Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H 4 receptor agonists and opportunity for combination with radiation

// Noelia A. Massari 1, 2 , Melisa B. Nicoud 1, 3 , Lorena Sambuco 4 , Graciela P. Cricco 1 , Diego J. Martinel Lamas 1, 3 , Maria V. Herrero Ducloux 5 , Horacio Blanco 6 , Elena S. Rivera 1 , Vanina A. Medina 1, 3 1 Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina 2 Immunology Department, School of Natural Sciences, National University of Patagonia San Juan Bosco, Chubut, Argentina 3 Laboratory of Tumor Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina 4 Institute of Immunooncology, Buenos Aires, Argentina 5 Pathology Department, School of Natural Sciences, National University of Patagonia San Juan Bosco, Chubut, Argentina 6 Hospital Municipal de Oncologia “Marie Curie”, Buenos Aires, Argentina Correspondence to: Vanina A. Medina, email: vmedina@ffyb.uba.ar Keywords: H 4 R, JNJ28610244, experimental melanoma, tumor growth, ionizing radiation Received: October 27, 2016      Accepted: February 06, 2017      Published: February 21, 2017 ABSTRACT The aims of the work were to improve our knowledge of the role of H 4 R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H 4 R 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 H 4 R and that histamine inhibits proliferation, in part through the stimulation of the H 4 R, and induces cell senescence and melanogenesis. Daily treatment with H 4 R 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 H 4 R agonist with higher specificity. H 4 R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H 4 R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo . We conclude that stimulation of H 4 R 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.