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PMID:17121910

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Citation

Ohno, H, Kubo, K, Murooka, H, Kobayashi, Y, Nishitoba, T, Shibuya, M, Yoneda, T and Isoe, T (2006) A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol. Cancer Ther. 5:2634-43

Abstract

In bone metastatic lesions, osteoclasts play a key role in the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor (M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions. We developed small molecule inhibitors against ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone metastasis model. We discovered a novel quinoline-urea derivative, Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl]urea), which is a c-Fms tyrosine kinase inhibitor. The IC(50)s of Ki20227 to inhibit c-Fms, vascular endothelial growth factor receptor-2 (KDR), stem cell factor receptor (c-Kit), and platelet-derived growth factor receptor beta were found to be 2, 12, 451, and 217 nmol/L, respectively. Ki20227 did not inhibit other kinases tested, such as fms-like tyrosine kinase-3, epidermal growth factor receptor, or c-Src (c-src proto-oncogene product). Ki20227 was also found to inhibit the M-CSF-dependent growth of M-NFS-60 cells but not the M-CSF-independent growth of A375 human melanoma cells in vitro. Furthermore, in an osteoclast-like cell formation assay using mouse bone marrow cells, Ki20227 inhibited the development of tartrate-resistant acid phosphatase-positive osteoclast-like cells in a dose-dependent manner. In in vivo studies, oral administration of Ki20227 suppressed osteoclast-like cell accumulation and bone resorption induced by metastatic tumor cells in nude rats following intracardiac injection of A375 cells. Moreover, Ki20227 decreased the number of tartrate-resistant acid phosphatase-positive osteoclast-like cells on bone surfaces in ovariectomized (ovx) rats. These findings suggest that Ki20227 inhibits osteolytic bone destruction through the suppression of M-CSF-induced osteoclast accumulation in vivo. Therefore, Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone metastasis and other bone diseases.

Links

PubMed Online version:10.1158/1535-7163.MCT-05-0313

Keywords

Acid Phosphatase/metabolism; Animals; Bone Neoplasms/secondary; Cell Differentiation/drug effects; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Isoenzymes/metabolism; Mice; Mice, Transgenic; Osteoclasts/drug effects; Osteoclasts/pathology; Osteoclasts/physiology; Osteolysis/drug therapy; Osteolysis/metabolism; Phenylurea Compounds/pharmacology; Phenylurea Compounds/therapeutic use; Protein Kinase Inhibitors/pharmacology; Protein Kinase Inhibitors/therapeutic use; Rats; Rats, Inbred F344; Rats, Nude; Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors; Receptor, Macrophage Colony-Stimulating Factor/metabolism; Thiazoles/pharmacology; Thiazoles/therapeutic use

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CSF1R

involved_in

GO:0030316: osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:CSF1R

involved_in

GO:0045124: regulation of bone resorption

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:CSF1R

involved_in

GO:0045672: positive regulation of osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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