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A C-Fms Tyrosine Kinase Inhibitor, Ki20227, Suppresses Osteoclast Differentiation and Osteolytic Bone Destruction in a Bone Metastasis Model

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A C-Fms Tyrosine Kinase Inhibitor, Ki20227, Suppresses Osteoclast Differentiation and Osteolytic Bone Destruction in a Bone Metastasis Model 2634 A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model Hiroaki Ohno,1 Kazuo Kubo,1 Hideko Murooka,1 In in vivo studies, oral administration of Ki20227 sup- Yoshiko Kobayashi,1 Tsuyoshi Nishitoba,1 pressed osteoclast-like cell accumulation and bone resorp- Masabumi Shibuya,2 Toshiyuki Yoneda,3 tion induced by metastatic tumor cells in nude rats and Toshiyuki Isoe1 following intracardiac injection of A375 cells. Moreover, Ki20227 decreased the number of tartrate-resistant acid 1Pharmaceutical Research Laboratories, Pharmaceutical Division, phosphatase–positive osteoclast-like cells on bone surfa- Kirin Brewery Co., Ltd., Gunma, Japan; 2Division of Genetics, ces in ovariectomized (ovx) rats. These findings suggest Institute of Medical Science, University of Tokyo, Tokyo, Japan; that Ki20227 inhibits osteolytic bone destruction through and 3Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan the suppression of M-CSF-induced osteoclast accumulation in vivo. Therefore, Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone metas- Abstract tasis and other bone diseases. [Mol Cancer Ther 2006; In bone metastatic lesions, osteoclasts play a key role in 5(11):2634–43] the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor Introduction (M-CSF) is important for the differentiation of osteoclasts. Bone metastasis of tumor cells is a clinical complication In this study, we investigated whether an inhibitor of frequently associated with breast, lung, and prostate M-CSF receptor (c-Fms) suppresses osteoclast-dependent cancers (1). In the process of bone metastasis, metastatic osteolysis in bone metastatic lesions. We developed small tumor cells in bone enhance osteolysis by inducing and molecule inhibitors against ligand-dependent phosphoryla- activating osteoclastic bone resorption through the signal- tion of c-Fms and examined the effects of these compounds ing pathway mediated by parathyroid hormone-related on osteolytic bone destruction in a bone metastasis model. peptide (PTHrP) or through the receptor activator of We discovered a novel quinoline-urea derivative, Ki20227 nuclear factor nB ligand (RANKL; refs. 2, 3). It has also N ( -{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}- been reported that transforming growth factor-h (TGF-h), N ¶ -[1-(1,3-thiazole-2-yl)ethyl]urea), which is a c-Fms tyro- which is stored in bone matrix and released by osteoclas- sine kinase inhibitor. The IC50s of Ki20227 to inhibit c-Fms, tic bone resorption, brings about enhanced PTHrP vascular endothelial growth factor receptor-2 (KDR), stem production of tumor cells in bone (4). Increased produc- cell factor receptor (c-Kit), and platelet-derived growth tion of PTHrP accelerates further bone resorption and B factor receptor were found to be 2, 12, 451, and 217 provides more space for tumor cell proliferation. Sup- nmol/L, respectively. Ki20227 did not inhibit other kinases pression of osteoclastic bone resorption may, therefore, be tested, such as fms-like tyrosine kinase-3, epidermal effective against bone metastasis. In studies using rodent c-src growth factor receptor, or c-Src ( proto-oncogene bone metastasis models, bisphosphonate, osteoprotegerin, product). Ki20227 was also found to inhibit the M-CSF- anti-PTHrP-neutralizing antibody, tissue inhibitor of dependent growth of M-NFS-60 cells but not the M-CSF- matrix metalloproteinase-2, and angiogenesis inhibitor independent growth of A375 human melanoma cells have all been found to suppress osteolytic bone metastasis in vitro . Furthermore, in an osteoclast-like cell formation (2, 5–11). Bisphosphonates exert an inhibitory action assay using mouse bone marrow cells, Ki20227 inhibited on mature osteoclasts and suppress bone resorption the development of tartrate-resistant acid phosphatase– enhanced by metastatic tumor cells by inducing apoptosis positive osteoclast-like cells in a dose-dependent manner. of osteoclasts (12, 13). Osteoprotegerin is a member of the tumor necrosis factor receptor family, which antagonizes the ability of RANKL by suppressing binding to its receptor RANK (14–19). The administration of osteopro- Received 8/10/06; revised 9/1/06; accepted 9/25/06. tegerin or bisphosphonates suppresses osteolytic bone The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked metastasis. advertisement in accordance with 18 U.S.C. Section 1734 solely to Osteoclasts are derived from monocytic progenitor cells indicate this fact. and experimentally differentiate from spleen and bone Requests for reprints: Hiroaki Ohno, Pharmaceutical Research marrow cells in the simultaneous presence of macrophage Laboratories, Kirin Brewery Co., Ltd., 3 Miyahara, Takasaki, Gunma, in vitro 370-1295, Japan. Phone: 