Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Dasatinib Inhibits Lyn and Fyn Src-Family Kinases in Mast Cells to Suppress Type I Hypersensitivity in Mice

  • Lee, Dajeong (Department of Immunology, College of Medicine, Konkuk University) ;
  • Park, Young Hwan (Department of Immunology, College of Medicine, Konkuk University) ;
  • Lee, Ji Eon (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Hyuk Soon (Department of Immunology, College of Medicine, Konkuk University) ;
  • Min, Keun Young (Department of Immunology, College of Medicine, Konkuk University) ;
  • Jo, Min Geun (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Hyung Sik (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Choi, Wahn Soo (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Young Mi (College of Pharmacy, Duksung Women's University)
  • Received : 2020.01.30
  • Accepted : 2020.03.13
  • Published : 2020.09.01
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Abstract

Mast cells (MCs) are systemically distributed and secrete several allergic mediators such as histamine and leukotrienes to cause type I hypersensitivity. Dasatinib is a type of anti-cancer agent and it has also been reported to inhibit human basophils. However, dasatinib has not been reported for its inhibitory effects on MCs or type I hypersensitivity in mice. In this study, we examined the inhibitory effect of dasatinib on MCs and MC-mediated allergic response in vitro and in vivo. In vitro, dasatinib inhibited the degranulation of MCs by antigen stimulation in a dose-dependent manner (IC50, ~34 nM for RBL-2H3 cells; ~52 nM for BMMCs) without any cytotoxicity. It also suppressed the secretion of inflammatory cytokines IL-4 and TNF-α by antigen stimulation. Furthermore, dasatinib inhibited MC-mediated passive cutaneous anaphylaxis (PCA) in mice (ED50, ~29 mg/kg). Notably, dasatinib significantly suppressed the degranulation of MCs in the ear tissue. As the mechanism of its effect, dasatinib inhibited the activation of Syk and Syk-mediated downstream signaling proteins, LAT, PLCγ1, and three typical MAP kinases (Erk1/2, JNK, and p38), which are essential for the activation of MCs. Interestingly, in vitro tyrosine kinase assay, dasatinib directly inhibited the activities of Lyn and Fyn, the upstream tyrosine kinases of Syk in MCs. Taken together, dasatinib suppresses MCs and PCA in vitro and in vivo through the inhibition of Lyn and Fyn Src-family kinases. Therefore, we suggest the possibility of repositioning the anti-cancer drug dasatinib as a treatment for various MC-mediated type I hypersensitive diseases.

Keywords

References

  1. Aketani, S., Teshima, R., Umezzawa, Y. and Sawada, J. (2001) Correlation between cytosolic calcium concentration and degranulation in RBL-2H3 cells in the presence of various concentrations of antigen-specific IgEs. Immunol. Lett. 75, 185-189. https://doi.org/10.1016/S0165-2478(00)00311-4
  2. Akin, C. (2017) Mast cell activation syndromes. J. Allergy Clin. Immunol. 140, 349-355. https://doi.org/10.1016/j.jaci.2017.06.007
  3. Atallah, E., Kantarjian, H. and Cortes, J. (2007) Emerging safety issues with imatinib and other Abl tyrosine kinase inhibitors. Clin. Lymphoma Myeloma 7, S105-S112. https://doi.org/10.3816/CLM.2007.s.010
