PR‐924, a selective inhibitor of the immunoproteasome subunit LMP‐7, blocks multiple myeloma cell growth both in vitro and in vivo

Abstract

SummaryPR-924 is an LMP-7-selective tripeptide epoxyketone proteasome inhibitor that covalently modifies proteasomal N-terminal threonine active sites. In the present study, we show that PR-924 inhibits growth and triggers apoptosis in multiple myeloma (MM) cell lines and primary patient MM cells, without significantly affecting normal peripheral blood mononuclear cells. PR-924-induced apoptosis in MM cells is associated with activation of caspase-3, caspase-8, caspase-9, BID, PARP and cytochrome-c release. In vivo administration of PR-924 inhibits tumour growth in human plasmacytoma xenografts. Results from SCID-hu model show a significant reduction in the shIL-6R levels in mice treated with PR-924 versus vehicle-control. PR-924 treatment was well tolerated as evidenced by the lack of weight loss. Importantly, treatment of tumour-bearing mice with PR-924, but not vehicle alone, prolonged survival. Our preclinical findings therefore validate immunoproteasome LMP-7 subunit as a novel therapeutic target in MM.

Antileukemic Activity and Mechanism of Drug Resistance to the Marine Salinispora tropica Proteasome Inhibitor Salinosporamide A (Marizomib)

“…Consistent with a genetic alteration in CEM/S20 cells, salinosporamide A resistance was stable when CEM/S20 cells were cultured in the absence of salinosporamide A for more than a month. Since inhibition of constitutive b 5 is required for the growth inhibitory activity of proteasome inhibitors (Singh et al, 2011;Niewerth et al, 2014b), active site mutations in the b 5 subunit are the most evident to be induced after chronic exposure to proteasome inhibitors. The mutation found in the CEM/S20 cells is likely to inflict a negative impact on the binding affinity of salinosporamide A, as was previously observed for bortezomib (Franke et al, 2012).…”

The novel 2-selective proteasome inhibitor LU-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells

“…8,9 The proteasome carries three proteolytically active sites (β1, β2 and β5), which differ in their substrate preferences. 10 These subunits of the so-called constitutive proteasome can be replaced by respective immunoproteasome subunits β1i, β2i and β5i in some cell types, including myeloma, 11 which results in a total of six different proteolytic enzymes with different substrate preferences in the 20S proteasome core particle. The two approved proteasome-inhibiting drugs, bortezomib and carfilzomib, by design target the β5 subunit of the constitutive proteasome and the immunoproteasome, which mediate the rate-limiting proteolytic proteasome activity.…”

Global Proteome Analysis Identifies Active Immunoproteasome Subunits in Human Platelets

“…Recognizing that platelets contain an active immunoproteasome, as well as gaining a clear understanding of the role of the proteasome/immunoproteasome in platelet function and viability, is crucial as both forms are targeted by chemotherapeutic agents (53). However, proteasome inhibitors have been shown to inhibit platelet aggregration (54), and a recent study demonstrated a negative FIG.…”

“…More recently immunoproteasome-specific inhibitors have been investigated as anti-cancer agents, with the hope that these may be more specific and have less side effects than proteasome inhibitors. Initial studies are very promising (53,56); however, in light of our discovery of an active immunoproteasome in platelets, it should be considered that these newer reagents could have the same negative effect on platelet biology as regular proteasome inhibitors.…”