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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Publicado:	2013
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:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09231811_v72_n3_p252_Massari 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

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spelling	paper:paper_09231811_v72_n3_p252_Massari2023-06-08T15:50:57Z Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma 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. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09231811_v72_n3_p252_Massari 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 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.
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
publishDate	2013
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09231811_v72_n3_p252_Massari http://hdl.handle.net/20.500.12110/paper_09231811_v72_n3_p252_Massari
_version_	1768546354771001344

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

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