Journal Article

Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca<sup>2+</sup> homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors

Shawkat-Muhialdin Jangi, M.Begoña Ruiz-Larrea, Francesca Nicolau-Galmés, Noelia Andollo, Yoana Arroyo-Berdugo, Idoia Ortega-Martínez, José Luís Díaz-Pérez and María D. Boyano

in Carcinogenesis

Volume 29, issue 3, pages 500-509
Published in print March 2008 | ISSN: 0143-3334
Published online January 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm292
Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+ homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors

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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, 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.

Journal Article.  7222 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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