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01.03.2012 | Laboratory Investigation-Human/Animal Tissue

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

verfasst von: Krista A. Van Nifterik, Jaap Van den Berg, Ben J. Slotman, M. Vincent M. Lafleur, Peter Sminia, Lukas J. A. Stalpers

Erschienen in: Journal of Neuro-Oncology | Ausgabe 1/2012

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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.

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Titel: Valproic acid sensitizes human glioma cells for temozolomide and γ-radiation
verfasst von: Krista A. Van Nifterik
Jaap Van den Berg
Ben J. Slotman
M. Vincent M. Lafleur
Peter Sminia
Lukas J. A. Stalpers
Publikationsdatum: 01.03.2012
Verlag: Springer US
Erschienen in: Journal of Neuro-Oncology / Ausgabe 1/2012
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-011-0725-z

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