TY - JOUR
T1 - Valproic acid sensitizes human glioma cells for temozolomide and gamma-radiation
AU - van Nifterik, Krista A.
AU - van den Berg, Jaap
AU - Slotman, Ben J.
AU - Lafleur, M. Vincent M.
AU - Sminia, Peter
AU - Stalpers, Lukas J. A.
AU - van der Berg, J..
PY - 2012
Y1 - 2012
N2 - 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 O-6-methylguanine-DNA-methyltransferase (MGMT) protein, causing resistance to TMZ and thereby antagonizing its effect. Therefore, this study investigates the interaction between VPA, TMZ, and gamma-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 gamma-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 gamma-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 gamma-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
AB - 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 O-6-methylguanine-DNA-methyltransferase (MGMT) protein, causing resistance to TMZ and thereby antagonizing its effect. Therefore, this study investigates the interaction between VPA, TMZ, and gamma-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 gamma-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 gamma-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 gamma-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
U2 - https://doi.org/10.1007/s11060-011-0725-z
DO - https://doi.org/10.1007/s11060-011-0725-z
M3 - Article
C2 - 22037799
SN - 0167-594X
VL - 107
SP - 61
EP - 67
JO - Journal of neuro-oncology
JF - Journal of neuro-oncology
IS - 1
ER -