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

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 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.

Long-term Anti-inflammatory and Antihistamine Medication Use and Adult Glioma Risk

“…This may explain the risk observed in the current study for the use of compounds that interfere with normal H 1 receptor activity. Lastly, one report showed that melanoma cells rich in H 1 receptors undergo intensive DNA damage and apoptosis in the presence of antihistamines (27). Such mechanisms could be important for glial cells that harbor high concentrations of H 1 receptors.…”

Evaluation of β-cyclodextrin-modified gemini surfactant-based delivery systems in melanoma models

“…During these events, cytochrome c plays a role in oxidizing and translocating the phosphatidylserine from the inner membrane to the outer leaflet of the cell. 42,43 In this work, Mel alone caused necrosis in ,1% of the cell populations and the cells passed through the apoptotic pathway ( Table 3). As far as elucidating the caspase pathways in the treated cells, as predicted, the Mel alone triggered caspase 2, involved in the DNA degradation pathway and caspase 9 in the mitochondrial pathway of apoptosis (Figure 2A).…”

Histamine in cancer: The dual faces of the coin

“…7,8 It has been reported recently that selective H 1 blockage can induce apoptosis through caspase-2 activation in human melanoma cells. 17 In addition to the actions directly exerted by histamine on tumor cells, it has to be taken into account that histamine can positively influence the immune response against cancer by augmenting the antitumoral properties of IL-2 and thus the antineoplastic capabilities of natural killer cells and T-cells. 18 This effect is presumably due to the histamine-induced decrease in the local production of reactive oxygen species by tumor-infiltrating monocytes.…”