Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model
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 hu...
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| Veröffentlicht in: | PloS one 2021-11, Vol.16 (11), p.e0251957-e0251957 |
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| creator | Serra, Riccardo Zhao, Tianna Huq, Sakibul Gorelick, Noah Leviton Casaos, Joshua Cecia, Arba Mangraviti, Antonella Eberhart, Charles Bai, Renyuan Olivi, Alessandro Brem, Henry Jackson, Eric M Tyler, Betty |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0251957 |
| format | Article |
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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.
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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0251957</identifier><identifier>PMID: 34731160</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aldehyde Dehydrogenase - metabolism ; Aldehydes ; Animals ; Apoptosis ; Apoptosis - drug effects ; Biocompatibility ; Biology and Life Sciences ; Brain cancer ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Brain research ; Brain tumors ; Cancer ; Cancer therapies ; Care and treatment ; Caspase-3 ; Cell Cycle - drug effects ; Cell death ; Cell Proliferation - drug effects ; Cell survival ; Combination therapy ; Copper ; Copper - pharmacology ; Cytometry ; Cytotoxicity ; Dehydrogenases ; Deoxyribonucleic acid ; Diagnosis ; Disulfiram ; Disulfiram - pharmacology ; DNA ; DNA damage ; Glial fibrillary acidic protein ; Health aspects ; Immunofluorescence ; Immunohistochemistry ; Laboratories ; Localization ; Medical prognosis ; Medicine ; Medicine and Health Sciences ; Medulloblastoma ; Medulloblastoma - metabolism ; Medulloblastoma - pathology ; Molecular modelling ; Morbidity ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Nestin ; Neurosurgery ; Nuclear safety ; Pediatrics ; Proteins ; Radiation ; Research funding ; Stem cells ; Survival ; Toxicity ; Tumors ; Xenografts ; Xenotransplantation</subject><ispartof>PloS one, 2021-11, Vol.16 (11), p.e0251957-e0251957</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Serra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Serra et al 2021 Serra et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c743t-56fd6788bf292e7866e1e0c10f45d5b490002e87e843be95636d63ed6c73448b3</citedby><cites>FETCH-LOGICAL-c743t-56fd6788bf292e7866e1e0c10f45d5b490002e87e843be95636d63ed6c73448b3</cites><orcidid>0000-0002-1975-393X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565761/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565761/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34731160$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ulasov, Ilya</contributor><creatorcontrib>Serra, Riccardo</creatorcontrib><creatorcontrib>Zhao, Tianna</creatorcontrib><creatorcontrib>Huq, Sakibul</creatorcontrib><creatorcontrib>Gorelick, Noah Leviton</creatorcontrib><creatorcontrib>Casaos, Joshua</creatorcontrib><creatorcontrib>Cecia, Arba</creatorcontrib><creatorcontrib>Mangraviti, Antonella</creatorcontrib><creatorcontrib>Eberhart, Charles</creatorcontrib><creatorcontrib>Bai, Renyuan</creatorcontrib><creatorcontrib>Olivi, Alessandro</creatorcontrib><creatorcontrib>Brem, Henry</creatorcontrib><creatorcontrib>Jackson, Eric M</creatorcontrib><creatorcontrib>Tyler, Betty</creatorcontrib><title>Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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.
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.</description><subject>Aldehyde Dehydrogenase - metabolism</subject><subject>Aldehydes</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biocompatibility</subject><subject>Biology and Life Sciences</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain research</subject><subject>Brain tumors</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Caspase-3</subject><subject>Cell Cycle - drug effects</subject><subject>Cell death</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell survival</subject><subject>Combination therapy</subject><subject>Copper</subject><subject>Copper - pharmacology</subject><subject>Cytometry</subject><subject>Cytotoxicity</subject><subject>Dehydrogenases</subject><subject>Deoxyribonucleic acid</subject><subject>Diagnosis</subject><subject>Disulfiram</subject><subject>Disulfiram - pharmacology</subject><subject>DNA</subject><subject>DNA damage</subject><subject>Glial fibrillary acidic protein</subject><subject>Health aspects</subject><subject>Immunofluorescence</subject><subject>Immunohistochemistry</subject><subject>Laboratories</subject><subject>Localization</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Medulloblastoma</subject><subject>Medulloblastoma - metabolism</subject><subject>Medulloblastoma - pathology</subject><subject>Molecular modelling</subject><subject>Morbidity</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Serra, Riccardo</au><au>Zhao, Tianna</au><au>Huq, Sakibul</au><au>Gorelick, Noah Leviton</au><au>Casaos, Joshua</au><au>Cecia, Arba</au><au>Mangraviti, Antonella</au><au>Eberhart, Charles</au><au>Bai, Renyuan</au><au>Olivi, Alessandro</au><au>Brem, Henry</au><au>Jackson, Eric M</au><au>Tyler, Betty</au><au>Ulasov, Ilya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2021-11-03</date><risdate>2021</risdate><volume>16</volume><issue>11</issue><spage>e0251957</spage><epage>e0251957</epage><pages>e0251957-e0251957</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34731160</pmid><doi>10.1371/journal.pone.0251957</doi><tpages>e0251957</tpages><orcidid>https://orcid.org/0000-0002-1975-393X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-11, Vol.16 (11), p.e0251957-e0251957 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2593006171 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Aldehyde Dehydrogenase - metabolism Aldehydes Animals Apoptosis Apoptosis - drug effects Biocompatibility Biology and Life Sciences Brain cancer Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain research Brain tumors Cancer Cancer therapies Care and treatment Caspase-3 Cell Cycle - drug effects Cell death Cell Proliferation - drug effects Cell survival Combination therapy Copper Copper - pharmacology Cytometry Cytotoxicity Dehydrogenases Deoxyribonucleic acid Diagnosis Disulfiram Disulfiram - pharmacology DNA DNA damage Glial fibrillary acidic protein Health aspects Immunofluorescence Immunohistochemistry Laboratories Localization Medical prognosis Medicine Medicine and Health Sciences Medulloblastoma Medulloblastoma - metabolism Medulloblastoma - pathology Molecular modelling Morbidity Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Nestin Neurosurgery Nuclear safety Pediatrics Proteins Radiation Research funding Stem cells Survival Toxicity Tumors Xenografts Xenotransplantation |
| title | Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T18%3A03%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Disulfiram%20and%20copper%20combination%20therapy%20targets%20NPL4,%20cancer%20stem%20cells%20and%20extends%20survival%20in%20a%20medulloblastoma%20model&rft.jtitle=PloS%20one&rft.au=Serra,%20Riccardo&rft.date=2021-11-03&rft.volume=16&rft.issue=11&rft.spage=e0251957&rft.epage=e0251957&rft.pages=e0251957-e0251957&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0251957&rft_dat=%3Cgale_plos_%3EA681151566%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2593006171&rft_id=info:pmid/34731160&rft_galeid=A681151566&rft_doaj_id=oai_doaj_org_article_e05e4fd3bbde45adb82280054e4266fb&rfr_iscdi=true |