H1 histamine receptor antagonists induce genotoxic and caspase-2-dependent apoptosis in human melanoma cells
| Autor: | Gorka Pérez-Yarza, María Dolores Boyano, José Luis Díaz-Ramón, Aintzane Asumendi, Shawkat-Muhialdin Jangi, J. L. Diaz-Perez, Jesús Gardeazabal, Itziar Martín-Ruiz, Borja Ochoa-Lizarralde |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
medicine.medical_specialty Programmed cell death Caspase 2 Apoptosis Histamine receptor chemistry.chemical_compound Cytosol Internal medicine Cell Line Tumor medicine Humans Fragmentation (cell biology) Melanoma biology General Medicine Fibroblasts medicine.disease Enzyme Activation Gene Expression Regulation Neoplastic Endocrinology UVB-induced apoptosis chemistry Caspases Cancer research biology.protein Histamine H1 Antagonists Melanocytes Histamine DNA Damage Mutagens |
| Zdroj: | Carcinogenesis. 27(9) |
| ISSN: | 0143-3334 |
| Popis: | 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 caspases 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 TEF-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. |
| Databáze: | OpenAIRE |
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