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

  • Authors:
    • Masatoshi Shoji
    • Itasu Ninomiya
    • Isamu Makino
    • Jun Kinoshita
    • Keishi Nakamura
    • Katsunobu Oyama
    • Hisatoshi Nakagawara
    • Hideto Fujita
    • Hidehiro Tajima
    • Hiroyuki Takamura
    • Hirohisa Kitagawa
    • Sachio Fushida
    • Shinichi Harada
    • Takashi Fujimura
    • Tetsuo Ohta
  • View Affiliations

  • Published online on: Monday, March 26, 2012
  • Pages: 2140-2146
  • DOI: 10.3892/ijo.2012.1416

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.
Journal Cover

June 2012
Volume 40 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

2013 Impact Factor: 2.773
Ranked #30/202 Oncology
(total number of cites)

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APA
Shoji, M., Ninomiya, I., Makino, I., Kinoshita, J., Nakamura, K., Oyama, K., Nakagawara, H., Fujita, H., Tajima, H., Takamura, H., Kitagawa, H., Fushida, S., Harada, S., Fujimura, T., & Ohta, T. (2012). Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma. International Journal of Oncology, 40(6), 2140-2146.
MLA
Shoji, Ninomiya, Makino, Kinoshita, Nakamura, Oyama, Nakagawara, Fujita, Tajima, Takamura, Kitagawa, Fushida, Harada, Fujimura, and Tetsuo Ohta. "Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma." International Journal of Oncology International Journal of Oncology 40.6 (2012): 2140-2146.
Chicago
Shoji, Ninomiya, Makino, Kinoshita, Nakamura, Oyama, Nakagawara, Fujita, Tajima, Takamura, Kitagawa, Fushida, Harada, Fujimura, and Tetsuo Ohta. "Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma." International Journal of Oncology International Journal of Oncology 40 no. 6 (2012): 2140-2146.