title: Dihydroartemisinin targets VEGFR2 via the NF-κB pathway in endothelial cells to inhibit angiogenesis.
abstract: The anti-malarial agent dihydroartemisinin (DHA) has strong anti-angiogenic activity. This study aimed to investigate the molecular mechanism underlying this effect of DHA on angiogenesis. We found that DHA shows a dose-dependent inhibition of proliferation and migration of in HUVECs. DHA specifically down-regulates the mRNA and protein expression of VEGFR2 in endothelial cells. Treatment with DHA increases IκB-α protein and blocks nuclear translocation of NF-κB p65. In addition, DHA directly regulates VEGFR2 promoter activity through p65 binding motif, and decreases the binding activity of p65 and VEGFR2 promoter, suggesting defective NF-κB signaling may underlie the observed effects of DHA on VEGFR2 expression. In the presence of the NF-κB inhibitor PDTC, DHA could not further repress VEGFR2. Co-treatment with PDTC and DHA produced minimal changes compared to the effects of either drug alone in in vitro angiogenesis assays. Similar findings were found in vivo through a mouse retinal neovascularization model examining the effects of PDTC and DHA. Our data suggested that DHA inhibits angiogenesis largely through repression of the NF-κB pathway. DHA is well tolerated, and therefore may be an ideal candidate to use clinically as an angiogenesis inhibitor for cancer treatment.
authors.affiliation: a Laboratory of Microvascular Medicine; Medical Research Center; Shandong Provincial Qianfoshan Hospital ; Shandong University ; Jinan , Shandong , China.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Dong
authors.forename: Xia
authors.initials: X
authors.lastname: Zhou
authors.forename: Changsheng
authors.initials: C
authors.lastname: Li
authors.forename: Suhua
authors.initials: S
authors.lastname: Yan
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Cao
authors.forename: Liqun
authors.initials: L
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.forename: Thaddeus D
authors.initials: TD
authors.lastname: Allen
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D037621:Artemisinins / Q000494:pharmacology*; D001665:Binding Sites; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D059372:Nucleotide Motifs; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D037621:Artemisinins; D016328:NF-kappa B; D013859:Thiocarbamates; D051996:Transcription Factor RelA; C066229:prolinedithiocarbamate; C039060:artenimol; D011392:Proline; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: DHA, Dihydroartemisinin; EC, Endothelial Cell; ECIS, Electric Cell-Substrate Impedance Sensing; EGF, Epidermal Growth Factor; HUVEC, Human Umbilical Vein Endothelial Cell; NF-κB; NF-κB, nuclear factor-kappa B; PDTC, Pyrrolidine Dithiocarbamate; VEGFR, Vascular Endothelial Growth Factor Receptor; VEGFR2; angiogenesis; dihydroartemisinin; endothelial cells