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The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

Abstract

Glioblastoma multiforme (GBM) has nearly uniformly fatal with a median survival of less than 2 years. While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients. This pre-clinical study aimed to determine the potential clinical utility of VPA in the treatment of GBM. Primary GBM cells were treated with VPA as a monotherapy and in combination with temozolomide and irradiation. At clinically achievable concentrations, VPA was shown to be effective as a monotherapy agent in the five primary lines tested. VPA was then used as a sensitizing agent to in vitro radiation and showed significant augmentation of in vitro irradiation therapy. In addition, when VPA, radiation and temozolomide were combined an additive, rather than synergistic effect was noted. Gene expression profiling demonstrated close clustering of triple treated cells with VPA mono-treated cells while untreated cells clustered closer with TMZ-irradiation dual treated cells. These microarray data suggest a dominant role of VPA at the gene expression level when combining these different treatment options. Moreover, in an in vivo tumor transplantation model, we were able to demonstrate an increase in animal survival when cells were pre-treated with irradiation-VPA and when triple treated. These findings provide a significant rationale for the investigation of VPA in the treatment of GBM patients.

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Acknowledgements

RBWH Department of Neurosurgery, RBWH patients with GBM consenting for brain cancer research on resected tissue, Rotary Rockhampton, RBWH Division of Cancer Care and RBWH Foundation for funding the brain biobank at QIMR. Experiments were approved by the human ethics committee of the Queensland Institute of Medical Research (QIMR) and Royal Brisbane and Women’s Hospital (RBWH).

Conflict of interest

Authors have no conficts of interest to declare.

Funding

Royal Brisbane and Women’s Hospital Foundation, Rotary Rockhampton, Cancer Council Queensland.

Author information

Correspondence to Jennifer H. Martin.

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Hosein, A.N., Lim, Y.C., Day, B. et al. The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells. J Neurooncol 122, 263–271 (2015). https://doi.org/10.1007/s11060-014-1713-x

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Keywords

  • Glioblastoma
  • Valproic acid
  • Radiosensitisation