PMID- 25586174
OWN - NLM
STAT- MEDLINE
DCOM- 20160524
LR  - 20210103
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 172
IP  - 10
DP  - 2015 May
TI  - Glucose modulation induces reactive oxygen species and increases 
      P-glycoprotein-mediated multidrug resistance to chemotherapeutics.
PG  - 2557-72
LID - 10.1111/bph.13079 [doi]
AB  - BACKGROUND AND PURPOSE: Cancer cells develop resistance to stress induced by 
      chemotherapy. In tumours, a considerable glucose gradient exists, resulting in 
      stress. Notably, hypoxia-inducible factor-1 (HIF-1) is a redox-sensitive 
      transcription factor that regulates P-glycoprotein (Pgp), a crucial drug-efflux 
      transporter involved in multidrug resistance (MDR). Here, we investigated how 
      glucose levels regulate Pgp-mediated drug transport and resistance. EXPERIMENTAL 
      APPROACH: Human tumour cells (KB31, KBV1, A549 and DMS-53) were incubated under 
      glucose starvation to hyperglycaemic conditions. Flow cytometry assessed reactive 
      oxygen species (ROS) generation and Pgp activity. HIF-1alpha, NF-kappaB and Pgp 
      expression were assessed by reverse transcriptase-PCR and Western blotting. 
      Fluorescence microscopy examined p65 distribution and a luciferase-reporter assay 
      assessed HIF-1 promoter-binding activity. The effect of glucose-induced stress on 
      Pgp-mediated drug resistance was examined after incubating cells with the 
      chemotherapeutic and Pgp substrate, doxorubicin (DOX), and performing MTT assays 
      validated by viable cell counts. KEY RESULTS: Changes in glucose levels markedly 
      enhanced cellular ROS and conferred Pgp-mediated drug resistance. Low and high 
      glucose levels increased (i) ROS generation via NADPH oxidase 4 and mitochondrial 
      membrane destabilization; (ii) HIF-1 activity; (iii) nuclear translocation of the 
      NF-kappaB p65 subunit; and (iv) HIF-1alpha mRNA and protein levels. Increased HIF-1alpha 
      could also be due to decreased prolyl hydroxylase protein under these conditions. 
      The HIF-1alpha target, Pgp, was up-regulated at low and high glucose levels, which 
      led to lower cellular accumulation of Pgp substrate, rhodamine123, and greater 
      resistance to DOX. CONCLUSIONS AND IMPLICATIONS: As tumour cells become 
      glucose-deprived or exposed to high glucose levels, this increases stress, 
      leading to a more aggressive MDR phenotype via up-regulation of Pgp.
CI  - (c) 2015 The British Pharmacological Society.
FAU - Seebacher, N A
AU  - Seebacher NA
AD  - Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch 
      Institute, Blackburn Building (D06), University of Sydney, Sydney, NSW, 
      Australia.
FAU - Richardson, D R
AU  - Richardson DR
FAU - Jansson, P J
AU  - Jansson PJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150317
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 80168379AG (Doxorubicin)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (NOX4 protein, human)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism
MH  - Cell Count
MH  - Cell Line, Tumor
MH  - Doxorubicin/pharmacology
MH  - *Drug Resistance, Multiple
MH  - *Drug Resistance, Neoplasm
MH  - Glucose/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mitochondria/metabolism
MH  - NADPH Oxidase 4
MH  - NADPH Oxidases/antagonists & inhibitors
MH  - NF-kappa B/biosynthesis
MH  - RNA, Small Interfering/pharmacology
MH  - Reactive Oxygen Species/*metabolism
PMC - PMC4409907
EDAT- 2015/01/15 06:00
MHDA- 2016/05/25 06:00
PMCR- 2016/05/01
CRDT- 2015/01/15 06:00
PHST- 2014/09/22 00:00 [received]
PHST- 2014/12/08 00:00 [revised]
PHST- 2015/01/05 00:00 [accepted]
PHST- 2015/01/15 06:00 [entrez]
PHST- 2015/01/15 06:00 [pubmed]
PHST- 2016/05/25 06:00 [medline]
PHST- 2016/05/01 00:00 [pmc-release]
AID - 10.1111/bph.13079 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2015 May;172(10):2557-72. doi: 10.1111/bph.13079. Epub 2015 Mar 
      17.