The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function

Br J Cancer. 2012 May 8;106(10):1638-47. doi: 10.1038/bjc.2012.131. Epub 2012 Apr 12.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Blood Vessels / drug effects
  • Blood Vessels / physiology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Diffusion Magnetic Resonance Imaging
  • Glucose / metabolism
  • Glucose Transporter Type 1 / antagonists & inhibitors
  • Humans
  • Hypoxia-Inducible Factor 1 / antagonists & inhibitors*
  • Isoenzymes / antagonists & inhibitors
  • Isoquinolines / pharmacology*
  • L-Lactate Dehydrogenase / antagonists & inhibitors
  • Lactate Dehydrogenase 5
  • Male
  • Mice
  • Necrosis
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Proto-Oncogene Proteins c-myc / analysis


  • Antineoplastic Agents
  • Glucose Transporter Type 1
  • Hypoxia-Inducible Factor 1
  • Isoenzymes
  • Isoquinolines
  • NSC-134754
  • Proto-Oncogene Proteins c-myc
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • Glucose