Clinical Translational Research

Combined Effects of p53 Gene Therapy and Leptomycin B in Human Esophageal Squamous Cell Carcinoma
Isamu Hoshino^a, Hisahiro Matsubara^a, Aki Komatsu^a, Yasunori Akutsu^a, Takanori Nishimori^a, Yasuo Yoneyama^a, Kentaro Murakami^a, Haruhito Sakata^a, Kazuyuki Matsushita^a, Yukimasa Miyazawa^a, Ryan Brooks^c, Minoru Yoshida^b, Takenori Ochiai<sup>a

a</sup>Departments ofFrontier Surgery, Chiba University, Graduate School of Medicine, Chiba, and
^bChemical Genetics Laboratory, RIKEN, Saitama, Japan;
^cDepartment of Physiology and Pathology, Michigan State University, East Lansing, Mich., USA

Address of Corresponding Author

Oncology 2008;75:113-119 (DOI: 10.1159/000155212)

  Key Words

• p53
• Genetherapy
• Leptomycin B
• Esophageal squamous cell carcinoma

  Abstract

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.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Hisahiro Matsubara
Department of Frontier Surgery, Graduate School of Medicine
Chiba University, Inohana 1-8-1, Chuo-ku
Chiba 260-8670 (Japan)
Tel. +81 43 226 2110, Fax +81 43 226 2113, E-Mail matsuhm@faculty.chiba-u.jp

  Article Information

Received: November 14, 2007
Accepted after revision: April 25, 2008
Published online: September 11, 2008
Number of Print Pages : 7
Number of Figures : 4, Number of Tables : 0, Number of References : 33