Research Papers:

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

Noelia A. Massari, Melisa B. Nicoud, Lorena Sambuco, Graciela P. Cricco, Diego J. Martinel Lamas, María V. Herrero Ducloux, Horacio Blanco, Elena S. Rivera and Vanina A. Medina _

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Oncotarget. 2017; 8:26471-26491. https://doi.org/10.18632/oncotarget.15594

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Noelia A. Massari1,2, Melisa B. Nicoud1,3, Lorena Sambuco4, Graciela P. Cricco1, Diego J. Martinel Lamas1,3, María V. Herrero Ducloux5, Horacio Blanco6, Elena S. Rivera1, Vanina A. Medina1,3

1Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

2Immunology Department, School of Natural Sciences, National University of Patagonia San Juan Bosco, Chubut, Argentina

3Laboratory 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

4Institute of Immunooncology, Buenos Aires, Argentina

5Pathology Department, School of Natural Sciences, National University of Patagonia San Juan Bosco, Chubut, Argentina

6Hospital Municipal de Oncología “Marie Curie”, Buenos Aires, Argentina

Correspondence to:

Vanina A. Medina, email: [email protected]

Keywords: H4R, JNJ28610244, experimental melanoma, tumor growth, ionizing radiation

Received: October 27, 2016     Accepted: February 06, 2017     Published: February 21, 2017


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.

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