The antimalaria agent artemisinin exerts antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies.
Artemisinin is widely used as an agent to treat malaria; the possible antiangiogenic effects of this compound are unknown. In the present study, the antiangiogenic effects of artemisinin were investigated in mouse embryonic stem cell-derived embryoid bodies, which are a model system for early postimplantation embryos and which efficiently differentiate capillaries. Artemisinin dose dependently inhibited angiogenesis in embryoid bodies and raised the level of intracellular reactive oxygen species. Furthermore impaired organization of the extracellular matrix component laminin and altered expression patterns of matrix metalloproteinases 1, 2, and 9 were observed during the time course of embryoid body differentiation. Consequently accelerated penetration kinetics of the fluorescent anthracycline doxorubicin occurred within the tissue, indicating increased tissue permeability. Artemisinin down-regulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor (VEGF) expression, which control endothelial cell growth. The antiangiogenic effects and the inhibition of hypoxia-inducible factor-1alpha and VEGF were reversed upon cotreatment with the free radical scavengers mannitol and vitamin E, indicating that artemisinin may act via reactive oxygen species generation. Furthermore, capillary formation was restored upon coadministration of exogenous VEGF. The data of the present study suggest that the antiangiogenic activity of artemisinin and the increase in tissue permeability for cytostatics may be exploited for anticancer treatment.
Wartenberg
Maria
M
Department of Neurophysiology and Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Wolf
Sandra
S
Budde
Paula
P
Grünheck
Frank
F
Acker
Helmut
H
Hescheler
Jürgen
J
Wartenberg
Gerda
G
Sauer
Heinrich
H
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000378:metabolism; D004622:Embryo, Mammalian / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000890:Anti-Infective Agents; D000962:Antimalarials; D037621:Artemisinins; D016166:Free Radical Scavengers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; C031327:artemisinin; D020782:Matrix Metalloproteinases