Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm292
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Terefenadine–induced apoptosis in human melanoma cells is mediated through Ca2+ homoestasis modulation and tyrosine kinase activity, independently of H1 histamine receptors
Department of Cell Biology and Histology. Faculty of Medicine and Dentistry, University of the Basque Country, Leioa E-48940, Bizkaia, Spain
1 Department of Medicine and Pharmacology, Faculty of Medicine, Hawler Medical University, Kurdistan-Irak
2 Department of Physiology. Faculty of Medicine and Dentistry, University of the Basque Country, Leioa E-48940, Bizkaia, Spain
3 Department of Dermatology. Cruces Hospital, Baracaldo E-48903, Bizkaia, Spain
* Address correspondence to: María D. Boyano, Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa E-48940, Vizcaya, Spain. E-mail: lola.boyano{at}ehu.es Tel: +34-94-601-5689. Fax: +34-94-601-3266
In our previous works we have demonstrated that terfenadine induces DNA damage and apoptosis in human melanoma cell lines. In this present work, we have studied the effect of histamine on viability of A375 human melanoma cells and the cell signalling pathways through which terfenadine may induce its apoptotic effect. We have found that exogenous histamine stimulates A375 melanoma cell proliferation in a dose- and time-dependent manner. Moreover, terfenadine-induced apoptosis seems to occur via other cellular pathways independent of the histamine signalling system, since co-treatment of histamine with terfenadine did not protect melanoma cells from the cytotoxic effect of terfenadine, and alphafluoromethyle histidine did not induce the same cytotoxic effect of terfenadine. In addition, we have observed that knocking down the H1 histamine receptor by siRNA approach protects melanoma cells only slightly from terfenadine induced-apoptosis. To explore the molecular mechanisms responsible for histamine and terfenadine effect on the cell growth, we analysed intracellular cyclic nucleotides and Ca2+ levels. Terfenadine did not modify intracellular levels of cAMP and cGMP; however, terfenadine induced a very sharp and sustained increase in cytosolic Ca2+ levels in A375 melanoma cells. On the contrary, histamine did not modulate intracellular Ca2+. Terfenadine-induced Ca2+ rise and apoptosis appear to be phospholipase C (PLC) dependent, since neomycin and U73122 [GenBank] , two inhibitors of PLC, abolished cytosolic Ca2+ increase and protected the cells completely from cell death. Furthermore, inhibition of tyrosine kinase activity by genistein blocked cytosolic Ca2+ rise and terfenadine-induced apoptosis. These results suggest that terfenadine modulates Ca2+ homeostasis and induces apoptosis through other cellular pathways involving tyrosine kinase activity, independently of H1 histamine receptors.
Key Words: H1 histamine receptor antagonists • terfenadine • histamine • cimetidine • cytosolic Ca2+ • apoptosis • siRNA • tyrosine kinase • human melanoma cells
Received June 1, 2007; revised October 30, 2007; accepted November 26, 2007.
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