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

Zirjacks, Lisa; Stransky, Nicolai; Klumpp, Lukas; Prause, Lukas; Eckert, Franziska; Zips, Daniel; Schleicher, Sabine; Handgretinger, Rupert; Huber, Stephan M.; Ganser, Katrin

doi:10.3390/biom11111561

Cited by 10 publications

(21 citation statements)

References 71 publications

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“…Further, we analyzed the differentially upregulated or downregulated genes of the above two kinds of cells, and the results showed that 201 genes were downregulated and 78 genes were upregulated (including ALDH1A3 ) ( Figure 4 B). Studies have shown that ALDH1A3 plays an important role in the mesenchymal differentiation and malignant progression of GBM cells [ 43 , 44 , 45 , 46 ]. Our previous studies showed that ALDH1A3 is one of the key metabolic enzymes involved in the occurrence and development of GBM [ 25 , 27 , 47 ].…”

Section: Resultsmentioning

confidence: 99%

EGFRvIII Promotes the Proneural–Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis

Shi

Zhai

et al. 2023

Genes

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(1) Background: Glioblastoma multiforme (GBM) is the most common and malignant intracranial tumor in adults. At present, temozolomide (TMZ) is recognized as the preferred chemotherapeutic drug for GBM, but some patients have low sensitivity to TMZ or chemotherapy resistance to TMZ. Our previous study found that GBM patients with EGFRvIII (+) have low sensitivity to TMZ. However, the reasons and possible mechanisms of the chemoradiotherapy resistance in GBM patients with EGFRvIII (+) are not clear. (2) Methods: In this study, tissue samples of patients with GBM, GBM cell lines, glioma stem cell lines, and NSG mice were used to explore the causes and possible mechanisms of low sensitivity to TMZ in patients with EGFRvIII (+)-GBM. (3) Results: The study found that EGFRvIII promoted the proneural–mesenchymal transition of GBM and reduced its sensitivity to TMZ, and EGFRvIII regulated of the expression of ALDH1A3. (4) Conclusions: EGFRvIII activated the NF-κB pathway and further regulated the expression of ALDH1A3 to promote the proneural–mesenchymal transition of GBM and reduce its sensitivity to TMZ, which will provide an experimental basis for the selection of clinical drugs for GBM patients with EGFRvIII (+).

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Section: Resultsmentioning

confidence: 99%

EGFRvIII Promotes the Proneural–Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis

Shi

Zhai

et al. 2023

Genes

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“…We were not able to translate the numerous encouraging preclinical results to the clinical setting . Several studies have indicated a synergistic effect between temozolomide (or other alkylating agents) and disulfiram, although 1 study found that temozolomide somehow antagonized the effects of disulfiram . It has been suggested that disulfiram-copper induce MGMT inhibition, but also increased replication stress and DNA damage, hence there are arguments that SOC plus disulfiram and copper could potentiate treatment effects, both for patients with unmethylated and with hypermethylated MGMT promoter .…”

Section: Discussionmentioning

confidence: 96%

“… 4 , 8 , 13 , 14 , 15 , 16 Several studies have indicated a synergistic effect between temozolomide (or other alkylating agents) and disulfiram, 8 , 16 , 33 although 1 study found that temozolomide somehow antagonized the effects of disulfiram. 34 It has been suggested that disulfiram-copper induce MGMT inhibition, but also increased replication stress and DNA damage, hence there are arguments that SOC plus disulfiram and copper could potentiate treatment effects, both for patients with unmethylated and with hypermethylated MGMT promoter. 8 , 16 , 19 , 35 The complete lack of positive signal in our trial indicate that this has no clinical relevance in patients with recurrent GB.…”

Section: Discussionmentioning

confidence: 99%

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

et al. 2023

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ImportanceDisulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.ObjectiveTo evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.Design, Setting, and ParticipantsThis was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.InterventionsPatients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).Main Outcomes and MeasuresThe primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.ResultsAmong the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.Conclusions and RelevanceThis randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

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“…In recent study, drugs related to cuproptosis can also be used to the treatment of tumors. Disulfiram, a copper ionophore, targeted glioblastoma stem cells ( 87 ). Elesclomol can targeted treatment of melanoma ( 88 ).…”

Section: Discussionmentioning

confidence: 99%

ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer

Zhu

Chen

Han³

et al. 2023

Front. Oncol.

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Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren’s histological classification. Integrin β1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC.

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

Cited by 10 publications

References 71 publications

EGFRvIII Promotes the Proneural–Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis

EGFRvIII Promotes the Proneural–Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer

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