Vol. 294, Issue 2, 421-427, August 2000

Cytochalasin E, an Epoxide Containing Aspergillus-Derived Fungal Metabolite, Inhibits Angiogenesis and Tumor Growth¹

Taturo Udagawa, Jenny Yuan, Dipak Panigrahy, Yie-Hwa Chang², Jamshed Shah³ and Robert J. D'Amato

Departments of Surgical Research (T.U., J.Y., D.P., R.J.D.) and Ophthalmology (R.J.D.), Children's Hospital, Harvard Medical School, Boston, Massachusetts

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.