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Cited by 16Glioma Diagnosis and TreatmentCancer Cells and MetastasisCancer, Hypoxia, and Metabolism

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

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Zirjacks, Lisa, Stransky, Nicolai, Klumpp, Lukas, Prause, Lukas, Eckert, Franziska, Zips, Daniel, Schleicher, Sabine, Handgretinger, Rupert +2 more·2021·Biomolecules
DOI 10.3390/biom11111561PMC PMC8615869
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Abstract

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 Cu2+ 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 CuSO4, 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.

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Authors
Zirjacks, L., Stransky, N., Klumpp, L., Prause, L., Eckert, F., Zips, D., Schleicher, S., Handgretinger, R., Huber, S. M., & Ganser, K.
Affiliations
  • University of Tübingen (DE)
  • University Children's Hospital Tübingen (DE)
Corresponding author
Huber, Stephan M.
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2021-10-21
Volume
11
Issue
11
Pages
1561
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom11111561
PMC
PMC8615869
OpenAlex
W3206851120
Cited by
16
References
75
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 1
FWCI
1.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
German Cancer Aid (70112872, 70113144)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
disulfiram, glioblastoma stem cells, ALDH1A3, copper sulfate, temozolomide, radiosensitization, clonogenic survival, cell cycle distribution, drug repurposing, mesenchymal glioblastoma, combination therapy
MeSH terms
Temozolomide, Aldehyde Oxidoreductases, Brain Neoplasms, Cell Survival, Disulfiram, Glioblastoma, Humans, Neoplastic Stem Cells, Drug Repositioning

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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