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Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction

Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involve...

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Autores principales: Suzuki, Shuhei, Yamamoto, Masahiro, Sanomachi, Tomomi, Togashi, Keita, Sugai, Asuka, Seino, Shizuka, Yoshioka, Takashi, Okada, Masashi, Kitanaka, Chifumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470402/
https://www.ncbi.nlm.nih.gov/pubmed/34575034
http://dx.doi.org/10.3390/life11090885
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author Suzuki, Shuhei
Yamamoto, Masahiro
Sanomachi, Tomomi
Togashi, Keita
Sugai, Asuka
Seino, Shizuka
Yoshioka, Takashi
Okada, Masashi
Kitanaka, Chifumi
author_facet Suzuki, Shuhei
Yamamoto, Masahiro
Sanomachi, Tomomi
Togashi, Keita
Sugai, Asuka
Seino, Shizuka
Yoshioka, Takashi
Okada, Masashi
Kitanaka, Chifumi
author_sort Suzuki, Shuhei
collection PubMed
description Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression.
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spelling pubmed-84704022021-09-27 Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction Suzuki, Shuhei Yamamoto, Masahiro Sanomachi, Tomomi Togashi, Keita Sugai, Asuka Seino, Shizuka Yoshioka, Takashi Okada, Masashi Kitanaka, Chifumi Life (Basel) Article Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression. MDPI 2021-08-27 /pmc/articles/PMC8470402/ /pubmed/34575034 http://dx.doi.org/10.3390/life11090885 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Suzuki, Shuhei
Yamamoto, Masahiro
Sanomachi, Tomomi
Togashi, Keita
Sugai, Asuka
Seino, Shizuka
Yoshioka, Takashi
Okada, Masashi
Kitanaka, Chifumi
Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction
title Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction
title_full Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction
title_fullStr Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction
title_full_unstemmed Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction
title_short Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction
title_sort dexamethasone sensitizes cancer stem cells to gemcitabine and 5-fluorouracil by increasing reactive oxygen species production through nrf2 reduction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470402/
https://www.ncbi.nlm.nih.gov/pubmed/34575034
http://dx.doi.org/10.3390/life11090885
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