Dihydroartemisinin Exerts Cytotoxic Effects and Inhibits Hypoxia Inducible factor-1alpha Activation in C6 Glioma Cells

J Pharm Pharmacol. 2007 Jun;59(6):849-56. doi: 10.1211/jpp.59.6.0011.

Abstract

Artemisinin and its analogue dihydroartemisinin exert cytotoxic effects in some kinds of cancer cell lines. Here we determined whether dihydroartemisinin inhibits the growth and induces apoptosis of rat C6 glioma cells. We found dihydroartemisinin (5-25 microM) inhibited the growth and induced apoptosis of C6 cells in a concentration- and time-dependent manner; however, it was much less toxic to rat primary astrocytes. Dihydroartemisinin (5-25 microM) also increased the generation of reactive oxygen species in C6 cells. These effects of dihydroartemisinin were enhanced by ferrous ions (12.5-100 microM) and reduced by the iron chelator deferoxamine (25-200 microM). Immunoblotting analysis revealed that dihydroartemisinin (5-25 microM) significantly reduced hypoxia- and deferoxamine-induced expression of hypoxia inducible factor-1alpha and its target gene protein, vascular endothelial growth factor, in C6 cells. The results showed that dihydroartemisinin exerts a selective cytotoxic effect on C6 cells by increasing the reactive oxygen species and inhibiting hypoxia inducible factor-1alpha activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Artemisinins / administration & dosage
  • Artemisinins / pharmacology*
  • Cell Hypoxia
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Deferoxamine / pharmacology
  • Ferrous Compounds / pharmacology
  • Glioma
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Rats
  • Reactive Oxygen Species / metabolism
  • Sesquiterpenes / administration & dosage
  • Sesquiterpenes / pharmacology*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factors / biosynthesis

Substances

  • Antineoplastic Agents
  • Artemisinins
  • Chelating Agents
  • Ferrous Compounds
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • Sesquiterpenes
  • Vascular Endothelial Growth Factors
  • ferrous sulfate
  • dihydroartemisinin
  • Deferoxamine