  4. Barnes, P. J. (1999) Therapeutic strategies for allergic diseases. Nature 402, 31-38.
  5. Begin, P. and Nadeau, K. C. (2014) Epigenetic regulation of asthma and allergic disease. Allergy Asthma Clin. Immunol. 10, 27. https://doi.org/10.1186/1710-1492-10-27
  6. Bradding, P., Walls, A. F. and Holgate, S. T. (2006) The role of the mast cell in the pathophysiology of asthma. J. Allergy Clin. Immunol. 117, 1277-1284. https://doi.org/10.1016/j.jaci.2006.02.039
  7. Bruhns, P., Fremont, S. and Daeron, M. (2005) Regulation of allergy by Fc receptors. Curr. Opin. Immunol. 17, 662-669. https://doi.org/10.1016/j.coi.2005.09.012
  8. Charles, N., Watford, W. T., Ramos, H. L., Hellman, L., Oettgen, H. C., Gomez, G., Ryan, J. J., O'Shea, J. J. and Rivera, J. (2009) Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation. Immunity 30, 533-543. https://doi.org/10.1016/j.immuni.2009.02.008
  9. Draber, P., Halova, I., Polakovicova, I. and Kawakami, T. (2016) Signal transduction and chemotaxis in mast cells. Eur. J. Pharmacol. 778, 11-23. https://doi.org/10.1016/j.ejphar.2015.02.057
  10. El-Agamy, D. S. (2012) Targeting c-kit in the therapy of mast cell disorders: current update. Eur. J. Pharmacol. 690, 1-3. https://doi.org/10.1016/j.ejphar.2012.06.030
  11. Feinberg, J. G. (1961) Pinnal anaphylaxis: an additional anaphyiactic site. Nature 191, 712.
  12. Galli, S. J., Kalesnikoff, J., Grimbaldeston, M. A., Piliponsky, A. M., Williams, C. M. and Tsai, M. (2005) Mast cells as "tunable" effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749-786. https://doi.org/10.1146/annurev.immunol.21.120601.141025
  13. Geha, R. S., Jabara, H. H. and Brodeur, S. R. (2003) The regulation of immunoglobulin E class-switch recombination. Nat. Rev. Immunol. 3, 721-732. https://doi.org/10.1038/nri1181
  14. Gomez, G. (2019) Current strategies to inhibit high affinity $Fc{\varepsilon}RI$-mediated signaling for the treatment of allergic disease. Front. Immunol. 10, 175. https://doi.org/10.3389/fimmu.2019.00175
  15. Heuchel, R., Berg, A., Tallquist, M., Ahlen, K., Reed, R. K., Rubin, K., Claesson-Welsh, L., Heldin, C. H. and Soriano, P. (1999) Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3' kinase signaling. Proc. Natl. Acad. Sci. U.S.A. 96, 11410-11415. https://doi.org/10.1073/pnas.96.20.11410
  16. Hide, I., Toriu, N., Nuibe, T., Inoue, A., Hide, M., Yamamoto, S. and Nakata, Y. (1997) Suppression of TNF-alpha secretion by azelastine in a rat mast (RBL-2H3) cell line: evidence for differential regulation of TNF-alpha release, transcription, and degranulation. J. Immunol. 159, 2932-2940.
  17. Hoffmann, A., Jamin, A., Foetisch, K., May, S., Aulepp, H., Haustein, D. and Vieths, S. (1999) Determination of the allergenic activity of birch pollen and apple prick test solutions by measurement of $\beta$-hexosaminidase release from RBL-2H3 cells. Comparison with classical methods in allergen standardization. Allergy 54, 446-454. https://doi.org/10.1034/j.1398-9995.1999.00917.x
  18. Horny, H. P., Sotlar, K. and Valent, P. (2007) Mastocytosis: state of the art. Pathobiology 74, 121-132. https://doi.org/10.1159/000101711
  19. Inagaki, N. and Nagai, H. (2009) Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment: mouse models for the development of remedies for human allergic dermatitis. J. Pharmacol. Sci. 110, 251-259. https://doi.org/10.1254/jphs.09R01FM
