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http://dx.doi.org/10.14348/molcells.2016.2300

A Receptor Tyrosine Kinase Inhibitor, Dovitinib (TKI-258), Enhances BMP-2-Induced Osteoblast Differentiation In Vitro  

Lee, Yura (Department of Biomedical Laboratory Science, School of Medicine, Eulji University)
Bae, Kyoung Jun (Department of Biomedical Laboratory Science, School of Medicine, Eulji University)
Chon, Hae Jung (Department of Biomedical Laboratory Science, School of Medicine, Eulji University)
Kim, Seong Hwan (Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology)
Kim, Soon Ae (Department of Pharmacology, School of Medicine, Eulji University)
Kim, Jiyeon (Department of Biomedical Laboratory Science, School of Medicine, Eulji University)
Publication Information
Molecules and Cells / v.39, no.5, 2016 , pp. 389-394 More about this Journal
Abstract
Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.
Keywords
ALP; BMP-2; Dovitinib; MAPK; osteoblast differentiation; Smad1/5/8;
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1 Andre, F., Bachelot, T., Campone, M., Dalenc, F., Perez-Garcia, J.M., Hurvitz, S.A., Turner, N., Rugo, H., Smith, J.W., Deudon, S., et al. (2013). Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer, Clin. Cancer Res. 19, 3693-3702.   DOI
2 Angevin, E., Lopez-Martin, J.A., Lin, C.C., Gschwend, J.E., Harzstark, A., Castellano, D., Soria, J.C., Sen, P., Chang, J., Shi, M., al. (2013). Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin. Cancer Res. 19, 1257-1268.   DOI
3 Ashburn ,T.T., and Thor, K.B. (2004). Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673-683.   DOI
4 Beeharry, N., Banina, E., Hittle, J., Skobeleva, N., Khazak, V., Deacon, S., Andrake, M., Egleston, B.L., Peterson, J.R., Astsaturov, I., et al. (2014). Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints. Cell Cycle 13, 2172-2191.   DOI
5 Bharadwaj, U., Eckols, T.K., Kolosov, M., Kasembeli, M.M., Adam, A., Torres, D., Zhang, X., Dobrolecki, L.E., Wei, W., Lewis, M.T., et al. (2015). Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against cancer. Oncogene 34, 1341-1353.   DOI
6 Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation, Nature 423, 337-342.   DOI
7 Candeliere, G.A., Liu, F., and Aubin, J.E. (2001). Individual osteoblasts in the developing calvaria express different gene repertoires, Bone 28, 351-361.   DOI
8 Cao, X., and Chen, D. (2005). The BMP signaling and in vivo bone formation. Gene. 357, 1-8.   DOI
9 Caverzasio, J., Biver, E., and Thouverey, C. (2013). Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation. J. Bone Miner. Res. 28, 260-270.   DOI
10 Chae, H.J., Jeong, B.J., Ha, M.S., Lee, J.K., Byun, J.O., Jung, W.Y., Yun, Y.G., Lee, D.G., Oh, S.H., and Chae, S.W., et al. (2002). ERK MAP kinase is required in 1, 25(OH)2D3-induced differentiation in human osteoblasts, Immunopharmacol. Immunotoxicol. 24, 31-41.   DOI
11 Chong, C.R., and Sullivan, D.J. Jr. (2007). New uses for old drugs. Nature 448, 645-646.   DOI
12 De Biase, P., and Capanna, R. (2005). Clinical applications of BMPs. Injury 36, S43-46.   DOI
13 Eritja, N., Domingo, M., Dosil, M.A., Mirantes, C., Santacana, M., Valls, J., Llombart-Cussac, A., Matias-Guiu, X., and Dolcet, X. (2014). Combinatorial therapy using dovitinib and ICI182.780 (fulvestrant) blocks tumoral activity of endometrial cancer cells. Mol. Cancer Ther. 13, 776-787.   DOI
14 Franceschi, R.T., and Iyer, B.S. (1992). Relationship between collagen synthesis and expression of the osteoblast phenotype in MC3T3-E1 cells. J. Bone Miner. Res. 7, 235-246.
