Role of histone deacetylase inhibitor in adenovirus-mediated p53 gene therapy in esophageal cancer.
BACKGROUND
Recently, the use of histone deacetylase inhibitors (HDACI) with gene therapy has been shown to improve the effect of this therapy. The effectiveness of one of the novel HDACIs, FK228, was examined in adenovirus-mediated p53 gene therapy of esophageal squamous cell carcinoma (ESCC).


METHODS
The expression levels of coxsackie and adenovirus receptor (CAR) in ESCC patients were examined immunohistochemically. CAR induction by FK228 in ESCC cells was analyzed by real-time PCR and Western blotting. The efficiencies of adenoviral transduction treated with FK228 were determined using AV1.0CMV-betagal. The acetylation of p53 protein was detected by Western blotting.


RESULTS
CAR expression was reduced in some tumor specimens compared to that in normal specimens. CAR expression was increased by FK228 in both in vitro and in vivo experiments. FK228 improved the efficiency of adenovirus infection. Acetylated p53 protein was increased in a dose- and a time-dependent manner.


CONCLUSIONS
Our findings suggest that FK228 has a potent ability to augment the effect of adenovirus-mediated p53 gene therapy in ESCC cells.
Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.
Isamu
I
Hoshino
Hisahiro
H
Matsubara
Yasunori
Y
Akutsu
Takanori
T
Nishimori
Yasuo
Y
Yoneyama
Kentaro
K
Murakami
Haruhito
H
Sakata
Kazuyuki
K
Matsushita
Aki
A
Komatsu
Ryan
R
Brooks
Takenori
T
Ochiai
D000107:Acetylation; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000628:therapy*; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011991:Receptors, Virus / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011991:Receptors, Virus; C087123:romidepsin