Document Detail

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1.
MedLine Citation:
PMID:  16373662     Owner:  NLM     Status:  MEDLINE    
CC-4047, an immunomodulatory analog of thalidomide, inhibits multiple myeloma with unknown effects on the human osteoclast lineage. Early osteoclast progenitors are of hematopoietic origin and differentiate into mature bone resorbing multinucleated osteoclasts. We investigated the effects of CC-4047 and thalidomide on human osteoclastogenesis, using in vitro receptor activator of NFkappa-B ligand/macrophage colony-stimulating factor-stimulated bone marrow cell cultures. Treating bone marrow cultures with CC-4047 for 3 weeks decreased osteoclast formation accompanied by complete inhibition of bone resorption. The inhibitory effect was similar when cultures were treated for 3 weeks or for only the first week (90% inhibition), indicating that CC-4047 inhibits early stages of osteoclast formation. Inhibition of osteoclastogenesis by CC-4047 was mediated by a shift of lineage commitment to granulocyte colony-forming units at the expense of granulocyte-macrophage colony-forming units. Further studies revealed that this shift in lineage commitment was mediated through down-regulation of PU.1. Treatment with thalidomide resulted in significantly less potent inhibition of osteoclast formation and bone resorption. These results provide evidence that CC-4047 blocks osteoclast differentiation during early phases of osteoclastogenesis. Therefore, CC-4047 might be a valuable drug for targeting both tumors and osteoclastic activity in patients with multiple myeloma and other diseases associated with osteolytic lesions.
Gülsüm Anderson; Margarete Gries; Noriyoshi Kurihara; Tadashi Honjo; Judy Anderson; Vera Donnenberg; Albert Donnenberg; Irene Ghobrial; Markus Y Mapara; David Stirling; David Roodman; Suzanne Lentzsch
Publication Detail:
Type:  Journal Article     Date:  2005-12-22
Journal Detail:
Title:  Blood     Volume:  107     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-04-06     Completed Date:  2006-05-22     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3098-105     Citation Subset:  AIM; IM    
University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, Pittsburgh, PA 15232, USA.
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MeSH Terms
Angiogenesis Inhibitors / adverse effects,  pharmacology*,  therapeutic use
Bone Resorption / drug therapy,  metabolism
Cell Differentiation / drug effects*,  physiology
Cells, Cultured
Dose-Response Relationship, Drug
Down-Regulation / drug effects,  physiology
Macrophage Colony-Stimulating Factor / pharmacology
Multiple Myeloma / drug therapy
Myeloid Progenitor Cells / cytology,  metabolism*
NF-kappa B / antagonists & inhibitors,  metabolism
Osteoclasts / cytology,  metabolism*
Proto-Oncogene Proteins / biosynthesis*
Thalidomide / adverse effects,  analogs & derivatives*,  pharmacology,  therapeutic use
Trans-Activators / biosynthesis*
Reg. No./Substance:
0/Angiogenesis Inhibitors; 0/NF-kappa B; 0/Proto-Oncogene Proteins; 0/Trans-Activators; 0/proto-oncogene protein Spi-1; 50-35-1/Thalidomide; 81627-83-0/Macrophage Colony-Stimulating Factor; D2UX06XLB5/pomalidomide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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