Cytotoxic effects of replication-competent adenoviruses on human esophageal carcinoma are enhanced by forced p53 expression

BMC Cancer

Research Article

Hiroshi Kobayashi¹  Kenzo Hiroshima²  Koichiro Tatsumi³  Yuji Tada³  Hideaki Shimada⁴  Kiyoko Kawamura⁵  Shinya Okamoto⁶  Suguru Yamauchi⁷  Masatoshi Tagawa⁷  Shan Yang⁷  Masato Shingyoji⁸  Ikuo Sekine⁸ 

[1] Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan;Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, Chiba, Japan;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan;Department of Surgery, School of Medicine, Toho University, Tokyo, Japan;Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, 260-8717, Chuo-ku, Chiba, Japan;Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, 260-8717, Chuo-ku, Chiba, Japan;Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan;Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, 260-8717, Chuo-ku, Chiba, Japan;Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan;Division of Respirology, Chiba Cancer Center, Chiba, Japan;

关键词: Esophageal carcinoma;    Replication-competent adenovirus;    p53;    Apoptosis;   

DOI  :  10.1186/s12885-015-1482-8

 received in 2014-11-28, accepted in 2015-06-02,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundImprovement of transduction and augmentation of cytotoxicity are crucial for adenoviruses (Ad)-mediated gene therapy for cancer. Down-regulated expression of type 5 Ad (Ad5) receptors on human tumors hampered Ad-mediated transduction. Furthermore, a role of the p53 pathways in cytotoxicity mediated by replication-competent Ad remained uncharacterized.MethodsWe constructed replication-competent Ad5 of which the E1 region genes were activated by a transcriptional regulatory region of the midkine or the survivin gene, which is expressed preferentially in human tumors. We also prepared replication-competent Ad5 which were regulated by the same region but had a fiber-knob region derived from serotype 35 (AdF35). We examined the cytotoxicity of these Ad and a possible combinatory use of the replication-competent AdF35 and Ad5 expressing the wild-type p53 gene (Ad5/p53) in esophageal carcinoma cells. Expression levels of molecules involved in cell death, anti-tumor effects in vivo and production of viral progenies were also investigated.ResultsReplication-competent AdF35 in general achieved greater cytotoxic effects to esophageal carcinoma cells than the corresponding replication-competent Ad5. Infection with the AdF35 induced cleavages of caspases and increased sub-G1 fractions, but did not activate the autophagy pathway. Transduction with Ad5/p53 in combination with the replication-competent AdF35 further enhanced the cytotoxicity in a synergistic manner. We also demonstrated the combinatory effects in an animal model. Transduction with Ad5/p53 however suppressed production of replication-competent AdF35 progenies, but the combination augmented Ad5/p53-mediated p53 expression levels and the downstream pathways.ConclusionsCombination of replication-competent AdF35 and Ad5/p53 achieved synergistic cytotoxicity due to enhanced p53-mediated apoptotic pathways.

【 授权许可】

Unknown   
© Yang et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.