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Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells

BACKGROUND: Hypoxia is as an indicator of poor treatment outcome. Consistently, hypoxic HCT116 colorectal cancer cells are resistant to oxaliplatin, although the mechanistic basis is unclear. This study sought to investigate the relative contribution of HIF-1 (hypoxia-inducible factor-1)-mediated ge...

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Autores principales: Roberts, D L, Williams, K J, Cowen, R L, Barathova, M, Eustace, A J, Brittain-Dissont, S, Tilby, M J, Pearson, D G, Ottley, C J, Stratford, I J, Dive, C
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768443/
https://www.ncbi.nlm.nih.gov/pubmed/19755992
http://dx.doi.org/10.1038/sj.bjc.6605311
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author Roberts, D L
Williams, K J
Cowen, R L
Barathova, M
Eustace, A J
Brittain-Dissont, S
Tilby, M J
Pearson, D G
Ottley, C J
Stratford, I J
Dive, C
author_facet Roberts, D L
Williams, K J
Cowen, R L
Barathova, M
Eustace, A J
Brittain-Dissont, S
Tilby, M J
Pearson, D G
Ottley, C J
Stratford, I J
Dive, C
author_sort Roberts, D L
collection PubMed
description BACKGROUND: Hypoxia is as an indicator of poor treatment outcome. Consistently, hypoxic HCT116 colorectal cancer cells are resistant to oxaliplatin, although the mechanistic basis is unclear. This study sought to investigate the relative contribution of HIF-1 (hypoxia-inducible factor-1)-mediated gene expression and drug penetrance to oxaliplatin resistance using three-dimensional spheroids. METHODS: Hypoxia-inducible factor-1α function was suppressed by the stable expression of a dominant-negative form in HCT116 cells (DN). Cells were drug exposed as monolayer or multicellular spheroid cultures. Cells residing at differing oxygenation status were isolated from Hoechst 33342-treated spheroids using flow cytometry. Sub-populations were subjected to clonogenic survival assays and to Inductively-Coupled Plasma Mass Spectroscopy to determine oxaliplatin uptake. RESULTS: In spheroids, a sensitivity gradient (hypoxic<aerobic) was revealed by survival assays and this correlated with levels of platinum-bound DNA. The resistance of hypoxic sub-populations exceeded relative changes in adduct levels, implicating factors other than drug penetrance in cell response. Dominant-negative monolayer cells showed no resistance to oxaliplatin in hypoxia and spheroids; the relative resistance of hypoxic compared with aerobic sub-populations was reduced compared with those from controls. CONCLUSION: Overall, data show that drug penetration, DNA damage levels and HIF-1-dependent processes, all contribute to the resistance of hypoxic cells to oxaliplatin.
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spelling pubmed-27684432010-10-20 Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells Roberts, D L Williams, K J Cowen, R L Barathova, M Eustace, A J Brittain-Dissont, S Tilby, M J Pearson, D G Ottley, C J Stratford, I J Dive, C Br J Cancer Translational Therapeutics BACKGROUND: Hypoxia is as an indicator of poor treatment outcome. Consistently, hypoxic HCT116 colorectal cancer cells are resistant to oxaliplatin, although the mechanistic basis is unclear. This study sought to investigate the relative contribution of HIF-1 (hypoxia-inducible factor-1)-mediated gene expression and drug penetrance to oxaliplatin resistance using three-dimensional spheroids. METHODS: Hypoxia-inducible factor-1α function was suppressed by the stable expression of a dominant-negative form in HCT116 cells (DN). Cells were drug exposed as monolayer or multicellular spheroid cultures. Cells residing at differing oxygenation status were isolated from Hoechst 33342-treated spheroids using flow cytometry. Sub-populations were subjected to clonogenic survival assays and to Inductively-Coupled Plasma Mass Spectroscopy to determine oxaliplatin uptake. RESULTS: In spheroids, a sensitivity gradient (hypoxic<aerobic) was revealed by survival assays and this correlated with levels of platinum-bound DNA. The resistance of hypoxic sub-populations exceeded relative changes in adduct levels, implicating factors other than drug penetrance in cell response. Dominant-negative monolayer cells showed no resistance to oxaliplatin in hypoxia and spheroids; the relative resistance of hypoxic compared with aerobic sub-populations was reduced compared with those from controls. CONCLUSION: Overall, data show that drug penetration, DNA damage levels and HIF-1-dependent processes, all contribute to the resistance of hypoxic cells to oxaliplatin. Nature Publishing Group 2009-10-20 2009-09-15 /pmc/articles/PMC2768443/ /pubmed/19755992 http://dx.doi.org/10.1038/sj.bjc.6605311 Text en Copyright © 2009 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Translational Therapeutics
Roberts, D L
Williams, K J
Cowen, R L
Barathova, M
Eustace, A J
Brittain-Dissont, S
Tilby, M J
Pearson, D G
Ottley, C J
Stratford, I J
Dive, C
Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
title Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
title_full Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
title_fullStr Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
title_full_unstemmed Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
title_short Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
title_sort contribution of hif-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768443/
https://www.ncbi.nlm.nih.gov/pubmed/19755992
http://dx.doi.org/10.1038/sj.bjc.6605311
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