Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma

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 met...

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Detalles Bibliográficos
Autores principales: Massari, N.A., Medina, V.A., Cricco, G.P., Martinel Lamas, D.J., Sambuco, L., Pagotto, R., Ventura, C., Ciraolo, P.J., Pignataro, O., Bergoc, R.M., Rivera, E.S.
Formato: JOUR
Materias:
ERK1/2
H4R
Histamine
Melanoma
Proliferation
Survival
1 (5 chloro 2 indolylcarbonyl) 4 methylpiperazine
1 [2 (amidinothio)ethyl]guanidine
2 [(aminoiminomethyl)amino]ethyl carbamimidothioic acid ester dihydrobromide
broxuridine
cell marker
clozapine
cyclic AMP
forskolin
histamine
histamine agonist
histamine H4 receptor
histamine receptor
mitogen activated protein kinase 1
mitogen activated protein kinase 3
unclassified drug
animal experiment
animal model
animal tissue
antineoplastic activity
article
cancer survival
cell line
cell proliferation
cellular distribution
clonogenic assay
concentration response
controlled study
drug screening
enzyme phosphorylation
histochemistry
human
human cell
IC 50
in vitro study
in vivo study
intracellular signaling
male
melanoma
melanoma cell
metastatic melanoma
mitosis index
mouse
nonhuman
primary tumor
priority journal
protein expression
protein induction
protein synthesis
treatment response
tumor growth
tumor vascularization
tumor volume
tumor xenograft
H(4)R
Animals
Cell Line, Tumor
Cell Proliferation
Clozapine
Cyclic AMP
Extracellular Signal-Regulated MAP Kinases
Humans
Male
Melanoma, Experimental
Mice
Mice, Nude
Neovascularization, Pathologic
Phosphorylation
Receptors, G-Protein-Coupled
Receptors, Histamine
Signal Transduction
Xenograft Model Antitumor Assays
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_09231811_v72_n3_p252_Massari
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario: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. © 2013 Japanese Society for Investigative Dermatology.

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