
Review

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

Piotr Kulig et al. Cancers (Basel). .

Abstract

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.

Keywords: bortezomib; drug resistance; epigenetic; methylation; non-coding RNA; proteasome inhibitor.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Proteasome activity without and with the presence of BTZ. (A) Proteasome degrades polyubiquitinated proteins into oligopeptides. (B) BTZ inhibits the 26S proteasome, leading to an intracellular accumulation of misfolded or otherwise defective proteins, and subsequent growth inhibition and apoptosis.
Figure 2
Figure 2
Epigenetic alterations elicited by BTZ. In addition to proteasome inhibition, BTZ exerts its cytotoxic effects through histone modifications, alterations in DNA methylation (mainly, loss of methylation), and non-coding RNs. Similar epigenetic alterations contribute to the development of resistance to this compound.
See this image and copyright information in PMC

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