title: Dehydro-alpha-lapachone, a plant product with antivascular activity.
abstract: Antivascular agents have become a standard of treatment for many malignancies. However, most of them target the VEGF pathway and lead to refractoriness. To improve the diversity of options for antivascular therapy, we applied a high-throughput screen for small molecules targeting cell adhesion. We then assayed the resulting antiadhesion hits in a transgenic zebrafish line with endothelial expression of EGFP (Tg(fli1:EGFP)(y1)) to identify nontoxic molecules with antivascular activity selective to neovasculature. This screen identified dehydro-α-lapachone (DAL), a natural plant product. We found that DAL inhibits vessel regeneration, interferes with vessel anastomosis, and limits plexus formation in zebrafish. Furthermore, DAL induces vascular pruning and growth delay in orthotopic mammary tumors in mice. We show that DAL targets cell adhesion by promoting ubiquitination of the Rho-GTPase Rac1, which is frequently up-regulated in many different cancers.
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. igorg@steele.mgh.harvard.edu
authors.forename: Igor
authors.initials: I
authors.lastname: Garkavtsev
authors.forename: Vikash P
authors.initials: VP
authors.lastname: Chauhan
authors.forename: Hon Kit
authors.initials: HK
authors.lastname: Wong
authors.forename: Arpita
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009285:Naphthoquinones / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D029663:Tabebuia / Q000737:chemistry; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D009285:Naphthoquinones; C107953:RAC1 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C029244:xyloidone; D020830:rac1 GTP-Binding Protein