Document Detail


Phenylbutyrate sensitizes human glioblastoma cells lacking wild-type p53 function to ionizing radiation.
MedLine Citation:
PMID:  17707275     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Histone deacetylase (HDAC) inhibitors induce growth arrest, differentiation, and apoptosis in cancer cells. Phenylbutyrate (PB) is a HDAC inhibitor used clinically for treatment of urea cycle disorders. Because of its low cytotoxicity, cerebrospinal fluid penetration, and high oral bioavailability, we investigated PB as a potential radiation sensitizer in human glioblastoma cell lines. METHODS AND MATERIALS: Four glioblastoma cell lines were selected for this study. Phenylbutyrate was used at a concentration of 2 mM, which is achievable in humans. Western blots were used to assess levels of acetylated histone H3 in tumor cells after treatment with PB. Flow cytometry was used for cell cycle analysis. Clonogenic assays were performed to assess the effect of PB on radiation sensitivity. We used shRNA against p53 to study the role of p53 in radiosensitization. RESULTS: Treatment with PB alone resulted in hyperacetylation of histones, confirmed by Western blot analysis. The PB alone resulted in cytostatic effects in three cell lines. There was no evidence of G(1) arrest, increase in sub-G(1) fraction or p21 protein induction. Clonogenic assays showed radiosensitization in two lines harboring p53 mutations, with enhancement ratios (+/- SE) of 1.5 (+/- 0.2) and 1.3 (+/- 0.1), respectively. There was no radiopotentiating effect in two cell lines with wild-type p53, but knockdown of wild-type p53 resulted in radiosensitization by PB. CONCLUSIONS: Phenylbutyrate can produce p21-independent cytostasis, and enhances radiation sensitivity in p53 mutant human glioblastoma cells in vitro. This suggests the potential application of combined PB and radiotherapy in glioblastoma harboring mutant p53.
Authors:
Carlos A Lopez; Felix Y Feng; Joseph M Herman; Mukesh K Nyati; Theodore S Lawrence; Mats Ljungman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of radiation oncology, biology, physics     Volume:  69     ISSN:  0360-3016     ISO Abbreviation:  Int. J. Radiat. Oncol. Biol. Phys.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-08-20     Completed Date:  2007-10-15     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7603616     Medline TA:  Int J Radiat Oncol Biol Phys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  214-20     Citation Subset:  IM    
Affiliation:
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109-0010, USA. carlopez@umich.edu
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MeSH Terms
Descriptor/Qualifier:
Acetylation / drug effects
Cell Line, Tumor / drug effects,  radiation effects
Cell Proliferation / drug effects
G1 Phase / drug effects,  radiation effects
Glioblastoma / enzymology,  genetics,  radiotherapy*
Histone Deacetylase Inhibitors*
Histones / metabolism
Humans
Phenylbutyrates / pharmacology*
Radiation Tolerance / drug effects*,  genetics
Radiation-Sensitizing Agents / pharmacology*
Tumor Suppressor Protein p53 / metabolism*
Chemical
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; 0/Histones; 0/Phenylbutyrates; 0/Radiation-Sensitizing Agents; 0/Tumor Suppressor Protein p53; 1821-12-1/4-phenylbutyric acid

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