15 Garces, C., and Garcia, L.E. (2006). Combination of anabolic and antiresorptive agents for the treatment of osteoporosis, Maturitas 54, 47-54.   DOI
16 Garrett, I.R. (2007). Anabolic agents and the bone morphogenetic protein pathway, Curr. Top. Dev. Biol. 78, 127-171.   DOI
17 Goltzman, D. (2002). Discoveries, drugs and skeletal disorders. Nat. Rev. Drug Discov. 1, 784-796.   DOI
18 Harada, S. and Rodan, G.A. (2003). Control of osteoblast function and regulation of bone mass. Nature 423, 349-355.   DOI
19 Guicheux, J., Lemonnier, J., Ghayor, C., Suzuki, A., Palmer, G., Caverzasio, J. (2003). Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. J. Bone Miner. Res. 18, 2060-2068.   DOI
20 Hanusova, V., Skalova, L., Kralova, V., and Matouskova, P. (2015). Potential anti-cancer drugs commonly used for other indications. Curr. Cancer Drug Targets 15, 35-52.   DOI
21 Hasinoff, B.B., Wu, X., Nitiss, J.L., Kanagasabai, R., and Yalowich, J.C. (2012). The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II, Biochem. Pharmacol. 84, 1617-1626.   DOI
22 Hipskind, R.A. and Bilbe, G. (1998). MAP kinase signaling cascand gene expression in osteoblasts. Front Biosci. 3, d804-816. s   DOI
23 Katagiri, T., Yamaguchi A., Komaki, M., Abe, E., Takahashi, N., Ikeda, T., Rosen, V., Wozney, J.M., Fujisawa-Sehara, A., and Suda, T. (1994). Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage, J. Cell Biol. 127, 1755-1766.   DOI
24 Katsuyama, T., Otsuka, F., Terasaka, T., Inagaki, K., Takano-Narazaki, M., Matsumoto, Y., Sada, K.E., and Makino, H. (2015). Regulatory effects of fibroblast growth factor-8 and tumor necrosis factor-${\alpha}$ on osteoblast marker expression induced by bone morphogenetic protein-2. Peptides 73, 88-94.   DOI
25 Livak, K.J., and Schmittgen, T.D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402-408.   DOI
26 Kim, K.B., Chesney, J., Robinson, D., Gardner, H., Shi, M.M., and Kirkwood, J.M. (2011). Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin. Cancer Res. 17, 7451-7461.   DOI
27 Kobayashi, Y., Uehara, S., Nobuyuki, U., and Takahashi, N. (2015). Regulation of bone metabolism by Wnt signals. J. Biochem. pii: mvv124.   DOI
28 Lee, S.H., Lopes de Menezes, D., Vora, J. Harris, A., Ye, H., Nordahl, L., Garrett, E., Samara, E., Aukerman, S.L., Gelb, A.B., and Heise, C. (2005). In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models, Clin. Cancer Res. 11, 3633-3641.   DOI
29 Long, F. (2012). Building strong bones: molecular regulation of the osteoblast lineage, Nat. Rev. Mol. Cell Biol. 13, 27-38.   DOI
30 Longman, R. (2004). Pharmaceutical strategies: jumpstart to products, In Vivo 22, 17.
31 Lopes de Menezes, D.E., Peng, J., Garrett, E.N., Louie, S.G., Lee, S.H., Wiesmann, M., Tang, Y., Shephard, L., Goldbeck, C., Oei, et al. (2005). CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin. Cancer Res. 11, 5281-5291.   DOI
32 Marie, P.J., Miraoui, H., and Severe, N. (2012). FGF/FGFR signaling in bone formation: progress and perspectives. Growth Factors 30, 117-123.   DOI
33 Porta, C., Giglione, P., Liguigli, W., and Paglino, C. (2015). Dovitinib (CHIR258, TKI258): structure, development and preclinical and clinical activity. Future Oncol. 11, 39-50.
