title: Effects of rhizoxin, a microbial angiogenesis inhibitor, on angiogenic endothelial cell functions.
abstract: Our previous study revealed that rhizoxin ([1S-[1R*,3R*,5S*,8R*(1R*,2S*,3E,5E,7E),10R*,11S*,13S*,14E,16S*,17S*]]-10-hydroxy-8-[2-methoxy-1,3,7-trimethyl-8-(2-methyl-4-oxazolyl)-3,5,7-octatrienyl]-11,16-dimethyl-4,7,12,18-tetraoxatetracyclo[15.3.1.03,5.011,13]heneicos-14-ene-6,19-dione) has a potent inhibitory effect on in vivo angiogenesis. However, little is known regarding the mechanism by which rhizoxin exhibits antiangiogenic activity. In this study, we examined its effects on the functions of endothelial cells associated with neovascular formation in vivo, using cultured vascular endothelial cells. Rhizoxin concentration-dependently inhibited the proliferation of bovine carotid artery endothelial cells, human umbilical vein endothelial cells and human dermal microvascular endothelial cells, the IC(50) values being 7, 5 and 0.4 nM, respectively. In addition, it reduced the extracellular plasminogen activator level in bovine vascular endothelial cells in the low nM range, and suppressed the migration of human dermal microvascular endothelial cells in the pM range. Furthermore, it blocked the tubular morphogenesis of human umbilical vein endothelial cells and human dermal microvascular endothelial cells on Matrigel in a concentration-dependent manner; the IC(50) values being 40 and 130 pM, respectively. These results suggest that rhizoxin exhibits antiangiogenic activity through the combined inhibition of some functions of endothelial cells responsible for induction of in vivo angiogenesis.
authors.affiliation: Medical Research and Development Center, The Tokyo Metropolitan Institute of Medical Science (Rinshoken), Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Tokyo 113-8613, Bunkyo, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aoki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Watanabe
authors.forename: Mayumi
authors.initials: M
authors.lastname: Sato
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ikekita
authors.forename: Takashi
authors.initials: T
authors.lastname: Hakamatsuka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Oikawa
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000935:Antifungal Agents; D007783:Lactones; D018942:Macrolides; C041443:rhizoxin; D010960:Plasminogen Activators