Dasatinib Inhibits Lyn and Fyn Src-Family Kinases in Mast Cells to Suppress Type I Hypersensitivity in Mice

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.

Dasatinib–SIK2 Binding Elucidated by Homology Modeling, Molecular Docking, and Dynamics Simulations

“… 37 , 41 − 43 Dasatinib is a broad-spectrum kinase inhibitor targeting certain protein kinases such as YES proto-oncogene 1 (YES1), proto-oncogene tyrosine-protein kinase SRC (SRC), tyrosine-protein kinase LYN (LYN), FYN related Src family tyrosine kinase (FRK), FYN, EPH receptor B2 (EPHB2), EPH receptor A2 (EPHA2), discoidin domain receptor tyrosine kinase 1 (DDR1), Abelson leukemia virus tyrosine kinase (ABL)2, receptor interacting protein kinase (RIPK)2, LIM kinase 1 (LIMK1), and SIK2. 14 , 44 , 45 Dasatinib noncovalently binds and inhibits SIK2 functions. 14 In vitro, it inhibits functions of SIK isoforms with half-maximal inhibitory concentration (IC 50 ) in a nanomolar range (<3 nM for SIK1, <3 nM for SIK2, and 18 nM for SIK3).…”

“…N -(2-Chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)­piperazin-1-yl)-2-methylpyrimidin-4-ylamino)­thiazole-5-carboxamide (dasatinib; BMS-354825; Sprycel; Figure ) is a first-line drug used for the treatment of BCR-ABL-positive leukemias . It can also be used to treat chronic myelogenous leukemia (CML), lymphomas, and advanced prostate and breast cancers. ,− Adverse events, such as gastrointestinal disorders, hemorrhage, and endothelial permeabilization, leading to the development of peripheral edema and pleural effusion were reported in certain patients who were administered with dasatinib. ,− Dasatinib is a broad-spectrum kinase inhibitor targeting certain protein kinases such as YES proto-oncogene 1 (YES1), proto-oncogene tyrosine-protein kinase SRC (SRC), tyrosine-protein kinase LYN (LYN), FYN related Src family tyrosine kinase (FRK), FYN, EPH receptor B2 (EPHB2), EPH receptor A2 (EPHA2), discoidin domain receptor tyrosine kinase 1 (DDR1), Abelson leukemia virus tyrosine kinase (ABL)­2, receptor interacting protein kinase (RIPK)­2, LIM kinase 1 (LIMK1), and SIK2. ,, Dasatinib noncovalently binds and inhibits SIK2 functions . In vitro, it inhibits functions of SIK isoforms with half-maximal inhibitory concentration (IC 50 ) in a nanomolar range (<3 nM for SIK1, <3 nM for SIK2, and 18 nM for SIK3). , As it exhibits remarkable activity against SIKs and is also a pan inhibitor against kinases, dasatinib may be considered a lead compound in the design and/or development of new, highly selective SIK2 inhibitors.…”

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

“…9) 16 . These discrepancies likely reflect the fact that dasatinib indiscriminately blocks the effect of other regulatory Src kinases that are known to collaborate and substitute in regulating endothelial homeostasis 3,17 . Recently, monogenic defects that reduce or eliminate phosphorylation of the conserved inhibitory tyrosine in the C-terminal tail of Src, Hck and Lyn illustrate diverging effects that suggest tissue and organ specificity of Src kinases 5,18,19 .…”

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation

“…Although it is not well known whether Fyn plays an important role in AD, a few reports suggest the protective role of Fyn in skin inflammation. For instance, dasatinib, an anti-cancer agent, suppressed the secretion of inflammatory cytokines by direct inhibition of Fyn in mast cells, which play an important role in type I hypersensitivity immune responses, including AD [ 65 ]. Similarly, Rhamnus davurica extract inhibited the activation of Fyn in antigen-stimulated mast cells [ 66 ].…”