Combined effects of p53 gene therapy and leptomycin B in human esophageal squamous cell carcinoma.
BACKGROUND
p53 gene therapy has been examined in several clinical trials, however, the results of those trials have mostly been unsatisfactory due to the low efficacy of this therapy. Leptomycin B (LMB) is an antibiotic originally isolated from Streptomyces that has the ability to inhibit the export of proteins containing a nuclear export signal from the nucleus to the cytoplasm. Currently, it has been shown that p53 protein has a nuclear export signal. In this study, we assessed whether LMB augments the transduced p53 gene effect.


METHODS
Antiproliferative effect of LMB was assessed in human esophageal squamous cancer cell lines. Accumulation of p53 protein into the nucleus by LMB was observed by fluorescence microscopy. The combined effect of p53 and LMB was evaluated in in vitro experiments.


RESULTS
LMB induced cell death in a dose-dependent manner and p53 drastically accumulated in the nucleus after LMB treatment. The combinatory treatment of p53 gene and LMB significantly increases the efficiency compared to either agent alone.


CONCLUSIONS
Our findings suggest that LMB has a potent ability to augment the effect of the tumor suppressor p53 in esophageal squamous cancer cell lines and that it is a promising component in p53 gene therapy.
Hoshino
Isamu
I
Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan.
Matsubara
Hisahiro
H
Komatsu
Aki
A
Akutsu
Yasunori
Y
Nishimori
Takanori
T
Yoneyama
Yasuo
Y
Murakami
Kentaro
K
Sakata
Haruhito
H
Matsushita
Kazuyuki
K
Miyazawa
Yukimasa
Y
Brooks
Ryan
R
Yoshida
Minoru
M
Ochiai
Takenori
T
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005231:Fatty Acids, Unsaturated / Q000627:therapeutic use; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans
D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; C038753:leptomycin B