PMID- 19755992
OWN - NLM
STAT- MEDLINE
DCOM- 20091028
LR  - 20211020
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 101
IP  - 8
DP  - 2009 Oct 20
TI  - Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic 
      colorectal cancer cells.
PG  - 1290-7
LID - 10.1038/sj.bjc.6605311 [doi]
AB  - 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.
FAU - Roberts, D L
AU  - Roberts DL
AD  - Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
FAU - Williams, K J
AU  - Williams KJ
FAU - Cowen, R L
AU  - Cowen RL
FAU - Barathova, M
AU  - Barathova M
FAU - Eustace, A J
AU  - Eustace AJ
FAU - Brittain-Dissont, S
AU  - Brittain-Dissont S
FAU - Tilby, M J
AU  - Tilby MJ
FAU - Pearson, D G
AU  - Pearson DG
FAU - Ottley, C J
AU  - Ottley CJ
FAU - Stratford, I J
AU  - Stratford IJ
FAU - Dive, C
AU  - Dive C
LA  - eng
GR  - C147/A6058/Cancer Research UK/United Kingdom
GR  - C84/A4394/Cancer Research UK/United Kingdom
GR  - G0500366/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090915
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Organoplatinum Compounds)
RN  - 04ZR38536J (Oxaliplatin)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Hypoxia
MH  - Cell Survival/drug effects
MH  - Colorectal Neoplasms/*drug therapy/metabolism/pathology
MH  - Drug Resistance, Neoplasm
MH  - HCT116 Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*physiology
MH  - Organoplatinum Compounds/pharmacokinetics/*pharmacology
MH  - Oxaliplatin
MH  - Spheroids, Cellular
PMC - PMC2768443
EDAT- 2009/09/17 06:00
MHDA- 2009/10/29 06:00
PMCR- 2010/10/20
CRDT- 2009/09/17 06:00
PHST- 2009/09/17 06:00 [entrez]
PHST- 2009/09/17 06:00 [pubmed]
PHST- 2009/10/29 06:00 [medline]
PHST- 2010/10/20 00:00 [pmc-release]
AID - 6605311 [pii]
AID - 10.1038/sj.bjc.6605311 [doi]
PST - ppublish
SO  - Br J Cancer. 2009 Oct 20;101(8):1290-7. doi: 10.1038/sj.bjc.6605311. Epub 2009 
      Sep 15.