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.

doi:10.1038/sj.bjc.6605311

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.

Authors

D.L. Roberts

K.J. Williams

R.L. Cowen

M. Barathova

A.J. Eustace

S. Brittain-Dissont

M.J. Tilby

D.G. Pearson

Dr Christopher Ottley c.j.ottley@durham.ac.uk
Senior Research Officer

I.J. Stratford

C. Dive

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-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

Citation

Roberts, D., Williams, K., Cowen, R., Barathova, M., Eustace, A., Brittain-Dissont, S., …Dive, C. (2009). Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells. British Journal of Cancer, 101(8), 1290-1297. https://doi.org/10.1038/sj.bjc.6605311

Journal Article Type	Article
Publication Date	Oct 1, 2009
Deposit Date	Jan 18, 2012
Journal	British Journal of Cancer
Print ISSN	0007-0920
Electronic ISSN	1532-1827
Publisher	Springer Nature [academic journals on nature.com]
Peer Reviewed	Peer Reviewed
Volume	101
Issue	8
Pages	1290-1297
DOI	https://doi.org/10.1038/sj.bjc.6605311
Keywords	Hypoxia, Apoptosis, DNA damage, Oxaliplatin, Tumour spheroids, Bioavailability.