| PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo. | |
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MedLine Citation:
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PMID: 21114484 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Ajita V Singh; Madhavi Bandi; Monette A Aujay; Christopher J Kirk; David E Hark; Noopur Raje; Dharminder Chauhan; Kenneth C Anderson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-29 |
Journal Detail:
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Title: British journal of haematology Volume: 152 ISSN: 1365-2141 ISO Abbreviation: Br. J. Haematol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-23 Completed Date: 2011-02-07 Revised Date: 2012-01-04 |
Medline Journal Info:
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Nlm Unique ID: 0372544 Medline TA: Br J Haematol Country: England |
Other Details:
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Languages: eng Pagination: 155-63 Citation Subset: IM |
Copyright Information:
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© 2010 Blackwell Publishing Ltd. |
Affiliation:
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Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / pharmacology*, therapeutic use Apoptosis / drug effects Cell Survival / drug effects Drug Evaluation, Preclinical / methods Humans Mice Mice, SCID Multiple Myeloma / metabolism, pathology* Neoplasm Proteins / antagonists & inhibitors, metabolism Oligopeptides / pharmacology*, therapeutic use Plasmacytoma / drug therapy, pathology Proteasome Endopeptidase Complex / antagonists & inhibitors*, metabolism Survival Analysis Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA078378-11A2/CA/NCI NIH HHS; P01-CA078378/CA/NCI NIH HHS; P50 CA100707-08/CA/NCI NIH HHS; P50 CA100707-09/CA/NCI NIH HHS; P50100707//PHS HHS; R01 CA050947-17A1/CA/NCI NIH HHS; R01 CA050947-20/CA/NCI NIH HHS; R01CA050947/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Neoplasm Proteins; 0/Oligopeptides; EC 3.4.25.1/LMP7 protein; EC 3.4.25.1/Proteasome Endopeptidase Complex |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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