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

2.50
Hdl Handle:
http://hdl.handle.net/10541/87559
Title:
Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells.
Authors:
Roberts, Darren L; Williams, Kaye J; Cowen, Rachel L; Barathova, M; Eustace, A J; Brittain-Dissont, S; Tilby, Michael J; Pearson, D Graham; Ottley, Christopher J; Stratford, Ian J; Dive, Caroline ( 0000-0002-1726-8850 )
Abstract:
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-1alpha 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.
Affiliation:
Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
Citation:
Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells. 2009, 101 (8):1290-7 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
20-Oct-2009
URI:
http://hdl.handle.net/10541/87559
DOI:
10.1038/sj.bjc.6605311
PubMed ID:
19755992
Type:
Article
Language:
en
ISSN:
1532-1827
Appears in Collections:
All Paterson Institute for Cancer Research; Clinical and Experimental Pharmacology Group

Full metadata record

DC FieldValue Language
dc.contributor.authorRoberts, Darren Len
dc.contributor.authorWilliams, Kaye Jen
dc.contributor.authorCowen, Rachel Len
dc.contributor.authorBarathova, Men
dc.contributor.authorEustace, A Jen
dc.contributor.authorBrittain-Dissont, Sen
dc.contributor.authorTilby, Michael Jen
dc.contributor.authorPearson, D Grahamen
dc.contributor.authorOttley, Christopher Jen
dc.contributor.authorStratford, Ian Jen
dc.contributor.authorDive, Carolineen
dc.date.accessioned2009-12-08T12:11:10Z-
dc.date.available2009-12-08T12:11:10Z-
dc.date.issued2009-10-20-
dc.identifier.citationContribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells. 2009, 101 (8):1290-7 Br. J. Canceren
dc.identifier.issn1532-1827-
dc.identifier.pmid19755992-
dc.identifier.doi10.1038/sj.bjc.6605311-
dc.identifier.urihttp://hdl.handle.net/10541/87559-
dc.description.abstractBACKGROUND: 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-1alpha 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.en
dc.language.isoenen
dc.subjectColorectal Canceren
dc.subjectCancer Drug Resistanceen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshCell Hypoxia-
dc.subject.meshCell Survival-
dc.subject.meshColorectal Neoplasms-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshHCT116 Cells-
dc.subject.meshHumans-
dc.subject.meshHypoxia-Inducible Factor 1-
dc.subject.meshOrganoplatinum Compounds-
dc.subject.meshSpheroids, Cellular-
dc.titleContribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, University of Manchester, Manchester, UK.en
dc.identifier.journalBritish Journal of Canceren

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