title: Evolutionarily repurposed networks reveal the well-known antifungal drug thiabendazole to be a novel vascular disrupting agent.
abstract: Studies in diverse organisms have revealed a surprising depth to the evolutionary conservation of genetic modules. For example, a systematic analysis of such conserved modules has recently shown that genes in yeast that maintain cell walls have been repurposed in vertebrates to regulate vein and artery growth. We reasoned that by analyzing this particular module, we might identify small molecules targeting the yeast pathway that also act as angiogenesis inhibitors suitable for chemotherapy. This insight led to the finding that thiabendazole, an orally available antifungal drug in clinical use for 40 years, also potently inhibits angiogenesis in animal models and in human cells. Moreover, in vivo time-lapse imaging revealed that thiabendazole reversibly disassembles newly established blood vessels, marking it as vascular disrupting agent (VDA) and thus as a potential complementary therapeutic for use in combination with current anti-angiogenic therapies. Importantly, we also show that thiabendazole slows tumor growth and decreases vascular density in preclinical fibrosarcoma xenografts. Thus, an exploration of the evolutionary repurposing of gene networks has led directly to the identification of a potential new therapeutic application for an inexpensive drug that is already approved for clinical use in humans.
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, USA.
authors.forename: Hye Ji
authors.initials: HJ
authors.lastname: Cha
authors.forename: Michelle
authors.initials: M
authors.lastname: Byrom
authors.forename: Paul E
authors.initials: PE
authors.lastname: Mead
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ellington
authors.forename: John B
authors.initials: JB
authors.lastname: Wallingford
authors.forename: Edward M
authors.initials: EM
authors.lastname: Marcotte
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D013827:Thiabendazole / Q000494:pharmacology*; D059008:Time-Lapse Imaging; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D020533:Angiogenesis Inhibitors; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D008148:Lovastatin; D013827:Thiabendazole; D042461:Vascular Endothelial Growth Factor A; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C467484:VEGFA protein, human