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

L C J Baker1, J K R Boult, S Walker-Samuel

  • 1Cancer 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

British Journal of Cancer
|April 14, 2012
PubMed
Abstract

Insights

The small-molecule inhibitor NSC-134754 alters cancer cell metabolism and shows early anti-tumour effects in vivo. This hypoxia-inducible factor (HIF) pathway inhibitor warrants further investigation as a potential anti-cancer therapeutic.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Hypoxia-inducible factor-1 (HIF-1) is crucial for cancer cell adaptation, progression, and survival under hypoxic stress.
  • Targeting the HIF pathway is a promising strategy for anti-cancer therapy.

Purpose of the Study:

  • To investigate the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754 on prostate cancer cells and tumours.
  • To assess the in vitro and in vivo anti-tumour activity of NSC-134754.

Main Methods:

  • Human prostate cancer cells (PC-3LN5) were treated with NSC-134754 under hypoxic conditions.
  • Orthotopic prostate tumours in mice were treated with a single dose of NSC-134754, with response assessed via MRI and ex-vivo histology.

Main Results:

  • In vitro, NSC-134754 reduced lactate and glucose uptake while increasing glutamine metabolism.
  • In vivo, NSC-134754 treatment led to increased tumour apparent diffusion coefficient and necrosis, with reduced HIF-1α and glucose transporter-1 expression.
  • Tumour hypoxia showed a transient increase, while vascular parameters remained unchanged.

Conclusions:

  • NSC-134754 effectively induces metabolic changes in cancer cells and demonstrates early anti-tumour effects in vivo.
  • The anti-tumour activity of NSC-134754 is independent of alterations in vascular function.
  • NSC-134754 shows potential as an anti-cancer agent, meriting further clinical evaluation.

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