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Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma
Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM an...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10139117/ https://www.ncbi.nlm.nih.gov/pubmed/37108667 http://dx.doi.org/10.3390/ijms24087506 |
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author | Takagi, Tadataka Fujiwara-Tani, Rina Mori, Shiori Kishi, Shingo Nishiguchi, Yukiko Sasaki, Takamitsu Ogata, Ruiko Ikemoto, Ayaka Sasaki, Rika Ohmori, Hitoshi Luo, Yi Bhawal, Ujjal Kumar Sho, Masayuki Kuniyasu, Hiroki |
author_facet | Takagi, Tadataka Fujiwara-Tani, Rina Mori, Shiori Kishi, Shingo Nishiguchi, Yukiko Sasaki, Takamitsu Ogata, Ruiko Ikemoto, Ayaka Sasaki, Rika Ohmori, Hitoshi Luo, Yi Bhawal, Ujjal Kumar Sho, Masayuki Kuniyasu, Hiroki |
author_sort | Takagi, Tadataka |
collection | PubMed |
description | Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl(2)-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future. |
format | Online Article Text |
id | pubmed-10139117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101391172023-04-28 Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma Takagi, Tadataka Fujiwara-Tani, Rina Mori, Shiori Kishi, Shingo Nishiguchi, Yukiko Sasaki, Takamitsu Ogata, Ruiko Ikemoto, Ayaka Sasaki, Rika Ohmori, Hitoshi Luo, Yi Bhawal, Ujjal Kumar Sho, Masayuki Kuniyasu, Hiroki Int J Mol Sci Article Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl(2)-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future. MDPI 2023-04-19 /pmc/articles/PMC10139117/ /pubmed/37108667 http://dx.doi.org/10.3390/ijms24087506 Text en © 2023 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 Takagi, Tadataka Fujiwara-Tani, Rina Mori, Shiori Kishi, Shingo Nishiguchi, Yukiko Sasaki, Takamitsu Ogata, Ruiko Ikemoto, Ayaka Sasaki, Rika Ohmori, Hitoshi Luo, Yi Bhawal, Ujjal Kumar Sho, Masayuki Kuniyasu, Hiroki Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma |
title | Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma |
title_full | Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma |
title_fullStr | Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma |
title_full_unstemmed | Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma |
title_short | Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma |
title_sort | lauric acid overcomes hypoxia-induced gemcitabine chemoresistance in pancreatic ductal adenocarcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10139117/ https://www.ncbi.nlm.nih.gov/pubmed/37108667 http://dx.doi.org/10.3390/ijms24087506 |
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