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

Sunday, October 30, 2011

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

Abstract

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 (DMF_0.2 1.4 and 1.5) but not after postirradiation (DMF_0.2 1.1 and 1.0). The combination of VPA and TMZ caused enhanced cytotoxicity (DMF_0.2 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 (DMF_0.2 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.

Content Type Journal Article
Category Laboratory Investigation-Human/Animal Tissue
Pages 1-7
DOI 10.1007/s11060-011-0725-z
Authors
- Krista A. Van Nifterik, Department of Radiation Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
- Jaap Van den Berg, Department of Radiation Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
- Ben J. Slotman, Department of Radiation Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
- M. Vincent M. Lafleur, Department of Radiation Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
- Peter Sminia, Department of Radiation Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
- Lukas J. A. Stalpers, Department of Radiotherapy, Academic Medical Center, Amsterdam, The Netherlands