Actinomycin D downregulates Sox2 and improves survival in preclinical models of recurrent glioblastoma
| Autor: | Helen Parker, Alina Pandele, Gabriella Forte, Alan J. Dickson, Jessica T. Taylor, Kaye J. Williams, Shaun Wood, Catherine McBain, Martin G. McCabe, Erica Nathan, Stuart M. Ellison, Egor Zindy, Konstantina Karabatsou, Brian W. Bigger, Mark Elvin |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Population Cell Biology glioblastoma multiforme SOX2 Cancer stem cell Glioma medicine AcademicSubjects/MED00300 education preclinical studies education.field_of_study Dactinomycin drug repurposing Sciences bio-médicales et agricoles medicine.disease medicine.anatomical_structure Oncology Tumor progression Basic and Translational Investigations Cancer research actinomycin D AcademicSubjects/MED00310 Neurology (clinical) Stem cell Sciences exactes et naturelles medicine.drug high throughput screening |
| Zdroj: | Neuro-Oncology Taylor, J T, Ellison, S, Pandele, A, Wood, S, Nathan, E, Forte, G, Parker, H, Zindy, E, Elvin, M, Dickson, A, Williams, K J, Karabatsou, K, McCabe, M, McBain, C & Bigger, B W 2020, ' Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma ', Neuro-Oncology, vol. 22, no. 9, pp. 1289-1301 . https://doi.org/10.1093/neuonc/noaa051 Neuro-oncology, 22 (9 |
| ISSN: | 1523-5866 1522-8517 |
| Popis: | Background Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multimodal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high-throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified actinomycin D (ACTD) to be highly cytotoxic over a panel of 12 patient-derived glioma stemlike cell (GSC) lines. ACTD is an antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for GBM in 3-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma. Methods Twelve patient-derived GSC lines were screened at 10 µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established half-maximal inhibitory concentrations (IC50). Downregulation of sex determining region Y–box 2 (Sox2), a stem cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue. Results Treatment with ACTD was shown to significantly reduce tumor growth in 2 recurrent GBM patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo. Conclusion These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression. Key Points 1. High-throughput chemosensitivity data demonstrated the broad efficacy of actinomycin D, which was validated in 3 preclinical models of glioblastoma. 2. Actinomycin D downregulated Sox2 in vitro and in vivo, indicating that this agent could target the stem cell population of GBM tumors. info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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