PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo.
PR-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.
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ajita V
AV
Singh
Madhavi
M
Bandi
Monette A
MA
Aujay
Christopher J
CJ
Kirk
David E
DE
Hark
Noopur
N
Raje
Dharminder
D
Chauhan
Kenneth C
KC
Anderson
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010954:Plasmacytoma / Q000188:drug therapy / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex