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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todo:paper_09231811_v72_n3_p252_Massari2023-10-03T15:45:50Z Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma 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. 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 ERK1/2 H(4)R Histamine Melanoma Proliferation Survival Animals Cell Line, Tumor Cell Proliferation Clozapine Cyclic AMP Extracellular Signal-Regulated MAP Kinases Histamine Humans Male Melanoma, Experimental Mice Mice, Nude Neovascularization, Pathologic Phosphorylation Receptors, G-Protein-Coupled Receptors, Histamine Signal Transduction Xenograft Model Antitumor Assays 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_09231811_v72_n3_p252_Massari |
institution |
Universidad de Buenos Aires |
institution_str |
I-28 |
repository_str |
R-134 |
collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
topic |
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 ERK1/2 H(4)R Histamine Melanoma Proliferation Survival Animals Cell Line, Tumor Cell Proliferation Clozapine Cyclic AMP Extracellular Signal-Regulated MAP Kinases Histamine Humans Male Melanoma, Experimental Mice Mice, Nude Neovascularization, Pathologic Phosphorylation Receptors, G-Protein-Coupled Receptors, Histamine Signal Transduction Xenograft Model Antitumor Assays |
spellingShingle |
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 ERK1/2 H(4)R Histamine Melanoma Proliferation Survival Animals Cell Line, Tumor Cell Proliferation Clozapine Cyclic AMP Extracellular Signal-Regulated MAP Kinases Histamine Humans Male Melanoma, Experimental Mice Mice, Nude Neovascularization, Pathologic Phosphorylation Receptors, G-Protein-Coupled Receptors, Histamine Signal Transduction Xenograft Model Antitumor Assays 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. Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma |
topic_facet |
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 ERK1/2 H(4)R Histamine Melanoma Proliferation Survival Animals Cell Line, Tumor Cell Proliferation Clozapine Cyclic AMP Extracellular Signal-Regulated MAP Kinases Histamine Humans Male Melanoma, Experimental Mice Mice, Nude Neovascularization, Pathologic Phosphorylation Receptors, G-Protein-Coupled Receptors, Histamine Signal Transduction Xenograft Model Antitumor Assays |
description |
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. |
format |
JOUR |
author |
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. |
author_facet |
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. |
author_sort |
Massari, N.A. |
title |
Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma |
title_short |
Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma |
title_full |
Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma |
title_fullStr |
Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma |
title_full_unstemmed |
Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma |
title_sort |
antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma |
url |
http://hdl.handle.net/20.500.12110/paper_09231811_v72_n3_p252_Massari |
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