title: FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism.
abstract: OBJECTIVE
  Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action.
  
  
  METHODS
  Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status.
  
  
  RESULTS
  rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL's antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype.
  
  
  CONCLUSIONS
  FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Valentine
authors.forename: Martin
authors.initials: M
authors.lastname: O'Rourke
authors.forename: Anita
authors.initials: A
authors.lastname: Yakkundi
authors.forename: Jenny
authors.initials: J
authors.lastname: Worthington
authors.forename: Michelle
authors.initials: M
authors.lastname: Hookham
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
authors.forename: Helen O
authors.initials: HO
authors.lastname: McCarthy
authors.forename: Keeva
authors.initials: K
authors.lastname: McClelland
authors.forename: Lynn
authors.initials: L
authors.lastname: McCallum
authors.forename: Hayder
authors.initials: H
authors.lastname: Dyer
authors.forename: Hayley
authors.initials: H
authors.lastname: McKeen
authors.forename: David J J
authors.initials: DJ
authors.lastname: Waugh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Roberts
authors.forename: Joanne
authors.initials: J
authors.lastname: McGregor
authors.forename: Graham
authors.initials: G
authors.lastname: Cotton
authors.forename: Iain
authors.initials: I
authors.lastname: James
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.forename: David G
authors.initials: DG
authors.lastname: Hirst
authors.forename: Tracy
authors.initials: T
authors.lastname: Robson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D042783:Endothelial Cells / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000235:genetics; D020104:Immunophilins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D022021:Tacrolimus Binding Proteins; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C476399:Cd44 protein, mouse; C400101:FKBPL protein, human; D018960:Hyaluronan Receptors; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D043823:Taxoids; D000077143:Docetaxel; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins