Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 152, Issue 2, Pages 155-163Publisher
WILEY
DOI: 10.1111/j.1365-2141.2010.08491.x
Keywords
apoptosis; Multiple-Myeloma; Immunoproteasome
Categories
Funding
- NIH [SPORE-P50100707, PO1-CA078378, RO1CA050947]
- MRF funds
- NATIONAL CANCER INSTITUTE [P01CA078378, P01CA155258, R01CA050947, P50CA100707] Funding Source: NIH RePORTER
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P>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.
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