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Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer
BACKGROUND: Gemcitabine (2′, 2′ –difluorodeoxycytidine) is one of many nonplatinum drugs that exhibit activity in recurrent, platinum-resistant ovarian cancer. However, the molecular mechanisms by which Gemcitabine treatment inhibits the proliferation of platinum-resistant ovarian cancer cells still...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234938/ https://www.ncbi.nlm.nih.gov/pubmed/24713296 http://dx.doi.org/10.1186/1757-2215-7-38 |
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author | Kawaguchi, Hiroshi Terai, Yoshito Tanabe, Akiko Sasaki, Hiroshi Takai, Masaaki Fujiwara, Satoe Ashihara, Keisuke Tanaka, Yoshimichi Tanaka, Tomohito Tsunetoh, Satoshi Kanemura, Masanori Ohmichi, Masahide |
author_facet | Kawaguchi, Hiroshi Terai, Yoshito Tanabe, Akiko Sasaki, Hiroshi Takai, Masaaki Fujiwara, Satoe Ashihara, Keisuke Tanaka, Yoshimichi Tanaka, Tomohito Tsunetoh, Satoshi Kanemura, Masanori Ohmichi, Masahide |
author_sort | Kawaguchi, Hiroshi |
collection | PubMed |
description | BACKGROUND: Gemcitabine (2′, 2′ –difluorodeoxycytidine) is one of many nonplatinum drugs that exhibit activity in recurrent, platinum-resistant ovarian cancer. However, the molecular mechanisms by which Gemcitabine treatment inhibits the proliferation of platinum-resistant ovarian cancer cells still remain unclear. We investigated whether Gemcitabine increases the efficacy of Cisplatin in platinum-resistant ovarian cancer models in vitro and in vivo. METHODS: We used Cisplatin-resistant Caov-3 cells, A2780CP cells and Cisplatin-sensitive A2780 cells to examine the sensitivity of the cell viability of Cisplatin and Gemcitabine using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and the sensitivity of the invasive activity of Cisplatin and Gemcitabine using an invasion assay with Matrigel. We examined the Akt kinase activity and matrix metalloproteinase 9 (MMP9) expression following Cisplatin and Gemcitabine treatment using a Western blot analysis and the mRNA expression of vascular endothelial growth factor (VEGF) using semi-quantitative RT-PCR. Moreover, we evaluated the effects of Cisplatin and Gemcitabine on the intra-abdominal dissemination of ovarian cancer in vivo. RESULTS: Gemcitabine significantly inhibited Cisplatin-induced Akt activation in the Caov-3 and A2780CP cells, but not in the A2780 cells. In the presence of Gemcitabine, Cisplatin-induced growth inhibition and apoptosis were significantly enhanced in the Caov-3 and A2780CP cells. Co-treatment with Cisplatin and Gemcitabine almost completely inhibited invasion of both types of cells through the Matrigel; however, neither Cisplatin nor Gemcitabine alone inhibited the invasion of both types of cells. Gemcitabine inhibited not only the Cisplatin-induced activation of Akt, but also the MMP9 and mRNA expression of VEGF. Moreover, treatment with Gemcitabine increased the efficacy of Cisplatin-induced growth inhibition of the intra-abdominal dissemination and production of ascites in the athymic nude mice inoculated with Caov-3 cells. CONCLUSIONS: We herein demonstrated that Gemcitabine inhibits the Akt kinase activity and angiogenetic activity following treatment with Cisplatin in platinum-resistant ovarian cancer cells. These results provide a rationale for using Gemcitabine in clinical regimens containing molecular targeting agents against platinum-resistant ovarian cancers. |
format | Online Article Text |
id | pubmed-4234938 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42349382014-11-19 Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer Kawaguchi, Hiroshi Terai, Yoshito Tanabe, Akiko Sasaki, Hiroshi Takai, Masaaki Fujiwara, Satoe Ashihara, Keisuke Tanaka, Yoshimichi Tanaka, Tomohito Tsunetoh, Satoshi Kanemura, Masanori Ohmichi, Masahide J Ovarian Res Research BACKGROUND: Gemcitabine (2′, 2′ –difluorodeoxycytidine) is one of many nonplatinum drugs that exhibit activity in recurrent, platinum-resistant ovarian cancer. However, the molecular mechanisms by which Gemcitabine treatment inhibits the proliferation of platinum-resistant ovarian cancer cells still remain unclear. We investigated whether Gemcitabine increases the efficacy of Cisplatin in platinum-resistant ovarian cancer models in vitro and in vivo. METHODS: We used Cisplatin-resistant Caov-3 cells, A2780CP cells and Cisplatin-sensitive A2780 cells to examine the sensitivity of the cell viability of Cisplatin and Gemcitabine using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and the sensitivity of the invasive activity of Cisplatin and Gemcitabine using an invasion assay with Matrigel. We examined the Akt kinase activity and matrix metalloproteinase 9 (MMP9) expression following Cisplatin and Gemcitabine treatment using a Western blot analysis and the mRNA expression of vascular endothelial growth factor (VEGF) using semi-quantitative RT-PCR. Moreover, we evaluated the effects of Cisplatin and Gemcitabine on the intra-abdominal dissemination of ovarian cancer in vivo. RESULTS: Gemcitabine significantly inhibited Cisplatin-induced Akt activation in the Caov-3 and A2780CP cells, but not in the A2780 cells. In the presence of Gemcitabine, Cisplatin-induced growth inhibition and apoptosis were significantly enhanced in the Caov-3 and A2780CP cells. Co-treatment with Cisplatin and Gemcitabine almost completely inhibited invasion of both types of cells through the Matrigel; however, neither Cisplatin nor Gemcitabine alone inhibited the invasion of both types of cells. Gemcitabine inhibited not only the Cisplatin-induced activation of Akt, but also the MMP9 and mRNA expression of VEGF. Moreover, treatment with Gemcitabine increased the efficacy of Cisplatin-induced growth inhibition of the intra-abdominal dissemination and production of ascites in the athymic nude mice inoculated with Caov-3 cells. CONCLUSIONS: We herein demonstrated that Gemcitabine inhibits the Akt kinase activity and angiogenetic activity following treatment with Cisplatin in platinum-resistant ovarian cancer cells. These results provide a rationale for using Gemcitabine in clinical regimens containing molecular targeting agents against platinum-resistant ovarian cancers. BioMed Central 2014-04-09 /pmc/articles/PMC4234938/ /pubmed/24713296 http://dx.doi.org/10.1186/1757-2215-7-38 Text en Copyright © 2014 Kawaguchi et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 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. |
spellingShingle | Research Kawaguchi, Hiroshi Terai, Yoshito Tanabe, Akiko Sasaki, Hiroshi Takai, Masaaki Fujiwara, Satoe Ashihara, Keisuke Tanaka, Yoshimichi Tanaka, Tomohito Tsunetoh, Satoshi Kanemura, Masanori Ohmichi, Masahide Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer |
title | Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer |
title_full | Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer |
title_fullStr | Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer |
title_full_unstemmed | Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer |
title_short | Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer |
title_sort | gemcitabine as a molecular targeting agent that blocks the akt cascade in platinum-resistant ovarian cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234938/ https://www.ncbi.nlm.nih.gov/pubmed/24713296 http://dx.doi.org/10.1186/1757-2215-7-38 |
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