PMID- 22946104
OWN - NLM
STAT- MEDLINE
DCOM- 20130314
LR  - 20211021
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 14
IP  - 10
DP  - 2012 Oct
TI  - Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by 
      upregulating the expression and function of ABCB1.
PG  - 1227-38
AB  - Tumor cycling hypoxia is now a well-recognized phenomenon in animal and human 
      solid tumors. However, how tumor cycling hypoxia impacts chemotherapy is unclear. 
      In the present study, we explored the impact and the mechanism of cycling hypoxia 
      on tumor microenvironment-mediated chemoresistance. Hoechst 33342 staining and 
      hypoxia-inducible factor-1 (HIF-1) activation labeling together with 
      immunofluorescence imaging and fluorescence-activated cell sorting were used to 
      isolate hypoxic tumor subpopulations from human glioblastoma xenografts. ABCB1 
      expression, P-glycoprotein function, and chemosensitivity in tumor cells derived 
      from human glioblastoma xenografts or in vitro cycling hypoxic stress-treated 
      glioblastoma cells were determined using Western blot analysis, drug accumulation 
      and efflux assays, and MTT assay, respectively. ABCB1 expression and 
      P-glycoprotein function were upregulated under cycling hypoxia in glioblastoma 
      cells concomitant with decreased responses to doxorubicin and BCNU. However, 
      ABCB1 knockdown inhibited these effects. Moreover, immunofluorescence imaging and 
      flow cytometric analysis for ABCB1, HIF-1 activation, and Hoechst 3342 in 
      glioblastoma revealed highly localized ABCB1 expression predominantly in 
      potentially cycling hypoxic areas with HIF-1 activation and blood perfusion in 
      the solid tumor microenvironment. The cycling hypoxic tumor cells derived from 
      glioblastoma xenografts exhibited higher ABCB1 expression, P-glycoprotein 
      function, and chemoresistance, compared with chronic hypoxic and normoxic cells. 
      Tumor-bearing mice that received YC-1, an HIF-1alpha inhibitor, exhibited suppressed 
      tumor microenvironment-induced ABCB1 induction and enhanced survival rate in BCNU 
      chemotherapy. Cycling hypoxia plays a vital role in tumor 
      microenvironment-mediated chemoresistance through the HIF-1-dependent induction 
      of ABCB1. HIF-1 blockade before and concurrent with chemotherapy could suppress 
      cycling hypoxia-induced chemoresistance.
FAU - Chou, Chii-Wen
AU  - Chou CW
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
FAU - Wang, Chi-Chung
AU  - Wang CC
FAU - Wu, Chung-Pu
AU  - Wu CP
FAU - Lin, Yu-Jung
AU  - Lin YJ
FAU - Lee, Yu-Chun
AU  - Lee YC
FAU - Cheng, Ya-Wen
AU  - Cheng YW
FAU - Hsieh, Chia-Hung
AU  - Hsieh CH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120903
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (ABCB1 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 1.13.12.- (Luciferases)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism
MH  - Animals
MH  - Biomarkers, Tumor/metabolism
MH  - Blotting, Western
MH  - Brain Neoplasms/drug therapy/metabolism/*pathology
MH  - Cell Proliferation
MH  - *Drug Resistance, Neoplasm
MH  - Flow Cytometry
MH  - Fluorescent Antibody Technique
MH  - Glioblastoma/drug therapy/metabolism/*pathology
MH  - Humans
MH  - Hypoxia/*physiopathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Luciferases/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Tumor Cells, Cultured
MH  - Up-Regulation
MH  - Xenograft Model Antitumor Assays
PMC - PMC3452342
EDAT- 2012/09/05 06:00
MHDA- 2013/03/15 06:00
PMCR- 2013/10/01
CRDT- 2012/09/05 06:00
PHST- 2012/09/05 06:00 [entrez]
PHST- 2012/09/05 06:00 [pubmed]
PHST- 2013/03/15 06:00 [medline]
PHST- 2013/10/01 00:00 [pmc-release]
AID - nos195 [pii]
AID - 10.1093/neuonc/nos195 [doi]
PST - ppublish
SO  - Neuro Oncol. 2012 Oct;14(10):1227-38. doi: 10.1093/neuonc/nos195. Epub 2012 Sep 
      3.