Induction of apoptosis and inhibition of cell migration and tube-like formation by dihydroartemisinin in murine lymphatic endothelial cells.
Dihydroartemisinin (DHA) is a semisynthesized agent from the artemisinin first extracted from the Chinese plant Artemisia annua. Previous studies have shown that artemisinin derivates, apart from their antimalarial activity, possess antitumor, antiangiogenic, and anti-inflammatory effects. In the present investigation, DHA was found to have a potent ability in influencing lymphatic endothelial cells (LECs) behavior. Murine LECs were isolated from benign lymphangiomas induced by intraperitoneal injection of incomplete Freund's adjuvant and identified by indirect immunofluorescence assay and fluorescence-activated cell sorting analysis to examine the expression of the specific marker VEGFR-3/Flt-4. When LECs were treated with DHA at 10 microg/ml, the growth of LECs was inhibited, and LECs showed typical apoptotic morphological features, with a higher apoptotic rate as compared with the controls. DHA also exerted a significant inhibitory effect on migration and tube-like formation of LECs in a dose-dependent manner. Quantitative RT-PCR further showed that DHA remarkably downregulated the expression of antiapoptotic bcl-2 mRNA, but upregulated that of the proapoptotic gene bax mRNA. In addition, DHA could strongly attenuate the mRNA and protein levels of VEGFR-3/Flt-4. In summary, these findings indicate that DHA may be useful as a potential lymphangiogenesis inhibitor under induction of cell apoptosis, inhibition of the migration, and formation of tube-like structures in LECs.
Wang
Jun
J
Cancer Institute of People's Liberation Army, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China.
Guo
Yan
Y
Zhang
Bi-Cheng
BC
Chen
Zheng-Tang
ZT
Gao
Jian-Fei
JF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000032:analysis; D012717:Sesquiterpenes / Q000494:pharmacology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000235:genetics
D037621:Artemisinins; D012333:RNA, Messenger; D012717:Sesquiterpenes; D051028:bcl-2-Associated X Protein; C039060:artenimol; D040321:Vascular Endothelial Growth Factor Receptor-3