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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...

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Autores principales: Kawaguchi, Hiroshi, Terai, Yoshito, Tanabe, Akiko, Sasaki, Hiroshi, Takai, Masaaki, Fujiwara, Satoe, Ashihara, Keisuke, Tanaka, Yoshimichi, Tanaka, Tomohito, Tsunetoh, Satoshi, Kanemura, Masanori, Ohmichi, Masahide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
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.
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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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