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

• Published in: Journal of dermatological science 2013-12, Vol.72 (3), p.252-262
• Main Authors: Massari, Noelia A, Medina, Vanina A, Cricco, Graciela P, Martinel Lamas, Diego J, Sambuco, Lorena, Pagotto, Romina, Ventura, Clara, Ciraolo, Pablo J, Pignataro, Omar, Bergoc, Rosa M, Rivera, Elena S
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Clozapine - pharmacology; Clozapine - therapeutic use; Cyclic AMP - metabolism; Dermatology; ERK1/2; Extracellular Signal-Regulated MAP Kinases - metabolism; H4R; Histamine; Histamine - pharmacology; Histamine - therapeutic use; Humans; Male; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Phosphorylation - drug effects; Proliferation; Receptors, G-Protein-Coupled - agonists; Receptors, Histamine; Receptors, Histamine H4; Signal Transduction - drug effects; Survival; Xenograft Model Antitumor Assays
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2013.07.012

Abstract Background Functional presence of histamine H4 receptor (H4 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 H4 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 H4 R, HA, PCNA, mitotic index (MI), and angiogenesis. Results The results indicate that H4 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.