Cytochalasin E, an epoxide containing Aspergillus-derived fungal metabolite, inhibits angiogenesis and tumor growth.
Several previously identified inhibitors of angiogenesis have been epoxide-containing fungus-derived metabolites. We therefore hypothesized that novel epoxide-containing low molecular weight compounds structurally resembling known antiangiogenic agents may also exhibit antiangiogenic activity. Cytochalasin E was found to be a potent and selective inhibitor of bovine capillary endothelial (BCE) cell proliferation. Cytochalasin E differed from other cytochalasins by the presence of an epoxide. The epoxide was required for activity, because acid-catalyzed hydrolysis of the epoxide abrogated the specificity and potency of cytochalasin E. Phalloidin staining indicated that disruption of actin stress fibers by cytochalasin E occurred only at relatively high concentrations. Lower concentrations of cytochalasin E preferentially inhibited BCE cell proliferation without disrupting actin stress fibers. In vivo, cytochalasin E inhibited angiogenesis induced by basic fibroblast growth factor by 40% to 50% in the mouse cornea assay and inhibited the growth of Lewis lung tumors by approximately 72%. Cytochalasin E is a potent antiangiogenic agent that may hold promise for the treatment of cancer and other types of pathologic angiogenesis.
Udagawa
T
T
Department of Surgical Research, Children's Hospital, Harvard Medical School, Boston, MA, USA.
Yuan
J
J
Panigrahy
D
D
Chang
Y H
YH
Shah
J
J
D'Amato
R J
RJ
D016475:3T3 Cells; D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001230:Aspergillus / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003315:Cornea / Q000098:blood supply; D003510:Cyclohexanes; D003572:Cytochalasins / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009183:Mycotoxins / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D003572:Cytochalasins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009183:Mycotoxins; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C007215:cytochalasin E; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol