Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Feb;40(1):21-32.
doi: 10.1007/s13402-016-0301-9. Epub 2016 Oct 20.

Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine

Mikkel Staberg  1 , Signe Regner Michaelsen  2 , Rikke Darling Rasmussen  3 , Mette Villingshøj  2 , Hans Skovgaard Poulsen  2 , Petra Hamerlik  4
Affiliations

Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine

Mikkel Staberg et al. Cell Oncol (Dordr). 2017 Feb.

Abstract

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.

Keywords: Epigenetics; Glioblastoma; HDACi; Lomustine; Sensitization; Trichostatin A.

PubMed Disclaimer

References

    1. Cell Oncol (Dordr). 2015 Oct;38(5):341-52 - PubMed
    1. J Clin Oncol. 2010 Mar 1;28(7):1168-74 - PubMed
    1. Cell Oncol (Dordr). 2015 Jun;38(3):183-94 - PubMed
    1. Curr Neurol Neurosci Rep. 2016 Feb;16(2):13 - PubMed
    1. Br J Cancer. 2008 Feb 12;98(3):604-10 - PubMed

MeSH terms