title: Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia.
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 kappaB (NF-kappaB) 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.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Monette
authors.initials: M
authors.lastname: Aujay
authors.forename: Hai T
authors.initials: HT
authors.lastname: Ngo
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Phong
authors.initials: P
authors.lastname: Quang
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Judith
authors.initials: J
authors.lastname: Runnels
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Susan
authors.initials: S
authors.lastname: Demo
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D017209:Apoptosis; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology
chemical_list: C540947:3-methoxy-2-(3-methoxy-2-((2-methyl-1,3-thiazol-5-yl)formamido)propanamido)-N-(1-(2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide; D004151:Dipeptides; D015850:Interleukin-6; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D013844:Thiazoles; D007334:Insulin-Like Growth Factor I; D048031:JNK Mitogen-Activated Protein Kinases; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex