title: In vitro and in vivo characterization of the actin polymerizing compound chondramide as an angiogenic inhibitor.
abstract: OBJECTIVE
  Inhibiting angiogenesis is a major approach in tumour therapy. To combat angiogenesis, the tubulin cytoskeleton has emerged as an interesting target in many pre- and clinical studies. Contrarily, the actin cytoskeleton has been largely neglected as a potential drug target in angiogenesis. However, due to the development of drug resistances, new therapeutic strategies are always needed in tumour treatment. Therefore, the therapeutic potential of actin-binding small molecules is of particular interest.
  
  
  RESULTS
  We investigate the impact of chondramide (Ch), an actin polymerizing myxobacterial compound, on angiogenesis and underlying signalling. Chondramide treatment not only reduces the migration of endothelial cells but also the maturation of endothelial tube networks on matrigel. These observations can partly be explained by a disintegration of stress fibres due to aggregation and subsequent accumulation of actin in cellular structures known as 'aggresomes'. Chondramide treatment impairs the maturation of focal adhesions and reduces the amount of active β1 integrin at the cell surface. Accordingly, signalling events downstream of focal adhesions are reduced. Thus, we observed that the activity of Src and downstream factors Rho-GTPases Rac1 and Rho is reduced upon Ch treatment. In vivo, Ch was well tolerated in mice and vascularization of a tumour xenograft as well as of the developing retina was significantly reduced.
  
  
  CONCLUSIONS
  Chondramide diminishes angiogenesis via two ways: (i) the disintegration of stress fibres and (ii) the reduction of promigratory signals. Our findings highlight Ch as a novel class of therapeutic lead compound with anti-angiogenic potential.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany.
authors.forename: Magdalena H
authors.initials: MH
authors.lastname: Menhofer
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Bartel
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Liebl
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Kubisch
authors.affiliation: Department of Pharmacy, Pharmaceutical Biotechnology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Busse
authors.affiliation: Department of Pharmacy, Pharmaceutical Biotechnology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, Munich 81377, Germany stefan.zahler@cup.uni-muenchen.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001426:Bacterial Proteins; D047630:Depsipeptides; D019012:Integrin beta1; C107953:RAC1 protein, human; C097819:chondramide A; C097820:chondramide B; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins
keywords: Actin; Angiogenesis; Chondramide