34 Milowsky, M.I., Dittrich, C., Duran, I., Jagdev, S., Millard, F.E., Sweeney, C.J., Bajorin, D., Cerbone, L., Quinn, D.I., Stadler, et al. (2014). Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur. J. Cancer 50, 3145-3152.   DOI
35 Pemovska, T., Johnson, E., Kontro, M., Repasky, G.A., Chen, J., Wells, P., Cronin, C.N., McTigue, M., Kallioniemi, O., Porkka, K., et al. (2015). Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation. Nature 519, 102-105.   DOI
36 Phimphilai, M., Zhao, Z., Boules, H., Roca, H., and Franceschi, R.T. (2006). BMP signaling is required for RUNX2-dependent induction of the osteoblst phenotype, J. Bone Miner. Res. 21, 637-646.   DOI
37 Rahman, M.S., Akhtar, N., Jamil, H.M., Banik, R.S., and Asaduzzaman, S.M. (2015). TGF-${\beta}$/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 3, 15005.   DOI
38 Reilly, G.C., Golden, E.B., Grasso-Knight, G., and Leboy, P.S. (2005). Differential effects of ERK and p38 signaling in BMP-2 stimulated hypertrophy of cultured chick sternal chondrocytes. Cell Commun. Signal. 3, 3.   DOI
39 Rosen, V. (2009). BMP2 signaling in bone development and repair, Cytokine Growth Factor Rev. 20, 475-480.   DOI
40 Rosen, C.J., and Bilezikian, J.P. (2001). Clinical review 123: anabolic therapy for osteoporosis, J. Clin. Endocrinol. Metab. 86, 957-964.   DOI
41 Stuart, M. (2004). Rediscovering existing drugs, Start-Up 9, 23-30.
42 Sarker, D., Molife, R., Evans, T.R., Hardie, M., Marriott, C., Butzberger-Zimmerli, P., Morrison, R., Fox, J.A., Heise, C., Louie, S., et al. (2008). A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors, Clin. Cancer Res. 14, 2075-2081.   DOI
43 Son, Y.H., Moon, S.H., and Kim, J. (2013). The protein kinase 2 inhibitor CX-4945 regulates osteoclast and osteoblast differentiation in vitro, Mol. Cells 36, 417-423   DOI
44 Song, M., Kim, S.H., and Yoon, S.K. (2015). Cabozantinib for the treatment of non-small cell lung cancer with KIF5B-RET fusion. An example of swift repositioning. Arch. Pharm. Res. 38, 2120-2123.   DOI
45 Suzukim, A., Guicheux, J., Palmer, G., Miura, Y., Oiso, Y., Bonjour, J., and Caverzasio, J.P. (2002). Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation, Bone 30, 91-98.   DOI
46 Trudel, S., Li, Z.H., Wei, E., Wiesmann, M., Chang, H., Chen, C., Reece, D., Heise, C., and Stewart, A.K. (2005). CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma, Blood 105, 2941-2948.   DOI
47 Wagner, D.O., Sieber, C., Bhushan, R., Borgermann, J.H., Graf, D., and Knaus, P. (2010). BMPs: from bone to body morphogenetic proteins, Sci. Signal 3, mr1.
48 Wang, X., Kay, A., Anak, O., Angevin, E., Escudier, B., Zhou, W., Feng, Y., Dugan, H., and Schran, M. (2013). Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib, J. Clin. Pharmacol. 53, 14-20.   DOI
49 Wu, C.C., Li, Y.S., Haga, J.H., Wang, N., Lian, I.Y., Su, F.C., Usamim, S., and Chien, S. (2006). Roles of MAP kinases in the regulation of bone matrix gene expressions in human osteoblasts by oscillatory fluid flow, J. Cell. Biochem. 98, 632-641.   DOI