Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma

Abstract Background Functional presence of histamine H 4 receptor (H 4 R) was demonstrated in human melanoma cell lines and biopsies. Objective The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H 4 R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts. Methods Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro . An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H 4 R, HA, PCNA, mitotic index (MI), and angiogenesis. Results The results indicate that H 4 R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1 mg kg −1 , sc ) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization. Conclusions We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma.