Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1.
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 (CD(31)), 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 approximately 50 micromol/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.
Chen
Huan-Huan
HH
Department of Clinical Pharmacology, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, PR China. chenh552@163.com
Zhou
Hui-Jun
HJ
Wu
Guo-Dong
GD
Lou
Xiao-E
XE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology; D037621:Artemisinins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000077332:Artesunate; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000473:pathology; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D000077332:Artesunate; D040281:Vascular Endothelial Growth Factor Receptor-1