Identification of a novel small molecule HIF-1alpha translation inhibitor

Clin Cancer Res. 2009 Oct 1;15(19):6128-36. doi: 10.1158/1078-0432.CCR-08-3180. Epub 2009 Sep 29.

Abstract

Purpose: Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular response to low oxygen, functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is overexpressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1alpha inhibitor was identified and its molecular mechanism was investigated.

Experimental design: Using a HIF-responsive reporter cell-based assay, a 10,000-member natural product-like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation, and protein degradation processes were analyzed.

Results: KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast, and prostate cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as carbonic anhydrase IX, matrix metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into the mechanism of action of KC7F2 showed that it worked through the down-regulation of HIF-1alpha protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and p70 S6 kinase, key regulators of HIF-1alpha protein synthesis.

Conclusion: These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / isolation & purification*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / physiology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disulfides / isolation & purification
  • Disulfides / pharmacology
  • Disulfides / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor / methods
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Models, Biological
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Oxygen / pharmacology
  • Protein Biosynthesis / drug effects*
  • Protein Processing, Post-Translational / drug effects
  • Small Molecule Libraries / analysis
  • Sulfonamides / isolation & purification
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use

Substances

  • Antineoplastic Agents
  • Disulfides
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • KC7F2 compound
  • Small Molecule Libraries
  • Sulfonamides
  • Oxygen