4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis

Autores
Piccioni, Flavia Valeria; Fiore, Esteban Juan; Bayo Fina, Juan Miguel; Atorrasagasti, María Catalina; Peixoto, Estanislao; Mazzolini Rizzo, Guillermo Daniel; Malvicini, Mariana; Tirado González, Irene; García, Mariana Gabriela; Alaniz, Laura Daniela; Mazzolini Rizzo, Guillermo Daniel
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cirrhosis is characterized by an excessive accumulation of extracellular matrix components including hyaluronic acid (HA) and is widely considered a pre-neoplastic condition for hepatocellular carcinoma (HCC). 4-methylumbelliferone (4MU) is an inhibitor of HA synthesis and has anti-cancer activity in an orthotopic HCC model with underlying fibrosis. Our aim was to explore the effects of HA inhibition by 4MU orally administered on tumour microenvironment. Hepa129 tumour cells were inoculated orthotopically in C3H/HeJ male mice with fibrosis induced by thioacetamide. Mice were orally treated with 4MU. The effects of 4MU on angiogenesis were evaluated by immunostaining of CD31 and quantification of proangiogenic factors (VEGF, IL-6, CXCL12). IL-6 was also quantified in Hepa129 cells in vitro after treatment with 4MU. Migration of endothelial cells and tube formation were also analyzed. As a result, 4MU treatment decreases tumour growth and increased animal survival. Systemic levels of VEGF were significantly inhibited in 4MU-treated mice. Expression of CD31 was reduced after 4MU therapy in liver parenchyma in comparison with control group. In addition, mRNA expression and protein levels of IL-6 and VEGF were inhibited both in tumour tissue and in non-tumoral liver parenchyma. Interestingly, IL-6 production was dramatically reduced in Kupffer cells isolated from 4MU-treated mice, and in Hepa129 cells in vitro. Besides, 4MU was able to inhibit endothelial cell migration and tube formation. In conclusion, 4MU has antitumour activity in vivo and its mechanisms of action involve an inhibition of angiogenesis and IL-6 production. 4MU is an orally available molecule with potential for HCC treatment.
Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bayo Fina, Juan Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Tirado González, Irene. Universität zu Berlin; Alemania
Fil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
4-Methylumbelliferone
Hcc
Il-6
Vegf
Angiogenesis
Hyaluronic Acid
Liver Fibrosis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/22524
Acceder
id CONICETDig_2fecc11350d3b5c017ea7b6a56de311f
oai_identifier_str oai:ri.conicet.gov.ar:11336/22524
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesisPiccioni, Flavia ValeriaFiore, Esteban JuanBayo Fina, Juan MiguelAtorrasagasti, María CatalinaPeixoto, EstanislaoMazzolini Rizzo, Guillermo DanielMalvicini, MarianaTirado González, IreneGarcía, Mariana GabrielaAlaniz, Laura DanielaMazzolini Rizzo, Guillermo Daniel4-MethylumbelliferoneHccIl-6VegfAngiogenesisHyaluronic AcidLiver Fibrosishttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cirrhosis is characterized by an excessive accumulation of extracellular matrix components including hyaluronic acid (HA) and is widely considered a pre-neoplastic condition for hepatocellular carcinoma (HCC). 4-methylumbelliferone (4MU) is an inhibitor of HA synthesis and has anti-cancer activity in an orthotopic HCC model with underlying fibrosis. Our aim was to explore the effects of HA inhibition by 4MU orally administered on tumour microenvironment. Hepa129 tumour cells were inoculated orthotopically in C3H/HeJ male mice with fibrosis induced by thioacetamide. Mice were orally treated with 4MU. The effects of 4MU on angiogenesis were evaluated by immunostaining of CD31 and quantification of proangiogenic factors (VEGF, IL-6, CXCL12). IL-6 was also quantified in Hepa129 cells in vitro after treatment with 4MU. Migration of endothelial cells and tube formation were also analyzed. As a result, 4MU treatment decreases tumour growth and increased animal survival. Systemic levels of VEGF were significantly inhibited in 4MU-treated mice. Expression of CD31 was reduced after 4MU therapy in liver parenchyma in comparison with control group. In addition, mRNA expression and protein levels of IL-6 and VEGF were inhibited both in tumour tissue and in non-tumoral liver parenchyma. Interestingly, IL-6 production was dramatically reduced in Kupffer cells isolated from 4MU-treated mice, and in Hepa129 cells in vitro. Besides, 4MU was able to inhibit endothelial cell migration and tube formation. In conclusion, 4MU has antitumour activity in vivo and its mechanisms of action involve an inhibition of angiogenesis and IL-6 production. 4MU is an orally available molecule with potential for HCC treatment.Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bayo Fina, Juan Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tirado González, Irene. Universität zu Berlin; AlemaniaFil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaOxford University Press2015-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/22524Piccioni, Flavia Valeria; Fiore, Esteban Juan; Bayo Fina, Juan Miguel; Atorrasagasti, María Catalina; Peixoto, Estanislao; et al.; 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis; Oxford University Press; Glycobiology; 25; 8; 8-2015; 825-8350959-6658CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/glycob/article-lookup/doi/10.1093/glycob/cwv023info:eu-repo/semantics/altIdentifier/doi/10.1093/glycob/cwv023info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:37:57Zoai:ri.conicet.gov.ar:11336/22524instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:37:57.37CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
title 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
spellingShingle 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
Piccioni, Flavia Valeria
4-Methylumbelliferone
Hcc
Il-6
Vegf
Angiogenesis
Hyaluronic Acid
Liver Fibrosis
title_short 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
