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EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation

Hui-Lung Sun1, An-Chi Tsai, Shiow-Lin Pan

  • 1Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 23, 2009
PubMed
Abstract

Insights

This study reveals that 3,6-di(2,3-epoxypropoxy)xanthone (EPOX) inhibits angiogenesis by depleting glutathione and inactivating extracellular signal-regulated kinase (ERK), leading to Mcl-1 degradation in endothelial cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Antiangiogenic therapy is crucial for controlling tumor growth and metastasis.
  • Xanthone derivatives show anticancer activity, but their molecular mechanisms require elucidation.
  • Mcl-1 is a key regulator in cell survival pathways.

Purpose of the Study:

  • To investigate the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX).
  • To determine if EPOX targets Mcl-1 for its antiangiogenic effects.
  • To explore the role of glutathione and ERK signaling in EPOX-induced antiangiogenesis.

Main Methods:

  • In vitro assays: cell viability, cell cycle, tube formation.
  • In vivo assay: Matrigel plug assay.
  • Molecular analyses: immunoblotting, immunoprecipitation, immunofluorescence, glutathione level determination.

Main Results:

  • EPOX induced endothelial cell apoptosis via proteasome-dependent Mcl-1 degradation.
  • Mcl-1 downregulation led to increased Mcl-1-free Bim, Bax activation, and mitochondria-mediated apoptosis.
  • EPOX caused glutathione depletion and ERK inactivation; glutathione supplementation reversed ERK inhibition.

Conclusions:

  • EPOX inhibits angiogenesis by inducing glutathione depletion, ERK inactivation, and Mcl-1 degradation in endothelial cells.
  • EPOX demonstrates potential as a novel antiangiogenic agent.
  • EPOX is a promising lead compound for treating angiogenesis-related pathologies.

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