Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine
Open accessAbstract
PURPOSE: Glioblastoma (GBM) ranks among the deadliest solid cancers worldwide and its prognosis has remained dismal, despite the use of aggressive chemo-irradiation treatment regimens. Limited drug delivery into the brain parenchyma and frequent resistance to currently available therapies are problems that call for a prompt development of novel therapeutic strategies. While only displaying modest efficacies as mono-therapy in pre-clinical settings, histone deacetylase inhibitors (HDACi) have shown promising sensitizing effects to a number of cytotoxic agents. Here, we sought to investigate the sensitizing effect of the HDACi trichostatin A (TSA) to the alkylating agent lomustine (CCNU), which is used in the clinic for the treatment of GBM. METHODS: Twelve primary GBM cell cultures grown as neurospheres were used in this study, as well as one established GBM-derived cell line (U87 MG). Histone deacetylase (HDAC) expression levels were determined using quantitative real-time PCR and Western blotting. The efficacy of either CCNU alone or its combination with TSA was assessed using various assays, i.e., cell viability assays (MTT), cell cycle assays (flow cytometry, FACS), double-strand DNA break (DSB) quantification assays (microscopy/immunofluorescence) and expression profiling assays of proteins involved in apoptosis and cell stress (Western blotting and protein array). RESULTS: We found that the HDAC1, 3 and 6 expression levels were significantly increased in GBM samples compared to non-neoplastic brain control samples. Additionally, we found that pre-treatment of GBM cells with TSA resulted in an enhancement of their sensitivity to CCNU, possibly via the accumulation of DSBs, decreased cell proliferation and viability rates, and an increased apoptotic rate. CONCLUSION: From our data we conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM.
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HDAC inhibitor CCNU has been shown to sensitize adult glioblastoma to chemotherapy with lomustine via degradation of mut-p53.
“Furthermore, HDAC inhibitor CCNU has been shown to sensitize adult GBM to chemotherapy with lomustine via degradation of mut-p53 [139]”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [139]
The Introduction and Discussion (page numbers unavailable) report that combining the HDAC inhibitor TSA with lomustine (CCNU) improved outcomes in GBM cells compared with either drug alone. The claim incorrectly calls CCNU an HDAC inhibitor; the paper identifies it as a DNA alkylator. The Discussion points to impaired DNA repair and increased apoptosis, not degradation of mutant p53, and the findings are in cells rather than demonstrated treatment of adults. (LLM, conf=0.88)
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- Authors
- Staberg, M., Michaelsen, S. R., Rasmussen, R. D., Villingshøj, M., Poulsen, H. S., & Hamerlik, P.
- Affiliations
- Rigshospitalet (DK)
- Danish Cancer Society (DK)
- Corresponding author
- Staberg, Mikkel
- Hamerlik, Petra
- Venue
- Cellular Oncology
- Published
- 2016-10-20
- Volume
- 40
- Issue
- 1
- Pages
- 21-32
- ISSN
- 1570-5870 (ISSN-L)
- 2211-3428
- 2211-3436
- OpenAlex
- W2539154075
- Cited by
- 62
- References
- 55
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 8 · 2018: 11 · 2017: 6
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular Oncology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Dansk Kræftforsknings Fond
- Kræftens Bekæmpelse
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- glioblastoma, histone deacetylase inhibitors, trichostatin A, lomustine, drug sensitization, combination therapy, HDAC1, HDAC3, HDAC6, DNA double-strand breaks, apoptosis, alkylating agents, neurospheres, U87 cells
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Brain Neoplasms, Cell Cycle, Cell Survival, Flow Cytometry, Fluorescent Antibody Technique, Glioblastoma, Humans, Hydroxamic Acids, Lomustine, Blotting, Western, Antineoplastic Agents, Alkylating, Cell Line, Tumor, Histone Deacetylase Inhibitors, Real-Time Polymerase Chain Reaction
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