Cancer Res Treat.  2015 Jul;47(3):527-533. 10.4143/crt.2014.026.

In Vitro and In Vivo Radiosensitizing Effect of Valproic Acid on Fractionated Irradiation

• Chie EK
• Shin JH
• Kim JH
• Kim HJ
• Kim IA
• Kim IH

• KMID: 2148504
• DOI: http://doi.org/10.4143/crt.2014.026

Abstract

PURPOSE
This study was conducted in order to validate the radiosensitization effect of valproic acid, a biologically available histone deacetylase inhibitor, for fractionated radiation.
MATERIALS AND METHODS
Radiosensitization effect of valproic acid was tested for the A549 cell line and U87MG cell line in vitro. Fractionated irradiation of 12 Gy in four fractions was administered on D2-5 with valproic acid, 150 mg/Kg, ip, bid for six consecutive days (D1-6) to A549 and U87MG tumors implanted in BALB/c-nude mice. A growth delay curve was formulated.
RESULTS
Radiosensitization effect of valproic acid was found for both cell lines; A549 at 1.5 mM and 3.0 mM concentration and U87MG at 3.0 mM concentration. In growth delay analysis, a statistically significant radiosensitization effect was observed for both tumors (p < 0.001 for both tumors). Difference for change in slope for control and valproic acid versus radiotherapy and radiotherapy plus valproic acid showed borderline significance for the U87MG cell line (p=0.065), indicating beyond additive effect, whereas this difference was statistically insignificant for A549 tumor (p=0.951), indicating additive effect.
CONCLUSION
Results of this study indicate that a radiosensitizing effect for fractionated radiotherapy of valproic acid for A549 and U87MG tumors in vivo is evident and that it may be more than additive for U87MG tumors. Further exploitation of histone deacetylase inhibitors in clinical trials is warranted.

Keyword

Radiation tolerance; Valproic acid; Radiation; Glioblastoma; Non-small-cell lung carcinoma

MeSH Terms

Animals
Carcinoma, Non-Small-Cell Lung
Cell Line
Glioblastoma
Histone Deacetylase Inhibitors
Mice
Radiation Tolerance
Radiation-Sensitizing Agents*
Radiotherapy
Valproic Acid*
Histone Deacetylase Inhibitors
Radiation-Sensitizing Agents
Valproic Acid

Figure

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  Fig. 1. Summary of vehicle/valproic acid and radiation administration schedule. Vehicle, phosphate buffered saline; VA, valproic acid 150 mg/kg (mouse, intraperitoneal injection); IR, irradiation.

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  Fig. 2. Survival curves of A549 and U87MG cells treated with valproic acid at various concentrations. (A) A549 cell treated with valproic acid at 1.5 mM. (B) A549 cell treated with valproic acid at 3.0 mM. (C) U87MG cell treated with valproic acid at 1.5 mM. (D) U87MG cell treated with valproic acid at 3.0 mM. Points, mean for three independent experiments; bars, standard error. *p < 0.05, versus control.

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  Fig. 3. Tumor growth delay by valproic acid (VA), irradiation (IR), and IR+VA in A549 tumor (A) and U87MG tumor (B).

Reference

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