STI571 (Glivec) affects histamine release and intracellular pH after alkalinisation in HMC-1560, 816.
The human mast cell line (HMC-1(560, 816)) was used to study the effect of the tyrosine kinase inhibitor STI571 (Glivec) on exocytosis, intracellular Ca(2+) and pH changes, because STI571 inhibits the proliferation of HMC-1(560) and induces its apoptosis. This drug does not have these effects on HMC-1(560, 816). Exocytosis in HMC-1(560, 816) cells can be stimulated by alkalinisation with NH(4)Cl as well as with ionomycin. Surprisingly 24-h pre-incubation with STI571 decreases spontaneous histamine release of HMC-1(560, 816) cells, but increases the histamine response after alkalinisation and not after ionomycin-stimulation. After addition of NH(4)Cl, pH(i) has a higher increase in STI571 pre-incubated cells, without changing intracellular Ca(2+) concentration. Activation of PKC in combination with tyrosine kinase inhibition increases also histamine release in HMC-1(560, 816) cells. Strangely, STI571 pre-incubated cells with PKC inhibited by rottlerin show the same effects. In these cells, cytosolic pH increases more than in control cells. This is the first report of STI571 effect in HMC-1(560, 816) cells. It seems that different pathways modulate signals for proliferation and exocytosis. STI571 does not only inhibit KIT TyrK, but may also influence cytosolic pH after alkalinisation in both cell lines, HMC-1(560) and HMC-1(560, 816), and this ends in induced histamine release. This work is important since HMC-1(560, 816) cells are reported in 80% of aggressive systemic mastocytosis cases and the understanding of some signalling pathways involved in mast cell response could facilitate drug targeting.
Löber
Kristin
K
Departamento de Farmacología, Facultad de Veterinaria, 27002 Lugo, Spain.
Alfonso
Amparo
A
Escribano
Luis
L
Botana
Luis M
LM
D000098:Acetophenones / Q000494:pharmacology; D000468:Alkalies / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000187:drug effects*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D003593:Cytoplasm / Q000737:chemistry; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D006636:Histamine Release / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000378:metabolism*; D034721:Mastocytosis, Systemic; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction
D000098:Acetophenones; D000468:Alkalies; D001549:Benzamides; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C085746:rottlerin; D006631:Amine Oxidase (Copper-Containing); D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium