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Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells

Ovarian cancer is the most lethal disease among gynecological malignancies. More effective therapy is required to counter high recurrence rates and chemotherapy resistance. We investigated the efficacy and molecular mechanisms of three combined treatments (TCTs)—a novel histone deacetylase (HDAC) in...

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Autores principales: Akiyama, Makoto, Sowa, Yoshihiro, Taniguchi, Tomoyuki, Watanabe, Motoki, Yogosawa, Shingo, Kitawaki, Jo, Sakai, Toshiyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cognizant Communication Corporation 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841106/
https://www.ncbi.nlm.nih.gov/pubmed/28117030
http://dx.doi.org/10.3727/096504017X14850164661097
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author Akiyama, Makoto
Sowa, Yoshihiro
Taniguchi, Tomoyuki
Watanabe, Motoki
Yogosawa, Shingo
Kitawaki, Jo
Sakai, Toshiyuki
author_facet Akiyama, Makoto
Sowa, Yoshihiro
Taniguchi, Tomoyuki
Watanabe, Motoki
Yogosawa, Shingo
Kitawaki, Jo
Sakai, Toshiyuki
author_sort Akiyama, Makoto
collection PubMed
description Ovarian cancer is the most lethal disease among gynecological malignancies. More effective therapy is required to counter high recurrence rates and chemotherapy resistance. We investigated the efficacy and molecular mechanisms of three combined treatments (TCTs)—a novel histone deacetylase (HDAC) inhibitor OBP-801/YM753, 5-fluorouracil (5-FU), and paclitaxel (PTX)—in human ovarian cancer SKOV-3 and OVCAR-3 cells. The inhibition of cell growth was stronger with TCTs than with each single agent and with two combined treatments. The TCTs significantly induce G(2) phase arrest in both cell lines. We then analyzed the molecular mechanisms and found that the TCTs increased the phosphorylation of p38 (Thr180/Tyr182), decreased the expression of CDC25C, and increased the phosphorylation of CDC2 (Tyr15), an inactive form of CDC2. To examine the responsibilities of the p38 pathway for G(2) phase arrest induced by the TCTs, we employed the p38 inhibitor SB203580. SB203580 inhibited G(2) phase arrest, suppression of CDC25C, and phosphorylation of CDC2 (Tyr15) induced by the TCTs. These results suggest that the TCTs can induce G(2) phase arrest through activation of the p38 signaling pathway. We therefore believe that this combination is promising as a novel therapeutic strategy against ovarian cancer.
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spelling pubmed-78411062021-02-16 Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells Akiyama, Makoto Sowa, Yoshihiro Taniguchi, Tomoyuki Watanabe, Motoki Yogosawa, Shingo Kitawaki, Jo Sakai, Toshiyuki Oncol Res Article Ovarian cancer is the most lethal disease among gynecological malignancies. More effective therapy is required to counter high recurrence rates and chemotherapy resistance. We investigated the efficacy and molecular mechanisms of three combined treatments (TCTs)—a novel histone deacetylase (HDAC) inhibitor OBP-801/YM753, 5-fluorouracil (5-FU), and paclitaxel (PTX)—in human ovarian cancer SKOV-3 and OVCAR-3 cells. The inhibition of cell growth was stronger with TCTs than with each single agent and with two combined treatments. The TCTs significantly induce G(2) phase arrest in both cell lines. We then analyzed the molecular mechanisms and found that the TCTs increased the phosphorylation of p38 (Thr180/Tyr182), decreased the expression of CDC25C, and increased the phosphorylation of CDC2 (Tyr15), an inactive form of CDC2. To examine the responsibilities of the p38 pathway for G(2) phase arrest induced by the TCTs, we employed the p38 inhibitor SB203580. SB203580 inhibited G(2) phase arrest, suppression of CDC25C, and phosphorylation of CDC2 (Tyr15) induced by the TCTs. These results suggest that the TCTs can induce G(2) phase arrest through activation of the p38 signaling pathway. We therefore believe that this combination is promising as a novel therapeutic strategy against ovarian cancer. Cognizant Communication Corporation 2017-09-21 /pmc/articles/PMC7841106/ /pubmed/28117030 http://dx.doi.org/10.3727/096504017X14850164661097 Text en Copyright © 2017 Cognizant, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.
spellingShingle Article
Akiyama, Makoto
Sowa, Yoshihiro
Taniguchi, Tomoyuki
Watanabe, Motoki
Yogosawa, Shingo
Kitawaki, Jo
Sakai, Toshiyuki
Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells
title Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells
title_full Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells
title_fullStr Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells
title_full_unstemmed Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells
title_short Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G(2) Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells
title_sort three combined treatments, a novel hdac inhibitor obp-801/ym753, 5-fluorouracil, and paclitaxel, induce g(2) phase arrest through the p38 pathway in human ovarian cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841106/
https://www.ncbi.nlm.nih.gov/pubmed/28117030
http://dx.doi.org/10.3727/096504017X14850164661097
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