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

Lookup NU author(s): Dr Michael Tilby

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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-1 alpha 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

Publication metadata

Author(s): Roberts DL, Williams KJ, Cowen RL, Barathova M, Eustace AJ, Brittain-Dissont S, Tilby MJ, Pearson DG, Ottley CJ, Stratford IJ, Dive C

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2009

Volume: 101

Issue: 8

Pages: 1290-1297

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/sj.bjc.6605311

DOI: 10.1038/sj.bjc.6605311

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