Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro

Koh, HyeJung; Seo, Soo Yeon; Kim, Jin Ho; Kim, Hak Jae; Chie, Eui Kyu; Kim, Seung Ki; Kim, Il Han

doi:10.4143/crt.2018.249

Cited by 20 publications

(24 citation statements)

References 31 publications

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“…Likewise, our present study did not identify any radiosensitization of both glioblastoma stem-cell cultures by disulfiram/Cu 2+ . This is in seeming contrast to previous studies that show a disulfiram/Cu 2+ -mediated radiosensitization in patient-derived spheroid glioblastoma stem (brain-tumor-initiating) cells [12] and human glioblastoma cell lines [58]. Notably, in the latter study, only one (U138MG) and in tendency also a second (T98G) out of five glioblastoma lines were radiosensitized by disulfiram (75-100 nM) when grown in Cu 2+ -containing serum-supplemented medium and when using clonogenic survival as the endpoint [58].…”

Section: Disulfiram As a Radiosensitizercontrasting

confidence: 97%

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

et al. 2021

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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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Section: Disulfiram As a Radiosensitizercontrasting

confidence: 97%

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

et al. 2021

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“…As expected, it was reported that the percentage of γH2AX-positive cells after irradiation decreased rapidly in T98G cells. In contrast, the proportion of γH2AX-positive cells after irradiation sustained until 24 h in U373 [ 33 ]. For this reason, while U373 cell was regarded as temozolomide-sensitive cell, T98G cell was known to be relatively resistant to temozolomide [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Antioxidant and Antiproliferative Activity of Finasteride against Glioblastoma Cells

Kim

et al. 2021

Pharmaceutics

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Glioblastoma is an actively growing and aggressive brain tumor with a high propensity of recurrence. Although the surgical removal of tumor mass is the primary therapeutic option against glioblastoma, supportive pharmacotherapy is highly essential due to incredibly infiltrative characteristic of glioblastoma. Temozolomide, an FDA-approved alkylating agent, has been used as a first-line standard pharmacological approach, but several evident limitations were repeatedly reported. Despite additional therapeutic options suggested, there are no medications that successfully prevent a recurrence of glioblastoma and increase the five-year survival rate. In this study, we tested the possibility that finasteride has the potential to be developed as an anti-glioblastoma drug. Finasteride, an FDA-approved medication for the treatment of benign prostate hyperplasia and androgenic alopecia, is already known to pass through the blood–brain barrier and possess antiproliferative activity of prostate epithelial cells. We showed that finasteride inhibited the maintenance of glioma stem-like cells and repressed the proliferation of glioblastoma. Mechanistically, finasteride lowered intracellular ROS level by upregulating antioxidant genes, which contributed to inefficient β-catenin accumulation. Downregulated β-catenin resulted in the reduction in stemness and cell growth in glioblastoma.

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“…Since GBM is considered as a radioresistant tumor [3] and most of the recurrence occurs in the radiotherapy field [4], radiosensitization of the tumor is an important target to improve the outcome in patients with GBM. Therefore, multiple radiosensitizing strategies are actively under development, including PI3K pathway inhibitors [5], DNA repair inhibitors [6], hyperthermia [7], aldehyde dehydrogenase inhibitors [8], and high atomic number (high-Z) metal nanoparticles (NPs) [9].…”

Section: Introductionmentioning

confidence: 99%

Radiosensitizing high-Z metal nanoparticles for enhanced radiotherapy of glioblastoma multiforme

et al. 2020

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Radiotherapy is an essential step during the treatment of glioblastoma multiforme (GBM), one of the most lethal malignancies. The survival in patients with GBM was improved by the current standard of care for GBM established in 2005 but has stagnated since then. Since GBM is a radioresistant malignancy and the most of GBM recurrences occur in the radiotherapy field, increasing the effectiveness of radiotherapy using high-Z metal nanoparticles (NPs) has recently attracted attention. This review summarizes the progress in radiotherapy approaches for the current treatment of GBM, the physical and biological mechanisms of radiosensitization through high-Z metal NPs, and the results of studies on radiosensitization in the in vitro and in vivo GBM models using high-Z metal NPs to date.

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Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro

Cited by 20 publications

References 31 publications

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

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

Antioxidant and Antiproliferative Activity of Finasteride against Glioblastoma Cells

Radiosensitizing high-Z metal nanoparticles for enhanced radiotherapy of glioblastoma multiforme

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