Inhibitory Effects of Artesunate on Angiogenesis and on Expressions of Vascular Endothelial Growth Factor and VEGF Receptor KDR/flk-1

Abstract

Artesunate (ART) is a semi-synthetic derivative of artemisinin extracted from the plant Artemisia annua is a safe and effective antimalarial drug. In the present investigation, ART was found also to inhibit angiogenesis in vivo and in vitro. The anti-angiogenic effect in vivo was evaluated in nude mice by means of human ovarian cancer HO-8910 implantation and immunohistochemical stainings for microvessel (CD₃₁), vascular endothelial growth factor (VEGF) and VEGF receptor KDR/flk-1. Tumor growth was decreased and microvessel density was reduced following drug treatment with no apparent toxicity to the animals. ART also remarkably lowered VEGF expression on tumor cells and KDR/flk-1 expression on endothelial cells as well as tumor cells. The in vitro effect of ART was tested on models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). The results showed that ART significantly inhibited angiogenesis in a dose-dependent form in the range of 0.5∼50 µmol/l. Additionally, the inhibitory effect of ART on HVUEC proliferation was stronger than that on Hela, JAR, HO-8910 cancer cells, NIH-3T3 fibroblast cells and human endometrial cells, indicating that ART was selectively against HUVEC. These findings and the known low toxicity of ART are clues that ART may be a promising angiogenesis inhibitor.

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.…”

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

“…This study was inspired by anticancer studies conducted with AS (Efferth et al, 2001;Chen et al, 2003;2004b GD 1-6 GD 7-13 GD 9.5, 10.5 GD 6-15 GD 6-17 GD 10 GD 10 GD10 GD 10 GD 11 GD 6-15 GD 6-15 GD 11 GD 6-13 FRD50 or 100 = drug dose induces 50% or 100% fetus re-absorbed; GD = gestation day (The day of mating was defined as day 0 of gestation.) * The severe toxic effects were detected in the animals treated with AS after single or multiple intramuscular, intravenous or subcutaneous injections.…”

Effect of interaction of magnetic nanoparticles of Fe3O4 and artesunate on apoptosis of K562 cells

“…Recently, several studies showed that ART could inhibit the growth of various carcinoma cell lines [1][2][3] and suppress tumor cell proliferation by inducing apoptosis, 4 indicating that ART may be a promising novel candidate for leukemia therapy. However, a variety of lines of evidence indicate that ART inhibited cell proliferation in a dose-dependent manner, and a high concentration of ART induced embryo toxicity, [5][6][7] reversible renal damage toxicity, 8 and toxicity to bone development, 9 which limit the usefulness of ART. To minimize side effects associated with dosage during chemotherapy, a promising approach is to combine a conventional chemotherapy with new strategies to maximize efficacy of tumor treatment through inducing cell apoptosis.…”