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Medientyp: E-Artikel Titel: Influence of the tyrosine kinase inhibitors STI571 (Glivec®), lavendustin A and genistein on human mast cell line (HMC‐1560) activation Beteiligte: Löber, Kristin; Alfonso, Amparo; Escribano, Luis; Botana, Luis M. Erschienen: Wiley, 2008 Erschienen in: Journal of Cellular Biochemistry Sprache: Englisch DOI: 10.1002/jcb.21480 ISSN: 0730-2312; 1097-4644 Schlagwörter: Cell Biology ; Molecular Biology ; Biochemistry Entstehung: Anmerkungen: Beschreibung: <jats:title>Abstract</jats:title><jats:p>The human mast cell line (HMC‐1<jats:sup>560</jats:sup>) was used to study the effects of tyrosine kinase (TyrK) inhibition on histamine release in consequence of intracellular Ca<jats:sup>2+</jats:sup> or pH changes. This is important since the TyrK inhibitor STI571 (Glivec®) inhibits proliferation and induces apoptosis in HMC‐1<jats:sup>560</jats:sup>. HMC‐1<jats:sup>560</jats:sup> cells have a mutation in c‐kit, which leads to a permanent phosphorylation of the KIT protein and their ligand‐independent proliferation. The TyrK inhibitors STI571, lavendustin A and genistein decrease spontaneous histamine release in 24‐h pre‐incubated cells. Results are compared with those of the mast cell stabiliser cromoglycic acid, which also drops spontaneous histamine release. When exocytosis is stimulated by alkalinisation, STI571 pre‐incubated cells release more histamine than non‐pre‐incubated cells. Alkalinisation‐induced histamine release reaches still higher levels in STI571 cells with activated protein kinase C (PKC) by PMA. We do not observe modifications on histamine release in cells, treated with PKC inhibitors (rottlerin, Gf109203 or Gö6976). Lavendustin A‐ and genistein 24‐h incubated cells behave similar to STI571 cells, whereas cromoglycic acid does not show effects after stimulation with alkalinisation. Stimulation of exocytosis with the Ca<jats:sup>2+</jats:sup> ionophore ionomycin does not modify histamine response in TyrK inhibited cells. Ca<jats:sup>2+</jats:sup> and pH changes are observed after long‐time incubation with STI571. Results show that pH is still higher in STI571 pre‐incubated cells after alkalinisation with NH<jats:sub>4</jats:sub>Cl, whereas intracellular Ca<jats:sup>2+</jats:sup> concentration remains stable. This work further strength the importance of pH<jats:sub>i</jats:sub> as a cell signal and suggest that STI571 has transduction pathways in common with other TyrKs. J. Cell. Biochem. 103: 1076–1088, 2008. © 2007 Wiley‐Liss, Inc.</jats:p>