title: Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma.
abstract: BACKGROUND
  Functional presence of histamine H4 receptor (H4R) was demonstrated in human melanoma cell lines and biopsies.
  
  
  OBJECTIVE
  The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H4R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts.
  
  
  METHODS
  Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro. An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H4R, HA, PCNA, mitotic index (MI), and angiogenesis.
  
  
  RESULTS
  The results indicate that H4R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1mgkg(-1), sc) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization.
  
  
  CONCLUSIONS
  We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma.
authors.affiliation: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires 1113, Argentina.
authors.forename: Noelia A
authors.initials: NA
authors.lastname: Massari
authors.forename: Vanina A
authors.initials: VA
authors.lastname: Medina
authors.forename: Graciela P
authors.initials: GP
authors.lastname: Cricco
authors.forename: Diego J
authors.initials: DJ
authors.lastname: Martinel Lamas
authors.forename: Lorena
authors.initials: L
authors.lastname: Sambuco
authors.forename: Romina
authors.initials: R
authors.lastname: Pagotto
authors.forename: Clara
authors.initials: C
authors.lastname: Ventura
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Ciraolo
authors.forename: Omar
authors.initials: O
authors.lastname: Pignataro
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Bergoc
authors.forename: Elena S
authors.initials: ES
authors.lastname: Rivera
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C418607:HRH4 protein, human; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D006632:Histamine; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D003024:Clozapine
keywords: ERK1/2; H(4)R; Histamine; Melanoma; Proliferation; Survival