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

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Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells DL Roberts1,2,5,7, KJ Williams2,7, RL Cowen2, M Barathova2,6, AJ Eustace2, S Brittain-Dissont2, MJ Tilby3, DG Pearson4, CJ Ottley4, IJ Stratford2 and C Dive*,1 1Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; 2Experimental Oncology, School of Pharmacy and Pharmaceutical Sciences, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK; 3Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Framlington Place, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK; 4Science Labs, Department of Geological Sciences, Durham University, Durham DH1 3LE, UK 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-1a 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 (hypoxicoaerobic) 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

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