Title |
Cytotoxic effects of replication-competent adenoviruses on human esophageal carcinoma are enhanced by forced p53 expression
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Published in |
BMC Cancer, June 2015
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DOI | 10.1186/s12885-015-1482-8 |
Pubmed ID | |
Authors |
Shan Yang, Kiyoko Kawamura, Shinya Okamoto, Suguru Yamauchi, Masato Shingyoji, Ikuo Sekine, Hiroshi Kobayashi, Yuji Tada, Koichiro Tatsumi, Kenzo Hiroshima, Hideaki Shimada, Masatoshi Tagawa |
Abstract |
Improvement 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. We 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. Replication-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. Combination of replication-competent AdF35 and Ad5/p53 achieved synergistic cytotoxicity due to enhanced p53-mediated apoptotic pathways. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 2 | 100% |
Demographic breakdown
Type | Count | As % |
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Science communicators (journalists, bloggers, editors) | 1 | 50% |
Members of the public | 1 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 12 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 3 | 25% |
Student > Ph. D. Student | 2 | 17% |
Unspecified | 1 | 8% |
Student > Bachelor | 1 | 8% |
Other | 1 | 8% |
Other | 2 | 17% |
Unknown | 2 | 17% |
Readers by discipline | Count | As % |
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Agricultural and Biological Sciences | 3 | 25% |
Biochemistry, Genetics and Molecular Biology | 3 | 25% |
Medicine and Dentistry | 2 | 17% |
Immunology and Microbiology | 1 | 8% |
Unspecified | 1 | 8% |
Other | 0 | 0% |
Unknown | 2 | 17% |