  20. Iqbal, N. and Iqbal, N. (2014) Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014, 357027.
  21. Kagan, R. S. (2003) Food allergy: an overview. Environ. Health Perspect. 111, 223-225. https://doi.org/10.1289/ehp.5702
  22. Kambayashi, T. and Koretzky, G. A. (2007) Proximal signaling events in Fc epsilon RI-mediated mast cell activation. J. Allergy Clin. Immunol. 119, 544-552. https://doi.org/10.1016/j.jaci.2007.01.017
  23. Kantarjian, H., Jabbour, E., Grimley, J. and Kirkpatrick, P. (2006) Dasatinib. Nat. Rev. Drug Discov. 5, 717-718. https://doi.org/10.1038/nrd2135
  24. Kay, A. B. (2001) Allergy allergic diseases. First of two parts. N. Engl. J. Med. 344, 30-37. https://doi.org/10.1056/NEJM200101043440106
  25. Kim, J. D., Kim, D. K., Kim, H. S., Kim, A. R., Kim, B., Her, E., Park, K. H., Kim, H. S., Kim, Y. M. and Choi, W. S. (2013) Morusbombycis extract suppresses mast cell activation and IgE-mediated allergic reaction in mice. J. Ethnopharmacol. 146, 287-293. https://doi.org/10.1016/j.jep.2012.12.046
  26. Kim, J. W., Lee, J. H., Hwang, B. Y., Mun, S. H., Ko, N. Y., Kim, D. K., Kim, B., Kim, H. S., Kim, Y. M. and Choi, W. S. (2009) Morin inhibits Fyn kinase in mast cells and IgE-mediated type I hypersensitivity response in vivo. Biochem. Pharmacol. 77, 1506-1512. https://doi.org/10.1016/j.bcp.2009.01.019
  27. Kitanaka, S., Nakayama, T., Shibano, T., Ohkoshi, E. and Takido, M. (1998) Antiallergic agent from natural sources. Structures and inhibitory effect of histamine release of naphthopyrone glycosides from seeds of Cassia obtusifolia L. Chem. Pharm. Bull. (Tokyo) 46, 1650-1652. https://doi.org/10.1248/cpb.46.1650
  28. Kneidinger, M., Schmidt, U., Rix, U., Gleixner, K. V., Vales, A., Baumgartner, C., Lupinek, C., Weghofer, M., Bennett, K. L., Herrmann, H., Schebesta, A., Thomas, W. R., Vrtala, S., Valenta, R., Lee, F. Y., Ellmeier, W., Superti-Furga, G. and Valent, P. (2008) The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood 111, 3097-3107. https://doi.org/10.1182/blood-2007-08-104372
  29. Krystel-Whittemore, M., Dileepan, K. N. and Wood, J. G. (2016) Mast cell: a multi-functional master cell. Front. Immunol. 6, 620. https://doi.org/10.3389/fimmu.2015.00620
  30. Lee, Y. S., Kang, O. H., Choi, J. G., Oh, Y. C., Keum, J. H., Kim, S. B., Jeong, G. S., Kim, Y. C., Shin, D. W. and Kwon, D. Y. (2010) Synergistic effect of emodin in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. 48, 1285-1290. https://doi.org/10.3109/13880201003770150
  31. Lin, S., Cicala, C., Scharenberg, A. M. and Kinet, J. P. (1996) The $Fc{\varepsilon}RI{\beta}$ subunit functions as an amplifier of $Fc{\varepsilon}RI{\gamma}$-mediated cell activation signals. Cell 85, 985-995. https://doi.org/10.1016/S0092-8674(00)81300-8
  32. Lindner, I., Meier, C., Url, A., Unger, H., Grassauer, A., Prieschl-Grassauer, E. and Doerfler, P. (2010) Beta-escin has potent anti-allergic efficacy and reduces allergic airway inflammation. BMC Immunol. 11, 24. https://doi.org/10.1186/1471-2172-11-24
