DOI QR코드

DOI QR Code

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)
  • Received : 2015.10.27
  • Accepted : 2016.02.25
  • Published : 2016.05.31

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

Acknowledgement

Supported by : National Research Foundation (NRF)

References

  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. https://doi.org/10.1158/1078-0432.CCR-13-0190
  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. https://doi.org/10.1158/1078-0432.CCR-12-2885
  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. https://doi.org/10.1038/nrd1468
  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. https://doi.org/10.4161/cc.29214
  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. https://doi.org/10.1038/onc.2014.72
  6. Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation, Nature 423, 337-342. https://doi.org/10.1038/nature01658
  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. https://doi.org/10.1016/S8756-3282(01)00410-0
  8. Cao, X., and Chen, D. (2005). The BMP signaling and in vivo bone formation. Gene. 357, 1-8. https://doi.org/10.1016/j.gene.2005.06.017
  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. https://doi.org/10.1002/jbmr.1748
  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. https://doi.org/10.1081/IPH-120003401
  11. Chong, C.R., and Sullivan, D.J. Jr. (2007). New uses for old drugs. Nature 448, 645-646. https://doi.org/10.1038/448645a
  12. De Biase, P., and Capanna, R. (2005). Clinical applications of BMPs. Injury 36, S43-46. https://doi.org/10.1016/j.injury.2005.07.034
  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. https://doi.org/10.1158/1535-7163.MCT-13-0794
  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. https://doi.org/10.1016/j.maturitas.2005.08.011
  16. Garrett, I.R. (2007). Anabolic agents and the bone morphogenetic protein pathway, Curr. Top. Dev. Biol. 78, 127-171. https://doi.org/10.1016/S0070-2153(06)78004-8
  17. Goltzman, D. (2002). Discoveries, drugs and skeletal disorders. Nat. Rev. Drug Discov. 1, 784-796. https://doi.org/10.1038/nrd916
  18. 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. https://doi.org/10.1359/jbmr.2003.18.11.2060
  19. 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. https://doi.org/10.2174/1568009615666141229152812
  20. Harada, S. and Rodan, G.A. (2003). Control of osteoblast function and regulation of bone mass. Nature 423, 349-355. https://doi.org/10.1038/nature01660
  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. https://doi.org/10.1016/j.bcp.2012.09.023
  22. Hipskind, R.A. and Bilbe, G. (1998). MAP kinase signaling cascand gene expression in osteoblasts. Front Biosci. 3, d804-816. s https://doi.org/10.2741/A323
  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. https://doi.org/10.1083/jcb.127.6.1755
  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. https://doi.org/10.1016/j.peptides.2015.09.007
  25. 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. https://doi.org/10.1158/1078-0432.CCR-11-1747
  26. Kobayashi, Y., Uehara, S., Nobuyuki, U., and Takahashi, N. (2015). Regulation of bone metabolism by Wnt signals. J. Biochem. pii: mvv124. https://doi.org/10.1093/jb/mvv124
  27. 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. https://doi.org/10.1158/1078-0432.CCR-04-2129
  28. 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. https://doi.org/10.1006/meth.2001.1262
  29. Long, F. (2012). Building strong bones: molecular regulation of the osteoblast lineage, Nat. Rev. Mol. Cell Biol. 13, 27-38. https://doi.org/10.1038/nrm3254
  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. https://doi.org/10.1158/1078-0432.CCR-05-0358
  32. Marie, P.J., Miraoui, H., and Severe, N. (2012). FGF/FGFR signaling in bone formation: progress and perspectives. Growth Factors 30, 117-123. https://doi.org/10.3109/08977194.2012.656761
  33. 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. https://doi.org/10.1016/j.ejca.2014.10.013
  34. 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. https://doi.org/10.1038/nature14119
  35. 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. https://doi.org/10.1359/jbmr.060109
  36. 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.
  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. https://doi.org/10.1038/boneres.2015.5
  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. https://doi.org/10.1186/1478-811X-3-3
  39. Rosen, V. (2009). BMP2 signaling in bone development and repair, Cytokine Growth Factor Rev. 20, 475-480. https://doi.org/10.1016/j.cytogfr.2009.10.018
  40. Rosen, C.J., and Bilezikian, J.P. (2001). Clinical review 123: anabolic therapy for osteoporosis, J. Clin. Endocrinol. Metab. 86, 957-964. https://doi.org/10.1210/jcem.86.3.7366
  41. 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. https://doi.org/10.1158/1078-0432.CCR-07-1466
  42. 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 https://doi.org/10.1007/s10059-013-0184-9
  43. 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. https://doi.org/10.1007/s12272-015-0660-1
  44. Stuart, M. (2004). Rediscovering existing drugs, Start-Up 9, 23-30.
  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. https://doi.org/10.1016/S8756-3282(01)00660-3
  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. https://doi.org/10.1182/blood-2004-10-3913
  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. https://doi.org/10.1177/0091270011433330
  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. https://doi.org/10.1002/jcb.20697

Cited by

  1. Effect of low-intensity pulsed ultrasound on the biological behavior of osteoblasts on porous titanium alloy scaffolds: An in vitro and in vivo study vol.80, 2017, https://doi.org/10.1016/j.msec.2017.05.078
  2. New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs vol.38, pp.5, 2018, https://doi.org/10.1002/med.21517