title: Inhibition of angiogenesis: a novel antitumor mechanism of the herbal compound arctigenin.
abstract: Arctigenin, a functional ingredient of several traditional Chinese herbs, has been reported to have potential antitumor activity. However, its mechanisms of action are still not well elucidated. Because the establishment and metastatic spread of tumors is crucially dependent on angiogenesis, here we investigated whether arctigenin inhibits tumor growth by disturbing blood vessel formation. For this purpose, human dermal microvascular endothelial cells were exposed to different arctigenin doses to study their viability, proliferation, protein expression, migration, and tube formation compared with vehicle-treated controls. In addition, arctigenin action on vascular sprouting was analyzed in an aortic ring assay. Furthermore, we studied direct arctigenin effects on CT26.WT colon carcinoma cells. Spheroids of these tumor cells were transplanted into the dorsal skinfold chamber of arctigenin-treated and vehicle-treated BALB/c mice for the in-vivo analysis of tumor vascularization and growth by intravital fluorescence microscopy, histology, and immunohistochemistry. We found that noncytotoxic doses of arctigenin dose dependently reduced the proliferation of human dermal microvascular endothelial cells without affecting their migratory and tube-forming capacity. Arctigenin treatment also resulted in a decreased cellular expression of phosphorylated serine/threonine protein kinase AKT, vascular endothelial growth factor receptor 2, and proliferating cell nuclear antigen and inhibited vascular sprouting from aortic rings. In addition, proliferation, but not secretion of vascular endothelial growth factor, was decreased in arctigenin-treated tumor cells. Finally, arctigenin suppressed the vascularization and growth of engrafting CT26.WT tumors in the dorsal skinfold chamber model. Taken together, these results show for the first time an antiangiogenic action of arctigenin, which may contribute considerably toward its antitumor activity.
authors.affiliation: Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gu
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Dilu
authors.initials: D
authors.lastname: Feng
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Laschke
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D008517:Phytotherapy; D010946:Plants, Medicinal; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors; D046509:Tissue Culture Techniques; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D017705:Lignans; C071942:arctigenin