  33. Lombardo, L. J., Lee, F. Y., Chen, P., Norris, D., Barrish, J. C., Behnia, K., Castaneda, S., Cornelius, L. A., Das, J., Doweyko, A. M., Fairchild, C., Hunt, J. T., Inigo, I., Johnston, K., Kamath, A., Kan, D., Klei, H., Marathe, P., Pang, S., Peterson, R., Pitt, S., Schieven, G. L., Schmidt, R. J., Tokarski, J., Wen, M. L., Wityak, J. and Borzilleri, R. M. (2004) Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem. 47, 6658-6661. https://doi.org/10.1021/jm049486a
  34. Mastuda, H., Morikawa, T., Ueda, K., Managi, H. and Yoshikawa, M. (2002) Structural requirements of flavonoids for inhibition of antigen-Induced degranulation, $TNF-{\alpha}$ and IL-4 production from RBL-2H3 cells. Bioorg. Med. Chem. 10, 3123-3128. https://doi.org/10.1016/S0968-0896(02)00227-4
  35. Masuda, E. S. and Schmitz, J. (2008) Syk inhibitors as treatment for allergic rhinitis. Pulm. Pharmacol. Ther. 21, 461-467. https://doi.org/10.1016/j.pupt.2007.06.002
  36. Minai-Fleminger, Y. and Levi-Schaffer, F. (2009) Mast cells and eosinophils: the two key effector cells in allergic inflammation. Inflamm. Res. 58, 631-638. https://doi.org/10.1007/s00011-009-0042-6
  37. Mitre, E. and Nutman, T. B. (2006) Basophils, basophilia and helminth infections. Chem. Immunol. Allergy 90, 141-156. https://doi.org/10.1159/000088886
  38. Montani, D., Bergot, E., Gunther, S., Savale, L., Bergeron, A., Bourdin, A., Bouvaist, H., Canuet, M., Pison, C., Macro, M., Poubeau, P., Girerd, B., Natali, D., Guignabert, C., Perros, F., O'Callaghan, D. S., Jais, X., Tubert-Bitter, P., Zalcman, G., Sitbon, O., Simonneau, G. and Humbert, M. (2012) Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125, 2128-2137. https://doi.org/10.1161/CIRCULATIONAHA.111.079921
  39. Murakami, M. and Kudo, I. (2001) Diversity and regulatory functions of mammalian secretory phospholipase A2s. Adv. Immunol. 77, 163-194.
  40. Nam, S. T., Park, Y. H., Kim, H. W., Kim, H. S., Lee, D., Lee, M. B., Kim, Y. M. and Choi, W. S. (2017) Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, $4{\mu}8C$. Toxicol. Appl. Pharmacol. 332, 25-31. https://doi.org/10.1016/j.taap.2017.07.015
  41. Ovary, Z. (1958) Passive cutaneous anaphylaxis in the mouse. J. Immunol. 81, 355-357.
  42. Park, Y. H., Kim, D. K., Kim, H. W., Kim, H. S., Lee, D., Lee, M. B., Min, K. Y., Koo, J., Kim, S. J., Kang, C., Kim, Y. M., Kim, H. S. and Choi, W. S. (2018) Repositioning of anti-cancer drug candidate, AZD7762, to an anti-allergic drug suppressing IgE-mediated mast cells and allergic responses via the inhibition of Lyn and Fyn. Biochem. Pharmacol. 154, 270-277. https://doi.org/10.1016/j.bcp.2018.05.012
  43. Park, Y. H., Kim, H. W., Kim, H. S., Nam, S. T., Lee, D., Lee, M. B., Min, K. Y., Koo, J., Kim, S. J., Kim, Y. M., Kim, H. S. and Choi, W. S. (2019) An anti-cancer drug candidate CYC116 suppresses type I hypersensitive immune responses through the inhibition of Fyn kinase in mast cells. Biomol. Ther. (Seoul) 27, 311-317. https://doi.org/10.4062/biomolther.2018.148
  44. Parravicini, V., Gadina, M., Kovarova, M., Odom, S., Gonzalez-Espinosa, C., Furumoto, Y., Saitoh, S., Samelson, L. E., O'Shea, J. J. and Rivera, J. (2002) Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nat. Immunol. 3, 741-748. https://doi.org/10.1038/ni817
