title: Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity             in esophageal squamous cell carcinoma.
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 (IC50) 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.
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medicine, Kanazawa 920-8641, Japan. m_shoji@staff.kanazawa-u.ac.jp
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Shoji
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.forename: Isamu
authors.initials: I
authors.lastname: Makino
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.forename: Keishi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Oyama
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Nakagawara
authors.forename: Hideto
authors.initials: H
authors.lastname: Fujita
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004938:Esophageal Neoplasms / Q000532:radiotherapy*; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D011838:Radiation-Sensitizing Agents; D014635:Valproic Acid; C495153:RAD51 protein, human; D051135:Rad51 Recombinase