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Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells

Canine urothelial carcinoma (cUC) is the most common tumor of the lower urinary tract in dogs. Although chemotherapy and radical surgery have improved the overall survival, most dogs with cUC succumb to metastasis or recurrence. Therefore, the development of an effective systematic therapy is warran...

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Autores principales: Eto, Shotaro, Saeki, Kohei, Yoshitake, Ryohei, Yoshimoto, Sho, Shinada, Masahiro, Ikeda, Namiko, Kamoto, Satoshi, Tanaka, Yuiko, Kato, Daiki, Maeda, Shingo, Tsuboi, Masaya, Chambers, James, Uchida, Kazuyuki, Nishimura, Ryohei, Nakagawa, Takayuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576781/
https://www.ncbi.nlm.nih.gov/pubmed/31206526
http://dx.doi.org/10.1371/journal.pone.0218382
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author Eto, Shotaro
Saeki, Kohei
Yoshitake, Ryohei
Yoshimoto, Sho
Shinada, Masahiro
Ikeda, Namiko
Kamoto, Satoshi
Tanaka, Yuiko
Kato, Daiki
Maeda, Shingo
Tsuboi, Masaya
Chambers, James
Uchida, Kazuyuki
Nishimura, Ryohei
Nakagawa, Takayuki
author_facet Eto, Shotaro
Saeki, Kohei
Yoshitake, Ryohei
Yoshimoto, Sho
Shinada, Masahiro
Ikeda, Namiko
Kamoto, Satoshi
Tanaka, Yuiko
Kato, Daiki
Maeda, Shingo
Tsuboi, Masaya
Chambers, James
Uchida, Kazuyuki
Nishimura, Ryohei
Nakagawa, Takayuki
author_sort Eto, Shotaro
collection PubMed
description Canine urothelial carcinoma (cUC) is the most common tumor of the lower urinary tract in dogs. Although chemotherapy and radical surgery have improved the overall survival, most dogs with cUC succumb to metastasis or recurrence. Therefore, the development of an effective systematic therapy is warranted. In this study, a comprehensive drug screening test using a cUC cell line was performed and the anti-tumor effect of a histone deacetylase (HDAC) inhibitor was evaluated. Comprehensive drug screening was performed on cUC cells. Based on this screening, the anti-proliferation effect of vorinostat, an HDAC inhibitor clinically applied in humans, was evaluated using several cUC cell lines in sulforhodamine B and flow cytometry assays. Western blot analysis was also performed to evaluate the degree of acetylation of histone H3 as well as the expression and phosphorylation of cell cycle-related molecules. The anti-tumor effect of vorinostat in vivo was evaluated using a xenograft model. Finally, immunohistochemistry was performed on acetyl-histone H3 in cUC and the relationship between the degree of acetylation and prognosis was examined using Kaplan–Meier survival analysis. Drug screening revealed that HDAC inhibitors consistently inhibited the growth of cUC cells. Vorinostat inhibited the growth of 6 cUC cell lines in a dose-dependent manner and induced G0/G1 cell cycle arrest. Western blot analysis showed that vorinostat mediated the acetylation of histone H3, the dephosphorylation of p-Rb, and the upregulation of p21 upon exposure to vorinostat. Furthermore, inhibition of tumor growth was observed in the xenograft model. In clinical cUC cases, neoplastic urothelium showed significant deacetylation of histones compared to the normal control, where lower histone acetylation levels were associated with a poor prognosis. In conclusion, the therapeutic potential of vorinostat was demonstrated in cUC. Histone deacetylation may be related to cUC tumor progression.
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spelling pubmed-65767812019-06-28 Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells Eto, Shotaro Saeki, Kohei Yoshitake, Ryohei Yoshimoto, Sho Shinada, Masahiro Ikeda, Namiko Kamoto, Satoshi Tanaka, Yuiko Kato, Daiki Maeda, Shingo Tsuboi, Masaya Chambers, James Uchida, Kazuyuki Nishimura, Ryohei Nakagawa, Takayuki PLoS One Research Article Canine urothelial carcinoma (cUC) is the most common tumor of the lower urinary tract in dogs. Although chemotherapy and radical surgery have improved the overall survival, most dogs with cUC succumb to metastasis or recurrence. Therefore, the development of an effective systematic therapy is warranted. In this study, a comprehensive drug screening test using a cUC cell line was performed and the anti-tumor effect of a histone deacetylase (HDAC) inhibitor was evaluated. Comprehensive drug screening was performed on cUC cells. Based on this screening, the anti-proliferation effect of vorinostat, an HDAC inhibitor clinically applied in humans, was evaluated using several cUC cell lines in sulforhodamine B and flow cytometry assays. Western blot analysis was also performed to evaluate the degree of acetylation of histone H3 as well as the expression and phosphorylation of cell cycle-related molecules. The anti-tumor effect of vorinostat in vivo was evaluated using a xenograft model. Finally, immunohistochemistry was performed on acetyl-histone H3 in cUC and the relationship between the degree of acetylation and prognosis was examined using Kaplan–Meier survival analysis. Drug screening revealed that HDAC inhibitors consistently inhibited the growth of cUC cells. Vorinostat inhibited the growth of 6 cUC cell lines in a dose-dependent manner and induced G0/G1 cell cycle arrest. Western blot analysis showed that vorinostat mediated the acetylation of histone H3, the dephosphorylation of p-Rb, and the upregulation of p21 upon exposure to vorinostat. Furthermore, inhibition of tumor growth was observed in the xenograft model. In clinical cUC cases, neoplastic urothelium showed significant deacetylation of histones compared to the normal control, where lower histone acetylation levels were associated with a poor prognosis. In conclusion, the therapeutic potential of vorinostat was demonstrated in cUC. Histone deacetylation may be related to cUC tumor progression. Public Library of Science 2019-06-17 /pmc/articles/PMC6576781/ /pubmed/31206526 http://dx.doi.org/10.1371/journal.pone.0218382 Text en © 2019 Eto et al http://creativecommons.org/licenses/by/4.0/ 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 author and source are credited.
spellingShingle Research Article
Eto, Shotaro
Saeki, Kohei
Yoshitake, Ryohei
Yoshimoto, Sho
Shinada, Masahiro
Ikeda, Namiko
Kamoto, Satoshi
Tanaka, Yuiko
Kato, Daiki
Maeda, Shingo
Tsuboi, Masaya
Chambers, James
Uchida, Kazuyuki
Nishimura, Ryohei
Nakagawa, Takayuki
Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells
title Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells
title_full Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells
title_fullStr Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells
title_full_unstemmed Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells
title_short Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells
title_sort anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576781/
https://www.ncbi.nlm.nih.gov/pubmed/31206526
http://dx.doi.org/10.1371/journal.pone.0218382
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