The resistance mechanisms of proteasome inhibitor bortezomib

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.

Figure 1

The structure of 26 s proteasome. The proteasome is a 26S enzyme complex that comprised of core 20S catalytic complex and 19S regulatory complex (A). The 20S proteasome core has chymotrypsin-like, trypsin-like, and peptidyl glutamyl-like activities that are associated with three distinct units: β5, β2, β1, respectively. Chymotrypsin-like activity at proteasome β5 subunit (PSMB5) is associated with the rate-limiting step of proteolysis. Proteasome inhibitor bortezomib (Bort) mainly inhibit the chymotrypsin-like activity at the PSMB5 (B).

Figure 2

Interaction model of bortezomib with active site of β5 subunit of proteasome. Ala49, Ala50, Thr21 cited at the specific pocket of β5 subunit of proteasome (PSMB5). Ala49, Ala50, Thr21 participate in the tight hydrogen-bonding network, when bortezomib (in blue) interacts with the active site of PSMB5.

Figure 3

The 3D protein-backbone structure of the β5 subunit of proteasome. The 3D model of protein-backbone structure of the β5 subunit of proteasome (PSMB5) consults the yeast proteasomal crystal structure in complex with bortezomib [22]; the bovine proteasomal crystal structure [23]; models made by Franke et al [19],. de Wilt et al [21]. and Suzuki et al [24]. Mutation sites are depicted in red. P1, substrate side chain 1; S1, specificity binding pocket 1.

Figure 4

The summary of possible bortezomin resistance mechanisms. The mechanisms of proteasome inhibitor bortezomib resistance mainly focused on the modifications of the mechanisms of its action. Mutations at key points of β5 subunit of proteasome (PSMB5) decrease the affinity of the PSMB5 to bortezomb, which result in the decreased inhibition of the chymotrypsin-like activity, up-regulation of proteasome subunits contributing to the high basal levels of proteasome activity, alterations of gene and protein expression in stress response and cell survival, antiapoptotic pathways are important mechanisms of bortezomib resistance. Efflux transporter P-gp was also shown to mediate a certain degree bortezomib resistance.