Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome inWaldenström macroglobulinemia

Aldo M. Roccaro, Antonio Sacco, Monette Aujay, Hai T. Ngo, Abdel Kareem Azab, Feda Azab, Phong Quang, Patricia Maiso, Judith Runnels, Kenneth C. Anderson, Susan Demo, Irene M. Ghobrial

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65 Scopus citations

Abstract

Proteasome inhibition represents a valid antitumor approach and its use has been validated in Waldenström macroglobulinemia (WM), where bortezomib has been successfully tested in clinical trials. Nevertheless, a significant fraction of patients relapses, and many present toxicity due to its off-target effects. Selective inhibition of the chymotrypsin-like (CT-L) activity of constitutive proteasome 20S (c20S) and immunoproteasome 20S (i20S) represents a sufficient and successful strategy to induce antineoplastic effect in hematologic tumors. We therefore studied ONX0912, a novel selective, irreversible inhibitor of the CT-L activity of i20S and c20S. Primary WM cells express higher level of i20S compared with c20S, and that ONX0912 inhibited the CT-L activity of both i20S and c20S, leading to induction of toxicity in primary WM cells, as well as of apoptosis through c-Jun N-terminal kinase activation, nuclear factor κB (NF-κB) inhibition, caspase cleavage, and initiation of the unfolded protein response. Importantly, ONX0912 exerted toxicity in WM cells, by reducing bone marrow (BM)-derived interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1) secretion, thus inhibiting BM-induced p-Akt and phosphorylated extracellular signal-related kinase (p-ERK) activation in WM cells. These findings suggest that targeting i20S and c20S CT-L activity by ONX0912 represents a valid antitumor therapy in WM.

Original languageEnglish
Pages (from-to)4051-4060
Number of pages10
JournalBlood
Volume115
Issue number20
DOIs
StatePublished - May 20 2010

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