  45. Qiao, H., Andrade, M. V., Lisboa, F. A., Morgan, K. and Beaven, M. A. (2006) $Fc{\varepsilon}RI$ and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107, 610-618. https://doi.org/10.1182/blood-2005-06-2271
  46. Randall, K. L. and Hawkins, C. A. (2018) Antihistamines and allergy. Aust. Prescr. 41, 41-45. https://doi.org/10.18773/austprescr.2018.010
  47. Rivera, J. (2002) Molecular adapters in $Fc{\varepsilon}RI$ signaling and the allergic response. Curr. Opin. Immunol. 14, 688-693. https://doi.org/10.1016/S0952-7915(02)00396-5
  48. Rivera, J., Cordero, J. R., Furumoto, Y., Luciano-Montalvo, C., Gonzalez-Espinosa, C., Kovarova, M., Odom, S. and Parravicini, V. (2002) Macromolecular protein signaling complexes and mast cell responses: a view of the organization of IgE-dependent mast cell signaling. Mol. Immunol. 38, 1253-1258. https://doi.org/10.1016/S0161-5890(02)00072-X
  49. Schroeder, J. T., MacGlashan, D.W., Jr. and Lichtenstein, L. M. (2001) Human basophils: mediator release and cytokine production. Adv. Immunol. 77, 93-122.
  50. Shah, N. P., Kasap, C., Weier, C., Balbas, M., Nicoll, J. M., Bleickardt, E., Nicaise, C. and Sawyers, C. L. (2008) Transient potent BCRABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell 14, 485-493. https://doi.org/10.1016/j.ccr.2008.11.001
  51. Shah, N. P., Nicoll, J. M., Nagar, B., Gorre, M. E., Paquette, R. L., Kuriyan, J. and Sawyers, C. L. (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117-125. https://doi.org/10.1016/S1535-6108(02)00096-X
  52. Siraganian, R. P., de Castro, R. O., Barbu, E. A. and Zhang, J. (2010) Mast cell signaling: the role of protein tyrosine kinase Syk, its activation and screening methods for new pathway participants. FEBS Lett. 584, 4933-4940. https://doi.org/10.1016/j.febslet.2010.08.006
  53. Wang, W., Zhou, Q., Liu, L. and Zou, K. (2012) Anti-allergic activity of emodin on IgE-mediated activation in RBL-2H3 cells. Pharmacol. Rep. 64, 1216-1222. https://doi.org/10.1016/S1734-1140(12)70917-9
  54. Warrington, R., Silviu-Dan, F. and Wong, T. (2018) Drug allergy. Allergy Asthma Clin. Immunol. 14, 60. https://doi.org/10.1186/s13223-018-0289-y
  55. Wedemeyer, J., Tsai, M. and Galli, S. J. (2000) Roles of mast cells and basophils in innate and acquired immunity. Curr. Opin. Immunol. 12, 624-631. https://doi.org/10.1016/S0952-7915(00)00154-0
  56. Weng, Z., Patel A. B., Panagiotidou, S. and Theoharides, T. C. (2015) The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J. Allergy Clin. Immunol. 135, 1044-1052. https://doi.org/10.1016/j.jaci.2014.10.032
  57. Xiao, J., Xu, M., Hou, T., Huang, Y., Yang, C. and Li, J. (2015) Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling. Mol. Med. Rep. 12, 3249-3256. https://doi.org/10.3892/mmr.2015.3784
  58. Yamaguchi, M., Sayama, K., Yano, K., Lantz, C. S., Noben-Trauth, N., Ra, C., Costa, J. J. and Galli, S. J. (1999) IgE enhances Fc epsilon receptor I expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell Fc epsilon receptor I expression and mediator release. J. Immunol. 162, 5455-5465.

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