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

Abstract

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.