title: The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function.
abstract: BACKGROUND
  Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754.
  
  
  METHODS
  Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought.
  
  
  RESULTS
  In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment.
  
  
  CONCLUSIONS
  NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent.
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Trust, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK. Lauren.Baker@icr.ac.uk
authors.forename: L C J
authors.initials: LC
authors.lastname: Baker
authors.forename: J K R
authors.initials: JK
authors.lastname: Boult
authors.forename: S
authors.initials: S
authors.lastname: Walker-Samuel
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chung
authors.forename: Y
authors.initials: Y
authors.lastname: Jamin
authors.forename: M
authors.initials: M
authors.lastname: Ashcroft
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D038524:Diffusion Magnetic Resonance Imaging; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D000080864:Lactate Dehydrogenase 5; D008297:Male; D051379:Mice; D009336:Necrosis; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D051793:Hypoxia-Inducible Factor 1; D007527:Isoenzymes; D007546:Isoquinolines; C502338:NSC-134754; D016271:Proto-Oncogene Proteins c-myc; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D005947:Glucose