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XB-ART-46350
PLoS Biol January 1, 2012; 10 (8): e1001379.

Evolutionarily repurposed networks reveal the well-known antifungal drug thiabendazole to be a novel vascular disrupting agent.

Cha HJ , Byrom M , Mead PE , Ellington AD , Wallingford JB , Marcotte EM .


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.

PubMed ID: 22927795
PMC ID: PMC3423972
Article link: PLoS Biol
Grant support: [+]
Genes referenced: actl6a aplnr erg hba1 hoxa9 kdr pecam1 rab11b.1 rab43 rho rho.2
Morpholinos: rab11b.1 MO1


Article Images: [+] show captions
References [+] :
Bayless, Sphingosine-1-phosphate markedly induces matrix metalloproteinase and integrin-dependent human endothelial cell invasion and lumen formation in three-dimensional collagen and fibrin matrices. 2003, Pubmed


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