H4R AGONISTS SUPPRESS HUMAN MELANOMA GROWTH AND LUNG METASTASES

MASSARI NA; MEDINA VA; CRICCO GP; MARTINEL LAMAS DJ; SAMBUCO L; CIRAOLO P; CORTINA JE; RIVERA ES

Lodz

Congreso; European Histamine Research Society, XLII Annual Meeting; 2013

Melanoma arises from epidermal melanocytes and is a major concern for health-care providers. It has been previously reported the expression of H1R, H2R, H3R and H4R in human primary (WM35) and metastatic (M1/15) melanoma cell lines. In these cell lines, histamine through the H4R decreases proliferation, inducing melanogenesis and senescence. Histamine and clozapine also show in vivo antitumor activity on human M1/15 melanoma xenografts. The aims of this work were: to investigate signal transduction pathways and biological responses triggered by the activation of H4R in human highly invasive and metastatic 1205Lu melanoma cells and to evaluate the in vivo antitumor activity of the H4R agonists histamine (HA), clozapine (CLZ) and JNJ28610244 (J28). Results indicate that 1205Lu cells express H4R determined by RT-PCR and western blot. H4R agonists increased phosphorylation levels of ERK1/2 while significantly decreased clonogenic proliferation of 1205Lu cells with a half maximal inhibitory concentration (IC50) of 1.6 µM for histamine and 10 µM for J28. The latter effect was associated with an enhanced cell differentiation. In vivo studies show that HA, CLZ and J28 (1 mg.kg-1, sc) significantly decreased tumor growth of 1205Lu melanoma xenografts developed in nude mice (P