Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(3):500-509; doi:10.1093/carcin/bgm292
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Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+ homeostasis 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, Iraq
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
* To whom correspondence should be addressed. Tel: +34 94 601 5689; Fax: +34 94 601 3266; Email: lola.boyano{at}ehu.es
In our previous works, we have demonstrated that terfenadine (TEF) 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 TEF may induce its apoptotic effect. We have found that exogenous histamine stimulates A375 melanoma cell proliferation in a dose- and time-dependent manner. Moreover, TEF-induced apoptosis seems to occur via other cellular pathways independent of the histamine-signalling system since co-treatment of histamine with TEF did not protect melanoma cells from the cytotoxic effect of TEF, and alpha fluoromethylhistidine did not induce the same cytotoxic effect of TEF. In addition, we have observed that knocking down the H1 histamine receptor (HRH1) by small interference RNA approach protects melanoma cells only slightly from TEF-induced apoptosis. To explore the molecular mechanisms responsible for histamine and TEF effect on the cell growth, we analysed intracellular cyclic nucleotides and Ca2+ levels. TEF did not modify intracellular levels of cyclic adenosine 3',5'-monophosphate and cyclic guanine 3',5'-monophosphate; however, TEF induced a very sharp and sustained increase in cytosolic Ca2+ levels in A375 melanoma cells. On the contrary, histamine did not modulate intracellular Ca2+. TEF-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 TEF-induced apoptosis. These results suggest that TEF modulates Ca2+ homeostasis and induces apoptosis through other cellular pathways involving tyrosine kinase activity, independently of HRH1.
Abbreviations: BAPTA-AM, (1,2-bis-(o-Aminophenoxy)-ethane –N,N,-N',N'- tetracetic acid tetraacetoxy-Methyl ester; cAMP, cyclic adenosine 3',5'-monophosphate; cGMP, cyclic guanine 3',5'-monophosphate; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethylsulfoxide; EGTA, ethyleneglycol-bis(aminoethylether)-tetraacetic acid; ER, endoplasmic reticulum; 
-FMH, alpha fluoromethylhistidine; GAPDH, glyceraldehydes-3-phosphate dehydrogenase; HRH1, H1 histamine receptor; IP3, inositol 1,4,5-trisphosphate; mRNA, messenger RNA; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PLC, phospholipase C; siRNA, small interference RNA; SOC, store-operated Ca2+ channel; TEF, terfenadine; XTT, Sodium 3'-[1-(phenylaminocarbonil)-3,4-tetrazolim] –bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate
Received June 1, 2007; revised October 30, 2007; accepted November 26, 2007.
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