The Antimalaria Agent Artemisinin Exerts Antiangiogenic Effects in Mouse Embryonic Stem Cell-Derived Embryoid Bodies

Abstract

SUMMARY: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-1␣ and vascular endothelial growth factor (VEGF) expression, which control endothelial cell growth. The antiangiogenic effects and the inhibition of hypoxia-inducible factor-1␣ 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. (Lab Invest 2003, 83:1647-1655.

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

“…We and others have described antiangiogenic effects of ARS in vitro and in vivo. [25][26][27][28][29][30][31][32] ART strongly reduced neovascularization of Matrigel plugs injected under the skin of mice when administered with the drinking water. No apoptotic effects on endothelial cells were observed.…”

“…27 ART and dihydroARS reduced the expression of the two major VEGF receptors, Flt-1 and Table 1 THBS1 TGFB2 PLAU AXL CYR61 FGF2 FGF2 EphA2 MPDZ IL6ST COL18A1 NID2 FN1 MMP9 BMP1 ANG PIN BMPR2 DVL3 MMP11 GJA4 COL4A2 HIF1A NOS2A ABCG1 COL1A2 VEGFC F3 TFPI2 NRCAM EFEMP1 EFEMP1 SNB- Angiogenesis-related genes predict cellular response to artemisinins L Anfosso et al induction of cellular apoptosis and inhibition of expression of VEGF receptors. 28,29,31 In addition to ARSs, other sesquiterpene lactones, such as costunolide also inhibit the VEGFR KDR/Flk-1 signaling pathway. 47 It merits further investigation to analyze, whether the correlations between gene expression and GI 50 values for ARSs found in the present investigation are events downstream of the inhibition of the VEGF ligand/receptor system or whether other angiogenic regulators are also causative affected by these drugs.…”

“…14 The observation that ART inhibits the growth of many transformed cell lines has led to the hypothesis that the drug can also be useful for the treatment of human neoplasia. [15][16][17][18][19][20][21][22][23][24] As shown by us and others, [25][26][27][28][29][30][31][32] ARSs reveal antiangiogenic features in vitro and in vivo. The molecular determinants of the antiangiogenic activity of ARSs are incompletely understood at present.…”

In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents

“…Studies have identified several potential mechanisms by which the artemisinins can act against cancer cells. They have been shown to be antiproliferative through action on key cell cycle regulatory proteins such as p21 waf1cip1 and cyclin D1 [20]; pro-apoptotic by manipulating the Bax:Bcl-2 rheostat [21,22]; antiangiogenic by targeting vascular endothelial growth factor [23,24]; and anti-migratory through their effects on αVβ3 integrins [25]. The multi-modal character of these antimalarial drugs, allied to their low host toxicity even at high doses [26,27], reinforces the priority for them to be developed as a novel anti-cancer agents.…”

Hypoxia modulates the effect of dihydroartemisinin on endothelial cells

“…There is evidence that DHA effects involve induction of oxidative stress [13,21] with increased production of reactive oxygen species (ROS) detected in different cell types, 17 especially tumor cells [45,46]. In this study, lipid damage, measured as TBARS production, occurred only with high doses (50μM DHA), and this both in normoxia and hypoxia.…”