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Abstract
The proteasome inhibitor, bortezomib, a boronic dipeptide which reversibly inhibit the chymotrypsin-like activity at the β5-subunit of proteasome (PSMB5), has marked efficacy against multiple myeloma and several non-Hodgkin’s lymphoma subtypes, and has a potential therapeutic role against other malignancy diseases. However, intrinsic and acquired resistance to bortezomib may limit its efficacy. In this article, we discuss recent advances in the molecular understanding of bortezomib resistance. Resistance mechanisms discussed include mutations of PSMB5 and the up-regulation of proteasome subunits, alterations of gene and protein expression in stress response, cell survival and antiapoptotic pathways, and multidrug resistance.
Highlights
The ubiquitin-proteasome pathway plays an essential role in the degradation of cellular proteins involved in a variety of cellular processes, including transcriptional regulation, cell cycle progression, proliferation, and apoptosis [1]
We found upregulated expression of the β5-subunit of proteasome (PSMB5) gene contributed to drug resistance in patient with multiple myeloma when treated with bortezomib-based regimen [29]
The mechanism of proteasome inhibitor bortezomib resistance mainly focused on the modifications of the mechanisms of its action
Summary
The ubiquitin-proteasome pathway plays an essential role in the degradation of cellular proteins involved in a variety of cellular processes, including transcriptional regulation, cell cycle progression, proliferation, and apoptosis [1]. Our previous study showed that the PSMB5 gene was over-expressed in some resistant JurkatB cells accompanied by increased chymotrypsin-like activity. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in bortezomib resistant HT-29 adenocarcinoma cells, which correlated to an increase in subunit gene expression [24] The results of these studies are important for the design of novel proteasome inhibitors without crossresistance with bortezomib. Alterations of gene and protein expression in stress response,cell survival and antiapoptotic pathways Bortezomib, inhibiting the chymotrypsin-like activity at the PSMB5, blocked the degradation of the polyubiquitinated proteins such as IkB-.alpha;, a negative regulator of the nuclear factor (NF)-κB pathway, and unfolded or oxidatively modified proteins followed by endoplasmic reticulum (ER) stress and effects on the tumor microenvironment associated apoptosis [4]. Though drug extrusion via the multidrug efflux transporter P-gp has been shown to mediate a low level of bortezomib resistance, MDR may be not the overwhelming mechanism of bortezomib resistance
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