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Your search keyword '"AGAWA-OHTA, Miyuki"' showing total 4 results
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4. Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation.

Author

Kawano T, Akiyama M, Agawa-Ohta M, Mikami-Terao Y, Iwase S, Yanagisawa T, Ida H, Agata N, and Yamada H

Subjects
Acetylation, Apoptosis drug effects, Apoptosis radiation effects, Caspase 3 metabolism, Cell Cycle Proteins, Cell Line, Tumor, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Humans, Nuclear Proteins metabolism, Phosphorylation, Poly(ADP-ribose) Polymerases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Retinoblastoma pathology, Serine, Depsipeptides pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Histones metabolism, Protein Processing, Post-Translational drug effects, Protein Processing, Post-Translational radiation effects, Radiation-Sensitizing Agents pharmacology, Retinoblastoma enzymology, Tumor Suppressor Protein p53 metabolism, Valproic Acid pharmacology
Abstract

Although p53 is intact in most cases of retinoblastoma, it is largely inactivated by the ubiqutin-proteasome system through interaction with murine double minute 2 (MDM2) and murine double minute X (MDMX). The present study showed that the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and depsipeptide (FK228) synergistically enhanced ionizing radiation (IR)-induced apoptosis, associated with activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in Y79 and WER1-Rb1 human retinoblastoma cells. Both VPA and FK228 enhanced IR-induced phosphorylation of histone H2AX on Ser139 preceding apoptosis. Exposure of cells to IR in the presence of VPA or FK228 induced the accumulation of p53 acetylated at Lys382 and phosphorylated at Ser46 through the reduction of binding affinity with MDM2 and MDMX. These results suggest that acetylation of p53 by HDAC inhibitors is a promising new therapeutic target in refractory retinoblastoma.

Published
2010
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