Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study

Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly presc...

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Autores principales:	Lisa Zirjacks, Nicolai Stransky, Lukas Klumpp, Lukas Prause, Franziska Eckert, Daniel Zips, Sabine Schleicher, Rupert Handgretinger, Stephan M. Huber, Katrin Ganser
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	brain tumor primary spheroid culture tumor-initiating cells propidium iodide Nicoletti staining survival fraction Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b762c8c38f64496dbf25ca231191fa66
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spelling	oai:doaj.org-article:b762c8c38f64496dbf25ca231191fa662021-11-25T16:51:52ZRepurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study10.3390/biom111115612218-273Xhttps://doaj.org/article/b762c8c38f64496dbf25ca231191fa662021-10-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1561https://doaj.org/toc/2218-273XMesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu<sup>2+</sup> ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO<sub>4</sub>, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0–8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.Lisa ZirjacksNicolai StranskyLukas KlumppLukas PrauseFranziska EckertDaniel ZipsSabine SchleicherRupert HandgretingerStephan M. HuberKatrin GanserMDPI AGarticlebrain tumorprimary spheroid culturetumor-initiating cellspropidium iodideNicoletti stainingsurvival fractionMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1561, p 1561 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	brain tumor primary spheroid culture tumor-initiating cells propidium iodide Nicoletti staining survival fraction Microbiology QR1-502
spellingShingle	brain tumor primary spheroid culture tumor-initiating cells propidium iodide Nicoletti staining survival fraction Microbiology QR1-502 Lisa Zirjacks Nicolai Stransky Lukas Klumpp Lukas Prause Franziska Eckert Daniel Zips Sabine Schleicher Rupert Handgretinger Stephan M. Huber Katrin Ganser Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
description	Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu<sup>2+</sup> ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO<sub>4</sub>, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0–8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.
format	article
author	Lisa Zirjacks Nicolai Stransky Lukas Klumpp Lukas Prause Franziska Eckert Daniel Zips Sabine Schleicher Rupert Handgretinger Stephan M. Huber Katrin Ganser
author_facet	Lisa Zirjacks Nicolai Stransky Lukas Klumpp Lukas Prause Franziska Eckert Daniel Zips Sabine Schleicher Rupert Handgretinger Stephan M. Huber Katrin Ganser
author_sort	Lisa Zirjacks
title	Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
title_short	Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
title_full	Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
title_fullStr	Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
title_full_unstemmed	Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
title_sort	repurposing disulfiram for targeting of glioblastoma stem cells: an in vitro study
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b762c8c38f64496dbf25ca231191fa66
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Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study

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