Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation

SAMBUCO L; HERRERO DUCLOUX; MEDINA VANINA; NICOUD MB; MARTINEL LAMAS DIEGO; RIVERA ES; MASSARI NA; CRICCO GP; BLANCO H

Oncotarget

Albany, N.Y. : Impact Journals

Lugar: Nueva York; Año: 2017 vol. 8 p. 26471 - 26491

1949-2553

The aims of the work were to improve our knowledge of the role of H4R inmelanoma proliferation and assess in vivo the therapeutic efficacy of histamine,clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model ofmelanoma. 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 thathistamine 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 cancerradiotherapy for the treatment of melanoma.