An inhibitor of proteasome β2 sites sensitizes myeloma cells to immunoproteasome inhibitors.

ABSTRACT: Proteasome inhibitors bortezomib, carfilzomib and ixazomib (approved by the US Food and Drug Administration [FDA]) induce remissions in patients with multiple myeloma (MM), but most patients eventually become resistant. MM and other hematologic malignancies express ubiquitous constitutive proteasomes and lymphoid tissue-specific immunoproteasomes; immunoproteasome expression is increased in resistant patients. Immunoproteasomes contain 3 distinct pairs of active sites, β5i, β1i, and β2i, which are different from their constitutive β5c, β1c, and β2c counterparts. Bortezomib and carfilzomib block β5c and β5i sites. We report here that pharmacologically relevant concentrations of β5i-specific inhibitor ONX-0914 show cytotoxicity in MM cell lines similar to that of carfilzomib and bortezomib.

SUBMITTER: Downey-Kopyscinski S 

PROVIDER: S-EPMC6177641 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature