Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells.
Artesunate (ART), a semi-synthetic derivative of artemisinin extracted from the Chinese herb Artemisia annua, is a safe and effective antimalarial drug. In the present investigation, we analyzed the inhibitory effects of ART on angiogenesis and on VEGF production in chronic myeloid leukemia (CML) K562 cells in vitro and in vivo. In order to analyze the effect of ART on VEGF secretion in K562 cells, we examined the level of VEGF secreted in conditioned media (CM) by ELISA assay. The result showed that ART could decrease the VEGF level in CM of K562 cells, even at a lower concentration (2 micromol/l, P<0.01). The inhibitory effect of in vitro angiogenesis was tested on aortic sprouting in fibrin gel. ART could effectively suppress the stimulating angiogenic ability of CM by pretreated with K562 cells for 48 h in a time-dependent manner (days 3-14). The antiangiogenic effect of ART was further evaluated in vivo in chicken chorioallantoic membrane (CAM) neovascularization model. The result indicated that the stimulating angiogenic activity was decreased in response to the K562 cells treated with ART or the CM from K562 cells pretreated with ART in a dose-dependent manner (3-12 micromol/l). Furthermore, we analyzed the level of VEGF expression by western blot and detected the form of VEGF mRNA by RT-PCR in K562 cells. The experiments showed that ART could inhibit the VEGF expression, correlated well with the level of VEGF secreted in CM. These findings suggest that ART might present potential antileukemia effect as a treatment for CML therapy, or as an adjunct to standard chemotherapeutic regimens.
Zhou
Hui-Jun
HJ
Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310031, PR China. zhouhj_zhouhj@yahoo.com
Wang
Wei-Qin
WQ
Wu
Guo-Dong
GD
Lee
Jun
J
Li
Ao
A
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D031172:Artemisia annua / Q000737:chemistry; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D000077332:Artesunate; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D037621:Artemisinins; D012333:RNA, Messenger; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D000077332:Artesunate