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Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer
5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770959/ https://www.ncbi.nlm.nih.gov/pubmed/31491980 http://dx.doi.org/10.3390/ijms20184366 |
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author | Kim, Ha Gyeong Kim, Chan Woo Lee, Don Haeng Lee, Jae-Seon Oh, Eun-Taex Park, Heon Joo |
author_facet | Kim, Ha Gyeong Kim, Chan Woo Lee, Don Haeng Lee, Jae-Seon Oh, Eun-Taex Park, Heon Joo |
author_sort | Kim, Ha Gyeong |
collection | PubMed |
description | 5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun N-terminal kinase-1 (JNK1) knockdown inhibited the QC-mediated Nrf2 degradation in CRC cells under hypoxic conditions. The treatment of CRC xenografts in mice with the combination of QC and 5-FU was more effective in suppressing tumor growth than QC or 5-FU alone. QC increases the susceptibility of CRC cells to 5-FU under hypoxic conditions by enhancing JNK1-dependent Nrf2 degradation. |
format | Online Article Text |
id | pubmed-6770959 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67709592019-10-30 Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer Kim, Ha Gyeong Kim, Chan Woo Lee, Don Haeng Lee, Jae-Seon Oh, Eun-Taex Park, Heon Joo Int J Mol Sci Article 5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun N-terminal kinase-1 (JNK1) knockdown inhibited the QC-mediated Nrf2 degradation in CRC cells under hypoxic conditions. The treatment of CRC xenografts in mice with the combination of QC and 5-FU was more effective in suppressing tumor growth than QC or 5-FU alone. QC increases the susceptibility of CRC cells to 5-FU under hypoxic conditions by enhancing JNK1-dependent Nrf2 degradation. MDPI 2019-09-05 /pmc/articles/PMC6770959/ /pubmed/31491980 http://dx.doi.org/10.3390/ijms20184366 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kim, Ha Gyeong Kim, Chan Woo Lee, Don Haeng Lee, Jae-Seon Oh, Eun-Taex Park, Heon Joo Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer |
title | Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer |
title_full | Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer |
title_fullStr | Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer |
title_full_unstemmed | Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer |
title_short | Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer |
title_sort | quinacrine-mediated inhibition of nrf2 reverses hypoxia-induced 5-fluorouracil resistance in colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770959/ https://www.ncbi.nlm.nih.gov/pubmed/31491980 http://dx.doi.org/10.3390/ijms20184366 |
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