BACKGROUND AND PURPOSEThe presence of the histamine H4 receptor (H4R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H4R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. EXPERIMENTAL APPROACHXenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H4R agonists were employed: histamine (5 mg kg RESULTSData indicate that developed tumours were highly undifferentiated, expressed H4R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 Ϯ 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H4R agonist groups (13.1 Ϯ 1.2, P < 0.01 in histamine group; 15.1 Ϯ 1.1, P < 0.001 in clozapine group; 10.8 Ϯ 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. CONCLUSIONS AND IMPLICATIONSHistamine through the H4R exhibits a crucial role in tumour progression. Therefore, H4R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment. LINKED ARTICLESThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 AbbreviationsBrdU, 5-bromo-2′-deoxyuridine; ER, oestrogen receptor; H1R, histamine receptor 1; H2R, histamine receptor 2; H3R, histamine receptor 3; H4R, histamine receptor 4; siRNA, small interfering RNA

We have previously reported that histamine at micromolar concentrations reduces the proliferation of melanoma cell lines. It is also known that melanoma cells express histamine H 1 , H 2 , and H 3 receptors. The aim of this study was to investigate the presence of histamine H 4 receptor (H 4 R) in human melanoma cells and its associated biological processes. To better understand the importance of histamine in tumor development, we explored the expression of H 4 R in human melanoma tissue biopsies. The expression of H 4 R in WM35 and M1/15 cells was analyzed by reverse-transcription-PCR, western blot, and immunocytochemistry. To characterize the biological responses we evaluated cell proliferation by clonogenic assay and 5-bromo-2 0 -deoxyuridine incorporation. In addition, cell senescence and differentiation were determined by b-galactosidase enzyme assay and dopa oxidase activity, respectively. The expression levels of H 4 R were determined by immunohistochemistry in 19 samples of human malignant lesions. Results indicate that melanoma cells express H 4 R at the messenger RNA and protein levels. By using histamine agonists, antagonists, and H 4 R small-interfering RNA we showed that the inhibitory effect of histamine on proliferation was in part mediated through the stimulation of the H 4 R. The decrease in proliferation was associated with an induction of cell senescence and an increase in melanogenesis, which is a differentiation marker of these cells. Furthermore, H 4 R was expressed in 42% of human melanoma biopsies. To our knowledge, this is the first report that describes the presence of the H 4 R in melanoma cells and tissue, suggesting a potential therapeutic application of H 4 R ligands.

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The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells.Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.