Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model

<h4>Background</h4> Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase...

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Autores principales:	Riccardo Serra, Tianna Zhao, Sakibul Huq, Noah Leviton Gorelick, Joshua Casaos, Arba Cecia, Antonella Mangraviti, Charles Eberhart, Renyuan Bai, Alessandro Olivi, Henry Brem, Eric M. Jackson, Betty Tyler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f8cb841dda8541a1b7d69527798e1470
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spelling	oai:doaj.org-article:f8cb841dda8541a1b7d69527798e14702021-11-11T06:44:15ZDisulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model1932-6203https://doaj.org/article/f8cb841dda8541a1b7d69527798e14702021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565761/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4> Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models. <h4>Methods</h4> The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting. <h4>Results</h4> Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo. <h4>Conclusions</h4> Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.Riccardo SerraTianna ZhaoSakibul HuqNoah Leviton GorelickJoshua CasaosArba CeciaAntonella MangravitiCharles EberhartRenyuan BaiAlessandro OliviHenry BremEric M. JacksonBetty TylerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Riccardo Serra Tianna Zhao Sakibul Huq Noah Leviton Gorelick Joshua Casaos Arba Cecia Antonella Mangraviti Charles Eberhart Renyuan Bai Alessandro Olivi Henry Brem Eric M. Jackson Betty Tyler Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model
description	<h4>Background</h4> Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models. <h4>Methods</h4> The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting. <h4>Results</h4> Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo. <h4>Conclusions</h4> Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.
format	article
author	Riccardo Serra Tianna Zhao Sakibul Huq Noah Leviton Gorelick Joshua Casaos Arba Cecia Antonella Mangraviti Charles Eberhart Renyuan Bai Alessandro Olivi Henry Brem Eric M. Jackson Betty Tyler
author_facet	Riccardo Serra Tianna Zhao Sakibul Huq Noah Leviton Gorelick Joshua Casaos Arba Cecia Antonella Mangraviti Charles Eberhart Renyuan Bai Alessandro Olivi Henry Brem Eric M. Jackson Betty Tyler
author_sort	Riccardo Serra
title	Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model
title_short	Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model
title_full	Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model
title_fullStr	Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model
title_full_unstemmed	Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model
title_sort	disulfiram and copper combination therapy targets npl4, cancer stem cells and extends survival in a medulloblastoma model
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/f8cb841dda8541a1b7d69527798e1470
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Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model

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