Journal of Neuro-Oncology

, Volume 107, Issue 1, pp 61–67 | Cite as

Valproic acid sensitizes human glioma cells for temozolomide and γ-radiation

  • Krista A. Van Nifterik
  • Jaap Van den Berg
  • Ben J. Slotman
  • M. Vincent M. Lafleur
  • Peter SminiaEmail author
  • Lukas J. A. Stalpers
Laboratory Investigation-Human/Animal Tissue


Temozolomide (TMZ) is given in addition to radiotherapy in glioma patients, but its interaction with the commonly prescribed antiepileptic drug valproic acid (VPA) is largely unknown. Induction of DNA demethylation by VPA could potentially induce expression of the O6-methylguanine-DNA-methyltransferase (MGMT) protein, causing resistance to TMZ and thereby antagonizing its effect. Therefore, this study investigates the interaction between VPA, TMZ, and γ-radiation. Two glioma cell lines were used that differ in TMZ sensitivity caused by the absence (D384) or presence (T98) of the MGMT protein. VPA was administered before (24/48 h) or after (24 h) single doses of γ-radiation; or, after 24 h, VPA treatment was accompanied by a single dose of TMZ for another 24 h. For trimodal treatment the combination of VPA and TMZ was followed by single doses of γ-radiation. In both cell lines VPA caused enhancement of the radiation response after preincubation (DMF0.2 1.4 and 1.5) but not after postirradiation (DMF0.2 1.1 and 1.0). The combination of VPA and TMZ caused enhanced cytotoxicity (DMF0.2 1.7) in both the TMZ-sensitive cell line (D384) and the TMZ-resistant cell line (T98). The combination of VPA and TMZ caused a significant radiation enhancement (DMF0.2 1.9 and 1.6) that was slightly more effective than that of VPA alone. VPA does not antagonize the cytotoxic effects of TMZ. Preincubation with VPA enhances the effect of both γ-radiation and TMZ, in both a TMZ-sensitive and a TMZ-resistant human glioma cell line. VPA combined with TMZ may lead to further enhancement of the radiation response.


Trimodal treatment γ-Radiation Temozolomide Valproic acid Glioma cells 



TMZ was a generous gift from Schering-Plough RS. This work was supported by the Dutch Cancer Society (grant no. VU 2000-2149).


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Krista A. Van Nifterik
    • 1
  • Jaap Van den Berg
    • 1
  • Ben J. Slotman
    • 1
  • M. Vincent M. Lafleur
    • 1
  • Peter Sminia
    • 1
    Email author
  • Lukas J. A. Stalpers
    • 2
  1. 1.Department of Radiation OncologyVU University Medical CenterAmsterdamThe Netherlands
  2. 2.Department of RadiotherapyAcademic Medical CenterAmsterdamThe Netherlands

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