Identification of the Syk kinase inhibitor R112 by a human mast cell screen

2006 ◽  
Vol 118 (3) ◽  
pp. 749-755 ◽  
Author(s):  
A ROSSI ◽  
E HERLAAR ◽  
S BRASELMANN ◽  
S HUYNH ◽  
V TAYLOR ◽  
...  
Keyword(s):  
Mast Cell ◽  
Kinase Inhibitor ◽  
Human Mast Cell ◽  
Syk Kinase

EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 315-322 ◽  
Author(s):  
Jingxuan Pan ◽  
Alfonso Quintás-Cardama ◽  
Hagop M. Kantarjian ◽  
Cem Akin ◽  
Taghi Manshouri ◽  
...  
Keyword(s):  
Mast Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Human Mast Cell ◽  
Activation Loop ◽  
Dependent Manner ◽  
Juxtamembrane Domain ◽  
Dose Dependent

Abstract Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

scholarly journals Thapsigargin-Stimulated LAD2 Human Mast Cell Line Is a Potent Cellular Adjuvant for the Maturation of Monocyte-Derived Dendritic Cells for Adoptive Cellular Immunotherapy

2021 ◽  
Vol 22 (8) ◽  
pp. 3978
Author(s):  
Pavla Taborska ◽  
Dmitry Stakheev ◽  
Jirina Bartunkova ◽  
Daniel Smrz
Keyword(s):  
Dendritic Cells ◽  
Mast Cell ◽  
Ex Vivo ◽  
Human Leukocyte ◽  
Poly I:C ◽  
Human Mast Cell ◽  
Cellular Immunotherapy ◽  
Adoptive Cellular Immunotherapy ◽  
Serum Free ◽  
Dc Maturation

The preparation of dendritic cells (DCs) for adoptive cellular immunotherapy (ACI) requires the maturation of ex vivo-produced immature(i) DCs. This maturation ensures that the antigen presentation triggers an immune response towards the antigen-expressing cells. Although there is a large number of maturation agents capable of inducing strong DC maturation, there is still only a very limited number of these agents approved for use in the production of DCs for ACI. In seeking novel DC maturation agents, we used differentially activated human mast cell (MC) line LAD2 as a cellular adjuvant to elicit or modulate the maturation of ex vivo-produced monocyte-derived iDCs. We found that co-culture of iDCs with differentially activated LAD2 MCs in serum-containing media significantly modulated polyinosinic:polycytidylic acid (poly I:C)-elicited DC maturation as determined through the surface expression of the maturation markers CD80, CD83, CD86, and human leukocyte antigen(HLA)-DR. Once iDCs were generated in serum-free conditions, they became refractory to the maturation with poly I:C, and the LAD2 MC modulatory potential was minimized. However, the maturation-refractory phenotype of the serum-free generated iDCs was largely overcome by co-culture with thapsigargin-stimulated LAD2 MCs. Our data suggest that differentially stimulated mast cells could be novel and highly potent cellular adjuvants for the maturation of DCs for ACI.

scholarly journals Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP)-induced histamine release is enhanced with SHIP-1 knockdown in cultured human mast cell and basophil models

2008 ◽  
Vol 84 (4) ◽  
pp. 1151-1158 ◽  
Author(s):  
Jacqueline M. Langdon ◽  
John T. Schroeder ◽  
Becky M. Vonakis ◽  
Anja P. Bieneman ◽  
Kristin Chichester ◽  
...  
Keyword(s):  
Mast Cell ◽  
Histamine Release ◽  
Human Mast Cell ◽  
Translationally Controlled Tumor Protein

scholarly journals Human mast cell activation through Fc receptors and Toll-like receptors

2004 ◽  
Vol 53 (3) ◽  
pp. 227-233 ◽  
Author(s):  
Yoshimichi Okayama ◽  
Shigeru Okumura ◽  
Hisashi Tomita ◽  
Hiroko Katayama ◽  
Keisuke Yuki ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Activation ◽  
Fc Receptors ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Toll Like Receptors

scholarly journals Transcriptional complexity of the HSPG2 gene in the human mast cell line, HMC-1

2014 ◽  
Vol 35 ◽  
pp. 123-131 ◽  
Author(s):  
Megan S. Lord ◽  
MoonSun Jung ◽  
Bill Cheng ◽  
John M. Whitelock
Keyword(s):  
Mast Cell ◽  
Cell Line ◽  
Human Mast Cell ◽  
Mast Cell Line

scholarly journals Alisol B 23-Acetate Inhibits IgE/Ag-Mediated Mast Cell Activation and Allergic Reaction

2018 ◽  
Vol 19 (12) ◽  
pp. 4092 ◽  
Author(s):  
Chen Shao ◽  
Bingjie Fu ◽  
Ning Ji ◽  
Shunli Pan ◽  
Xiaoxia Zhao ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Allergic Reaction ◽  
Nuclear Factor Kappa B ◽  
Immunoglobulin E ◽  
Mast Cell Activation ◽  
Human Mast Cell ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa

Alisol B 23-acetate (AB23A), a natural triterpenoid, has been reported to exert hepatoprotective and antitumor activities. Aiming to investigate the anti-inflammatory activity, this study examined the effect of AB23A on mast cells and allergic reaction. AB23A inhibited the degranulation of mast cells stimulated by immunoglobulin E/antigen (IgE/Ag), and also decreased the synthesis of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner with no significant cytotoxicity in bone marrow-derived mast cells (BMMCs). AB23A inhibited spleen tyrosine kinase (Syk) and the downstream signaling molecules including phospholipase Cγ (PLCγ), serine-threonine protein kinase/inhibitor of nuclear factor kappa-B kinase/nuclear factor kappa-B (Akt/IKK/NF-κB), and mitogen-activated protein kinases/cytosolic phospholipase A2 (MAPK/cPLA2). Furthermore, AB23A blocked mobilization of Ca2+. Similar results were obtained in other mast cell lines Rat basophilic leukemia (RBL)-2H3 cells and a human mast cell line (HMC-1). In addition, AB23A attenuated allergic responses in an acute allergy animal model, passive cutaneous anaphylaxis (PCA). Taken together, this study suggests that AB23A inhibits the activation of mast cells and ameliorates allergic reaction, and may become a lead compound for the treatment of mast cell-mediated allergic diseases.

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