title: ENMD-1198, a new analogue of 2-methoxyestradiol, displays both antiangiogenic and vascular-disrupting properties.
abstract: The formation of a new vascular network by angiogenesis is a key driver in tumor growth and metastasis, making this an attractive therapeutic target. Different strategies are being developed to either prevent tumor angiogenesis or disrupt the tumor vasculature already in place. In this in vitro study, we investigated the antivascular properties of ENMD-1198, a new anticancer drug currently in clinical trials. ENMD-1198 is a new analogue of 2-methoxyestradiol, a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma and hormone-refractory prostate cancer. Using both bone marrow-derived and dermal microvascular endothelial cell lines, we analyzed the effect of ENMD-1198 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-methoxyestradiol at inhibiting endothelial cell proliferation, motility, migration, and morphogenesis. In addition, ENMD-1198 induced a significant decrease in vascular endothelial growth factor receptor-2 protein expression in endothelial cells. Furthermore, videomicroscopy experiments showed that ENMD-1198 was able to completely disrupt preformed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerization of the microtubule network and accumulation of actin stress fibers and large focal adhesions in vascular endothelial cells. Collectively, our results show that this new compound displays potent antivascular properties, and this study provides important insights into the mechanism of action of this promising new anticancer drug.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia.
authors.forename: Eddy
authors.initials: E
authors.lastname: Pasquier
authors.forename: Snega
authors.initials: S
authors.lastname: Sinnappan
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Munoz
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
mesh_terms: D000077584:2-Methoxyestradiol; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D004963:Estrenes / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: C530263:2-methoxyoestra-1,3,5(10),16-tetraene-3-carboxamide; D020533:Angiogenesis Inhibitors; D004963:Estrenes; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol