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Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha

Chemotherapy is the backbone of subsequent treatment for patients with lung adenocarcinoma (LUAD) exhibiting radiation resistance, and pemetrexed plays a critical role in this chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to pemetrexed under radioresistant...

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Autores principales: Wang, Yuqing, Huang, Jie, Wu, Qiong, Zhang, Jingjing, Ma, Zhiyuan, Zhu, Lucheng, Xia, Bin, Ma, Shenglin, Zhang, Shirong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165306/
https://www.ncbi.nlm.nih.gov/pubmed/34079760
http://dx.doi.org/10.3389/fonc.2021.668798
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author Wang, Yuqing
Huang, Jie
Wu, Qiong
Zhang, Jingjing
Ma, Zhiyuan
Zhu, Lucheng
Xia, Bin
Ma, Shenglin
Zhang, Shirong
author_facet Wang, Yuqing
Huang, Jie
Wu, Qiong
Zhang, Jingjing
Ma, Zhiyuan
Zhu, Lucheng
Xia, Bin
Ma, Shenglin
Zhang, Shirong
author_sort Wang, Yuqing
collection PubMed
description Chemotherapy is the backbone of subsequent treatment for patients with lung adenocarcinoma (LUAD) exhibiting radiation resistance, and pemetrexed plays a critical role in this chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to pemetrexed under radioresistant circumstances. Therefore, the objectives of this study were to delineate changes in the sensitivity of radioresistant LUAD cells to pemetrexed and to elucidate the related mechanisms and then develop an optimal strategy to improve the cytotoxicity of pemetrexed in radioresistant LUAD cells. Our study showed a much lower efficacy of pemetrexed in radioresistant cells than in parental cells, and the mechanism of action was the significant downregulation of folate receptor alpha (FRα) by long-term fractionated radiotherapy, which resulted in less cellular pemetrexed accumulation. Interestingly, decitabine effectively reversed the decrease in FRα expression in radioresistant cells through an indirect regulatory approach. Thereafter, we designed a combination therapy of pemetrexed and decitabine and showed that the activation of FRα by decitabine sensitizes radioresistant LUAD cells to pemetrexed both in vitro and in xenografts. Our findings raised a question regarding the administration of pemetrexed to patients with LUAD exhibiting acquired radioresistance and accordingly suggested that a combination of pemetrexed and decitabine would be a promising treatment strategy.
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spelling pubmed-81653062021-06-01 Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha Wang, Yuqing Huang, Jie Wu, Qiong Zhang, Jingjing Ma, Zhiyuan Zhu, Lucheng Xia, Bin Ma, Shenglin Zhang, Shirong Front Oncol Oncology Chemotherapy is the backbone of subsequent treatment for patients with lung adenocarcinoma (LUAD) exhibiting radiation resistance, and pemetrexed plays a critical role in this chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to pemetrexed under radioresistant circumstances. Therefore, the objectives of this study were to delineate changes in the sensitivity of radioresistant LUAD cells to pemetrexed and to elucidate the related mechanisms and then develop an optimal strategy to improve the cytotoxicity of pemetrexed in radioresistant LUAD cells. Our study showed a much lower efficacy of pemetrexed in radioresistant cells than in parental cells, and the mechanism of action was the significant downregulation of folate receptor alpha (FRα) by long-term fractionated radiotherapy, which resulted in less cellular pemetrexed accumulation. Interestingly, decitabine effectively reversed the decrease in FRα expression in radioresistant cells through an indirect regulatory approach. Thereafter, we designed a combination therapy of pemetrexed and decitabine and showed that the activation of FRα by decitabine sensitizes radioresistant LUAD cells to pemetrexed both in vitro and in xenografts. Our findings raised a question regarding the administration of pemetrexed to patients with LUAD exhibiting acquired radioresistance and accordingly suggested that a combination of pemetrexed and decitabine would be a promising treatment strategy. Frontiers Media S.A. 2021-05-17 /pmc/articles/PMC8165306/ /pubmed/34079760 http://dx.doi.org/10.3389/fonc.2021.668798 Text en Copyright © 2021 Wang, Huang, Wu, Zhang, Ma, Zhu, Xia, Ma and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Wang, Yuqing
Huang, Jie
Wu, Qiong
Zhang, Jingjing
Ma, Zhiyuan
Zhu, Lucheng
Xia, Bin
Ma, Shenglin
Zhang, Shirong
Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha
title Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha
title_full Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha
title_fullStr Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha
title_full_unstemmed Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha
title_short Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha
title_sort decitabine sensitizes the radioresistant lung adenocarcinoma to pemetrexed through upregulation of folate receptor alpha
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165306/
https://www.ncbi.nlm.nih.gov/pubmed/34079760
http://dx.doi.org/10.3389/fonc.2021.668798
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