Histone deacetylase inhibitor, valproic acid, radiosensitizes the C6 glioma cell line in vitro

Abstract

Valproic acid (VPA) is a well-tolerated drug that is used to treat seizure disorders and that has recently been shown to inhibit histone deacetylase. The present study investigated the effects of VPA on the radiosensitization of the rat C6 glioma cell line in vitro. To select an appropriate treatment concentration and time, MTT and flow cytometry assays were performed to measure the inhibitory effects of VPA at various concentrations and incubation time-points. The radiosensitizing effect of VPA was determined using clonogenic experiments. VPA- and radiation-induced C6 apoptosis was analyzed using quantitative polymerase chain reaction and western blot analysis. Cell proliferation was significantly inhibited by VPA in a time- and dose-dependent manner (P<0.05). VPA enhanced radiation-induced C6 cell death and there was clear inhibition of clonogenic formation [sensitizer enhancement ratio (SER), 1.30]. This effect was closely associated with the concentration of VPA. VPA treatment decreased the mRNA and protein levels of Bcl-2, whereas increased changes were detected with Bax. At a concentration of 0.5 mmol/l, VPA had a low toxicity and enhanced the radiosensitization of the C6 cells. VPA may radiosensitize glioma cells by inhibiting cellular proliferation and inducing apoptosis by regulating apoptosis-related molecular changes.

Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage

“…Their radio-protective effects have also previously been associated with reduced apoptosis (26). On the other hand VA has a radio-sensitizing effect on cancer cells through apoptosis induction (27). Our data on the radio-protective effect of VA are consistent with previous studies.…”

Assessment of Interactions between Cisplatin and Two Histone Deacetylase Inhibitors in MCF7, T47D and MDA-MB-231 Human Breast Cancer Cell Lines – An Isobolographic Analysis

“…Thereby, reintroduction of p21 expression, together with inhibition of cyclin D1 could be regarded as a more universal mechanism of VPA action on cancer cells. Several studies demonstrated that VPA can decrease activity/expression of proteins necessary for cancer progression, including anti-apoptotic protein survivin in neuroblastoma cells [ 23 ] or Bcl-2 on the mRNA and protein levels of in C6 glioma cells [ 24 ]. VPA could down-regulate of SMAD4, which resulted in reduced prostate cancer cell invasiveness probably trough the inhibition of the epithelial-mesenchymal transition [ 25 ].…”

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

“…Through this HDAC inhibitor function, VPA has been shown to be cytotoxic and proapoptotic in cancer cells, particularly in regards to glioma [19][20][21]. It is also structurally similar to butyrate, a known apoptotic agent [22].…”