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Carcinogenesis Advance Access published online on March 28, 2006
Carcinogenesis, doi:10.1093/carcin/bgl021
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received October 12, 2005
Revised March 11, 2006
Accepted March 17, 2006

CANCER BIOLOGY

H1 histamine receptor antagonists induce genotoxic and caspase-2 dependent apoptosis in human melanoma cells

Shawkat-Muhialdin Jangi 1, José Luís Díaz-Pérez 2, Borja Ochoa-Lizarralde 3, Itziar Martín-Ruiz 3, Aintzane Asumendi 3, Gorka Pérez-Yarza 3, Jesús Gardeazabal 2, José Luis Díaz-Ramón 2, and María D. Boyano 3 *

1 Department of Medicine and Pharmacology, Faculty of Medicine, University of Salahaddin, Kurdistan-Iraq
2 Department of Dermatology, Cruces Hospital, Baracaldo E-48903, Vizcaya, Spain
3 Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa E-48940, Vizcaya, Spain

* To whom correspondence should be addressed.
María D. Boyano, E-mail: lola.boyano{at}ehu.es


  Abstract

Previously, we found that the H1 histamine receptor antagonist diphenhydramine induces apoptosis in human acute T- lymphocytic leukemia cells. Since histamine has been shown to act as a growth factor in malignant melanoma cells, we decided to evaluate the in vitro effect of diphenhydramine and other H1 histamine receptor antagonists, such as terfenadine, astemizol and triprolidine on four malignant human melanoma cell lines. These antagonists were found to induce apoptotic cell death in all four melanoma cell lines. Apoptosis was determined by assessment of phosphatidylserine exposure on the surface of the cells and nuclear fragmentation. Importantly, H1 antagonist treatments did not adversely affect the viability of human melanocytes and murine fibroblasts at the same doses and duration of exposure. Treatment of melanoma cells with terfenadine induced DNA damage and caspase-2, -3, -6, -8 and -9 activation. Furthermore, the general caspase inhibitor (z-VAD-FMK) and a selective inhibitor of caspase-2 (z-VDVAD-FMK) protected melanoma cells from terfenadine-induced apoptosis. In contrast, the caspase-8 inhibitor (z-IETD-FMK) was ineffective. In addition, we found that mitochondria are involved in terfenadine-induced apoptosis, characterized by the dissipation of the mitochondrial transmembrane potential, the release of cytochrome c into the cytosolic compartment and caspase-9 activation. On the basis of these results we conclude that H1 histamine receptor antagonists induce apoptosis in human melanoma cells but not in normal melanocytes and embryonic murine fibroblasts; this apoptosis appears to be caspase-2 dependent and involves the mitochondrial pathway. The present results may contribute to the elaboration of novel therapeutic strategies for the treatment of malignant human melanoma.

Keywords: H1 receptor antagonist; apoptosis; human melanoma; caspase-2; DNA damage.
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