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Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation

Kouhei Tsuchida1, Tadayuki Tsujita2, Makiko Hayashi1

  • 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

Free Radical Biology & Medicine
|January 1, 2017
PubMed

Insights

The KEAP1-NRF2 pathway protects cells from stress, but its overactivation in cancer causes drug resistance. Halofuginone, a novel NRF2 inhibitor, depletes NRF2 and overcomes this resistance, offering a new cancer treatment strategy.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Pharmacology

Background:

  • The KEAP1-NRF2 system controls cellular defense against oxidative and xenobiotic stresses.
  • NRF2 (Nuclear factor erythroid 2-related factor 2) is a transcription factor activating cytoprotective genes.
  • Dysregulated NRF2 accumulation in cancer promotes proliferation and resistance to therapies.

Purpose of the Study:

  • To identify inhibitors of the KEAP1-NRF2 pathway to overcome cancer chemo- and radio-resistance.
  • To evaluate the therapeutic potential of identified inhibitors in NRF2-addicted cancer cells.

Main Methods:

  • High-throughput chemical library screening for NRF2 inhibitors.
  • Utilized febrifugine derivatives, specifically halofuginone, for in vitro and in vivo studies.
  • Assessed NRF2 protein levels, cellular amino acid starvation response, and protein synthesis inhibition.

Main Results:

  • Halofuginone, a less-toxic febrifugine derivative, rapidly reduced NRF2 protein levels at low doses.
  • Halofuginone induced amino acid starvation, repressed protein synthesis, and depleted NRF2.
  • Halofuginone treatment ameliorated chemo- and radio-resistance in NRF2-addicted cancer cells.

Conclusions:

  • Halofuginone acts as an effective NRF2 inhibitor by inducing cellular amino acid starvation.
  • This study provides preclinical evidence for halofuginone as a potential therapeutic agent against chemo- and radio-resistant cancers.
Keywords:
CancerHalofuginoneInhibitorKEAP1NRF2

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