Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma

Abstract

Abstract. Histone deacetylase (HDAC) inhibitors have been shown to enhance radiation response in various cancer cell lines. Valproic acid (VPA) has been used in clinical practice for the treatment of epilepsy and other seizure disorders and is also one of the most represented HDAC inhibitors. The aim of this study was to evaluate the radiosensitizing ability of VPA and its mechanisms in four esophageal squamous cell carcinoma (ESCC) cell lines (TE9, TE10, TE11 and TE14). VPA inhibited the viability of all ESCC cells in a dose-dependent manner. The 50% inhibitory concentration (IC 50 ) value of VPA in each cell line was between 1.02-2.15 mM, which is higher than clinically used safe concentrations. VPA induced the hyperacetylation of histones H3 and H4, as well as apoptosis and had a radiosensitizing effect on all four ESCC cell lines at a concentration of 0.5 mM which is equivalent to the therapeutic plasma concentration of anti-epilepsy therapy in humans. The radiosensitization was accompanied by an increase in γH2AX levels, indicating the presence of double-strand breaks (DSBs), and decrease in Rad51 expression, a DSB repair protein. These results suggest that a clinically safe dose of VPA can enhance radiation-induced cytotoxicity in human ESCC cells by chromatin decondensation with histone hyperacetylation and downregulation of Rad51. In conclusion, VPA appears to be a safe and promising radiosensitizer for esophageal cancer radiotherapy.

Altered intrinsic brain activity in patients with familial cortical myoclonic tremor and epilepsy: An amplitude of low-frequency fluctuation study

“…In addition, it is worth noting that a lessening of tremulous movements and a decrease in the number of seizures were found in three FCMTE patients after treatment with VPA and CBZ. These anti-epileptic drugs (AEDs) could raise the inhibitory neurotransmitter (e.g., GABA) concentrations by increasing GABA synthesis and decreasing GABA degradation, thus reducing the excitability of neurons and inhibiting seizures [28]. Here, this result is in line with the view that some AEDs (especially VBA and clonazepam) could improve the tremulous movements and lessen the number of seizures [4,7,8].…”

Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells

“…Therapeutic plasma concentrations used clinically for epilepsy treatment range from 50-100 µg/ml, which is equivalent to 0.3-0.6 mM. Therefore, 0.5 mM VPA is a clinically safe concentration (46) that we used in the present study based on our previous growth inhibition assay in which 0.5 mM VPA did not inhibit the growth of ESCC cells (36).…”

“…We recently showed that VPA enhanced the radiosensitizing effect by chromatin decondensation with histone hyperacetylation and downregulation of Rad51 (36). Various mechanisms are responsible for this VPA-mediated enhancement in radiosensitivity.…”

“…VPA was also shown to be an effective inhibitor of HDACs (31,32), and to enhance radiosensitivity in various cancer cell lines (18,(33)(34)(35). We recently reported a clinically safe dose of VPA that can enhance radiation-induced cytotoxicity in human ESCC cells by chromatin decondensation with histone hyperacetylation and the downregulation of Rad51 (36). For certain HDAC inhibitors, the acetylation of proteins in NHEJ has been demonstrated to be involved in the inhibition of radiation-induced DSBs repair (37).…”

Human small cell lung cancer cell line (NCI-H146) tumor behaviour on the chicken embryo chorioallantoic membrane after the sodium valproate treatment

“…Similar results have been shown testing valproic acid on diff erent tumor cell lines other than SCLC. Masatoshi and co-authors showed a potential usefulness of NaVP in combination with radiotherapy for treating oesophageal cancer [18]. Nowak-Sliwinska with collaborators tested the eff ect of minimally invasive PDT (photodynamic therapy) that can potentially destroy the unwanted neoplastic tissue while sparing the neighbouring normal tissue.…”