title_full 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
title_fullStr 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
title_full_unstemmed 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
title_sort 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis
dc.creator.none.fl_str_mv Piccioni, Flavia Valeria
Fiore, Esteban Juan
Bayo Fina, Juan Miguel
Atorrasagasti, María Catalina
Peixoto, Estanislao
Mazzolini Rizzo, Guillermo Daniel
Malvicini, Mariana
Tirado González, Irene
García, Mariana Gabriela
Alaniz, Laura Daniela
Mazzolini Rizzo, Guillermo Daniel
author Piccioni, Flavia Valeria
author_facet Piccioni, Flavia Valeria
Fiore, Esteban Juan
Bayo Fina, Juan Miguel
Atorrasagasti, María Catalina
Peixoto, Estanislao
Mazzolini Rizzo, Guillermo Daniel
Malvicini, Mariana
Tirado González, Irene
García, Mariana Gabriela
Alaniz, Laura Daniela
author_role author
author2 Fiore, Esteban Juan
Bayo Fina, Juan Miguel
Atorrasagasti, María Catalina
Peixoto, Estanislao
Mazzolini Rizzo, Guillermo Daniel
Malvicini, Mariana
Tirado González, Irene
García, Mariana Gabriela
Alaniz, Laura Daniela
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 4-Methylumbelliferone
Hcc
Il-6
Vegf
Angiogenesis
Hyaluronic Acid
Liver Fibrosis
topic 4-Methylumbelliferone
Hcc
Il-6
Vegf
Angiogenesis
Hyaluronic Acid
Liver Fibrosis
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cirrhosis is characterized by an excessive accumulation of extracellular matrix components including hyaluronic acid (HA) and is widely considered a pre-neoplastic condition for hepatocellular carcinoma (HCC). 4-methylumbelliferone (4MU) is an inhibitor of HA synthesis and has anti-cancer activity in an orthotopic HCC model with underlying fibrosis. Our aim was to explore the effects of HA inhibition by 4MU orally administered on tumour microenvironment. Hepa129 tumour cells were inoculated orthotopically in C3H/HeJ male mice with fibrosis induced by thioacetamide. Mice were orally treated with 4MU. The effects of 4MU on angiogenesis were evaluated by immunostaining of CD31 and quantification of proangiogenic factors (VEGF, IL-6, CXCL12). IL-6 was also quantified in Hepa129 cells in vitro after treatment with 4MU. Migration of endothelial cells and tube formation were also analyzed. As a result, 4MU treatment decreases tumour growth and increased animal survival. Systemic levels of VEGF were significantly inhibited in 4MU-treated mice. Expression of CD31 was reduced after 4MU therapy in liver parenchyma in comparison with control group. In addition, mRNA expression and protein levels of IL-6 and VEGF were inhibited both in tumour tissue and in non-tumoral liver parenchyma. Interestingly, IL-6 production was dramatically reduced in Kupffer cells isolated from 4MU-treated mice, and in Hepa129 cells in vitro. Besides, 4MU was able to inhibit endothelial cell migration and tube formation. In conclusion, 4MU has antitumour activity in vivo and its mechanisms of action involve an inhibition of angiogenesis and IL-6 production. 4MU is an orally available molecule with potential for HCC treatment.
Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bayo Fina, Juan Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Tirado González, Irene. Universität zu Berlin; Alemania
Fil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Cirrhosis is characterized by an excessive accumulation of extracellular matrix components including hyaluronic acid (HA) and is widely considered a pre-neoplastic condition for hepatocellular carcinoma (HCC). 4-methylumbelliferone (4MU) is an inhibitor of HA synthesis and has anti-cancer activity in an orthotopic HCC model with underlying fibrosis. Our aim was to explore the effects of HA inhibition by 4MU orally administered on tumour microenvironment. Hepa129 tumour cells were inoculated orthotopically in C3H/HeJ male mice with fibrosis induced by thioacetamide. Mice were orally treated with 4MU. The effects of 4MU on angiogenesis were evaluated by immunostaining of CD31 and quantification of proangiogenic factors (VEGF, IL-6, CXCL12). IL-6 was also quantified in Hepa129 cells in vitro after treatment with 4MU. Migration of endothelial cells and tube formation were also analyzed. As a result, 4MU treatment decreases tumour growth and increased animal survival. Systemic levels of VEGF were significantly inhibited in 4MU-treated mice. Expression of CD31 was reduced after 4MU therapy in liver parenchyma in comparison with control group. In addition, mRNA expression and protein levels of IL-6 and VEGF were inhibited both in tumour tissue and in non-tumoral liver parenchyma. Interestingly, IL-6 production was dramatically reduced in Kupffer cells isolated from 4MU-treated mice, and in Hepa129 cells in vitro. Besides, 4MU was able to inhibit endothelial cell migration and tube formation. In conclusion, 4MU has antitumour activity in vivo and its mechanisms of action involve an inhibition of angiogenesis and IL-6 production. 4MU is an orally available molecule with potential for HCC treatment.
publishDate 2015
dc.date.none.fl_str_mv 2015-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/22524
Piccioni, Flavia Valeria; Fiore, Esteban Juan; Bayo Fina, Juan Miguel; Atorrasagasti, María Catalina; Peixoto, Estanislao; et al.; 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis; Oxford University Press; Glycobiology; 25; 8; 8-2015; 825-835
0959-6658
CONICET Digital
CONICET
url http://hdl.handle.net/11336/22524
identifier_str_mv Piccioni, Flavia Valeria; Fiore, Esteban Juan; Bayo Fina, Juan Miguel; Atorrasagasti, María Catalina; Peixoto, Estanislao; et al.; 4-Methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis; Oxford University Press; Glycobiology; 25; 8; 8-2015; 825-835
0959-6658
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
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dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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