81-27-346-9815; Fax: 81-27-346-1672. colony-stimulating factor (M-CSF) and RANKL E-mail: [email protected] (16). M-CSF-deficient osteopetrotic (op/op) mice suffer Copyright C 2006 American Association for Cancer Research. severe osteopetrosis because of the depletion of osteoclasts; doi:10.1158/1535-7163.MCT-05-0313 however, this pathologic condition is improved by the Mol Cancer Ther 2006;5(11). November 2006 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. Molecular Cancer Therapeutics 2635 administration of M-CSF (20–23). A recent report on profiler Express (Upstate Ltd., Dundee, United Kingdom). M-CSF receptor (c-Fms)–null mice also found a severe Cell-free kinase inhibition assays against c-Fms, Bruton’s deficiency of osteoclasts and abnormal skeletal develop- tyrosine kinase, KDR, c-Kit, platelet-derived growth factor ment, as found in op/op mice (24). These data strongly receptor h, fms-like tyrosine kinase-3, c-Src, Fyn, epidermal suggest that M-CSF is essential for the development growth factor receptor, basic fibroblast growth factor of osteoclasts in vivo, and that the suppression of the receptor 2, hepatocyte growth factor/scatter factor receptor M-CSF/c-Fms signaling pathway is also effective against (c-Met), protein kinase A, and protein kinase Ca were done. bone metastasis. In our present study, we examined All kinases are human derived. the inhibitory effects of Ki20227, a c-Fms inhibitor, on Western Blotting the development of tartrate-resistant acid phosphatase RAW264.7 cells were serum starved for 12 hours in (TRAP)–positive osteoclast-like cells and osteolytic bone DMEM containing 0.1% FCS. Serial dilutions of Ki20227 destruction induced by the A375 human melanoma were then added to the cells, and they were incubated for cell line. 1 hour. RAW264.7 cells were stimulated with 50 ng/mL of recombinant mouse M-CSF for 4 minutes. c-Fms protein in the RAW264.7 cell lysate was prepared with ice-cold lysis Materials and Methods buffer [50 mmol/L Tris/HCl (pH 7.4), 150 mmol/L NaCl, Ki20227 1.0 mmol/L NaF, 0.1% sodium deoxycholate, 4 mmol/L N Ki20227 ( -{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2- EDTA, 1.0 mmol/L Na3VO4, 1 mmol/L phenylmethylsul- methoxyphenyl}-N¶-[1-(1,3-thiazole-2-yl)ethyl]urea; race- fonyl fluoride, 1 Ag/mL aprotinin, 1% NP40]. Lysates were mic) and its enantiomers were synthesized in the Kirin immunoprecipitated with rabbit polyclonal antibody to Pharmaceutical Research Laboratories (Gunma, Japan). The c-Fms (C-20; Santa Cruz Biotechnology, Inc., Santa Cruz, racemic form is called Ki20227, and its enantiomers are CA), subjected to SDS-PAGE, and transferred to a dubbed (R)-Ki20227 and (S)-Ki20227. For in vitro studies, polyvinylidene fluoride microporous membrane. The compounds were dissolved in DMSO and diluted in membrane was probed with phosphotyrosine antibody growth medium immediately before use. As a rule, the PY20 (Transduction Laboratories, Lexington, KY), and concentration of DMSO was 0.5% in all in vitro assays. For phosphorylation was detected with peroxidase-conjugated in vivo studies, Ki20227 was suspended in vehicle (0.5% anti-immunoglobulin G (Amersham Biosciences, Inc., methyl cellulose in distilled water). Piscataway, NJ). After the PY20 was removed, the same Cell Lines and Cultures membrane was probed with anti-c-Fms antibody (C-20) RAW264.7 (a mouse macrophage cell line) and THP-1 following the same protocol. (a human monocytic cell line) were obtained from In vitro GrowthInhibitionAssay Dainippon Pharmaceutical Co., Ltd. (Osaka, Japan). M- M-NFS-60, HUVEC, and A375 cells were seeded on a NFS-60 mouse myelogenous leukemia cell line was 96-well culture plate and cultured for 24 hours. Then, obtained from the American Type Culture Collection culture mediums were changed and incubated for a further (Manassas, VA), and human umbilical vein endothelial 72 hours in the presence or absence of test compounds cells (HUVEC) were obtained from Cambrex (Walkersville, (0.1–3,000 nmol/L). The detail were as follows: M-NFS-60 MD). RAW264.7 and A375 were maintained in DMEM cells were seeded at a density of 5.0 Â 103 per well in DMEM (Invitrogen Corp., Carlsbad, CA) containing 10% FCS at supplemented with 10% FCS and 50 ng/mL recombinant j 37 Cin5%CO2 in a water-saturated atmosphere. THP-1 mouse M-CSF, and the culture medium was changed to cells were maintained in RPMI 1640 (Invitrogen) containing DMEM supplemented with 3% FCS and 50 ng/mL 10% FCS. M-NFS-60 cells were maintained in RPMI 1640 recombinant mouse M-CSF. HUVEC cells were planted at containing 10% FCS in the presence of 50 ng/mL M-CSF 2.0 Â 103 per well in EGM-2, and the culture medium was (R&D Systems, Inc., Minneapolis, MN). HUVEC cells were changed to EBM-2 (Cambrex) supplemented with 3% FCS cultured in EGM-2 (Cambrex). and 20 ng/mL recombinant human vascular endothelial Animals growth factor (VEGF; Peprotech EC, Ltd., London, United All in vivo experiments were conducted under Kirin Kingdom). A375 cells were planted at a density of 2.0 Â 103 Animal Care and Use Committee guidelines.
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