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The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma
OBJECTIVE: To explore the antitumor role of the attenuated Salmonella typhimurium ΔppGpp with inducible cytolysin A (ClyA) in advanced stage of glioma. MATERIALS AND METHODS: The C6 rat glioma cells were orthotopically implanted by surgery into the caudate nucleus of rat brains. The rats were then r...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592054/ https://www.ncbi.nlm.nih.gov/pubmed/26451114 http://dx.doi.org/10.2147/OTT.S86899 |
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author | Chen, Jian-qiang Zhan, Yue-fu Wang, Wei Jiang, Sheng-nan Li, Xiang-ying |
author_facet | Chen, Jian-qiang Zhan, Yue-fu Wang, Wei Jiang, Sheng-nan Li, Xiang-ying |
author_sort | Chen, Jian-qiang |
collection | PubMed |
description | OBJECTIVE: To explore the antitumor role of the attenuated Salmonella typhimurium ΔppGpp with inducible cytolysin A (ClyA) in advanced stage of glioma. MATERIALS AND METHODS: The C6 rat glioma cells were orthotopically implanted by surgery into the caudate nucleus of rat brains. The rats were then randomly divided into the treatment group (SL + ClyA) (n=12), negative control group (SL) (n=12), and control group (phosphate-buffered saline [PBS]) (n=12). In the treatment group, the attenuated S. typhimurium were transformed with the plasmid-encoded antitumor gene ClyA. The expression of ClyA was controlled by the TetR-regulated promoter in response to extracellular doxycycline. The plasmid also contained an imaging gene lux to allow illumination of the tumor infected by the bacteria. The rat glioma C6 cells were implanted into the caudate nucleus of all rats. The engineered S. typhimurium and respective controls were injected intravenously into the rats 21 days after initial tumor implantation. The pathological analysis of the glioma tumor was performed at 21 days and 28 days (7 days after doxycycline treatment) postimplantation. All rats underwent MRI (magnetic resonance imaging) and bioluminescence study at 21 days and 28 days postimplantation to detect tumor volume. The differences between the three groups in tumor volume and survival time were analyzed. RESULTS: Advanced stage glioma was detected at 21 days postimplantation. Bioluminescence showed that the engineered S. typhimurium accumulated in glioma tumors and disappeared in the normal reticuloendothelial tissues 3 days after intravenous injection. MRI showed that the tumor volume in the S. typhimurium with ClyA group were significantly reduced compared to the bacteria alone and no bacteria groups 7 days post-doxycycline treatment (P<0.05), while the necrotic tumor volume in the S. typhimurium with ClyA group and S. typhimurium alone group increased significantly compared to the control group (P<0.01). In addition, the survival time was significantly prolonged in the bacteria-treated group compared to the PBS-treated control group (P<0.01). CONCLUSION: The engineered S. typhimurium can significantly induce cancer cell apoptosis in the tumor center and inhibit cancer cell proliferation in the outer zone of advanced glioma tumor, leading to a prolonged survival time in rats. In addition, the engineered S. typhimurium that carried the antitumor and imaging genes controlled by the TetR-regulated promoter have high delivery efficiency with tolerable side effects in rats. |
format | Online Article Text |
id | pubmed-4592054 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-45920542015-10-08 The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma Chen, Jian-qiang Zhan, Yue-fu Wang, Wei Jiang, Sheng-nan Li, Xiang-ying Onco Targets Ther Original Research OBJECTIVE: To explore the antitumor role of the attenuated Salmonella typhimurium ΔppGpp with inducible cytolysin A (ClyA) in advanced stage of glioma. MATERIALS AND METHODS: The C6 rat glioma cells were orthotopically implanted by surgery into the caudate nucleus of rat brains. The rats were then randomly divided into the treatment group (SL + ClyA) (n=12), negative control group (SL) (n=12), and control group (phosphate-buffered saline [PBS]) (n=12). In the treatment group, the attenuated S. typhimurium were transformed with the plasmid-encoded antitumor gene ClyA. The expression of ClyA was controlled by the TetR-regulated promoter in response to extracellular doxycycline. The plasmid also contained an imaging gene lux to allow illumination of the tumor infected by the bacteria. The rat glioma C6 cells were implanted into the caudate nucleus of all rats. The engineered S. typhimurium and respective controls were injected intravenously into the rats 21 days after initial tumor implantation. The pathological analysis of the glioma tumor was performed at 21 days and 28 days (7 days after doxycycline treatment) postimplantation. All rats underwent MRI (magnetic resonance imaging) and bioluminescence study at 21 days and 28 days postimplantation to detect tumor volume. The differences between the three groups in tumor volume and survival time were analyzed. RESULTS: Advanced stage glioma was detected at 21 days postimplantation. Bioluminescence showed that the engineered S. typhimurium accumulated in glioma tumors and disappeared in the normal reticuloendothelial tissues 3 days after intravenous injection. MRI showed that the tumor volume in the S. typhimurium with ClyA group were significantly reduced compared to the bacteria alone and no bacteria groups 7 days post-doxycycline treatment (P<0.05), while the necrotic tumor volume in the S. typhimurium with ClyA group and S. typhimurium alone group increased significantly compared to the control group (P<0.01). In addition, the survival time was significantly prolonged in the bacteria-treated group compared to the PBS-treated control group (P<0.01). CONCLUSION: The engineered S. typhimurium can significantly induce cancer cell apoptosis in the tumor center and inhibit cancer cell proliferation in the outer zone of advanced glioma tumor, leading to a prolonged survival time in rats. In addition, the engineered S. typhimurium that carried the antitumor and imaging genes controlled by the TetR-regulated promoter have high delivery efficiency with tolerable side effects in rats. Dove Medical Press 2015-09-15 /pmc/articles/PMC4592054/ /pubmed/26451114 http://dx.doi.org/10.2147/OTT.S86899 Text en © 2015 Chen et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Chen, Jian-qiang Zhan, Yue-fu Wang, Wei Jiang, Sheng-nan Li, Xiang-ying The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma |
title | The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma |
title_full | The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma |
title_fullStr | The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma |
title_full_unstemmed | The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma |
title_short | The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma |
title_sort | engineered salmonella typhimurium inhibits tumorigenesis in advanced glioma |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592054/ https://www.ncbi.nlm.nih.gov/pubmed/26451114 http://dx.doi.org/10.2147/OTT.S86899 |
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