title: Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice.
abstract: Hemangiomas are the most common type of tumor in infants. As they are endothelial cell-derived neoplasias, their growth can be regulated by the autocrine-acting Tie2 ligand angiopoietin 2 (Ang2). Using an experimental model of human hemangiomas, in which polyoma middle T-transformed brain endothelial (bEnd) cells are grafted subcutaneously into nude mice, we compared hemangioma growth originating from bEnd cells derived from wild-type, Ang2+/-, and Ang2-/- mice. Surprisingly, Ang2-deficient bEnd cells formed endothelial tumors that grew rapidly and were devoid of the typical cavernous architecture of slow-growing Ang2-expressing hemangiomas, while Ang2+/- cells were greatly impaired in their in vivo growth. Gene array analysis identified a strong downregulation of NADPH oxidase 4 (Nox4) in Ang2+/- cells. Correspondingly, lentiviral silencing of Nox4 in an Ang2-sufficient bEnd cell line decreased Ang2 mRNA levels and greatly impaired hemangioma growth in vivo. Using a structure-based approach, we identified fulvenes as what we believe to be a novel class of Nox inhibitors. We therefore produced and began the initial characterization of fulvenes as potential Nox inhibitors, finding that fulvene-5 efficiently inhibited Nox activity in vitro and potently inhibited hemangioma growth in vivo. In conclusion, the present study establishes Nox4 as a critical regulator of hemangioma growth and identifies fulvenes as a potential class of candidate inhibitor to therapeutically interfere with Nox function.
authors.affiliation: Department of Dermatology and Atlanta Veterans Administration Medical Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Sulochana S
authors.initials: SS
authors.lastname: Bhandarkar
authors.forename: Marisa
authors.initials: M
authors.lastname: Jaconi
authors.forename: Levi E
authors.initials: LE
authors.lastname: Fried
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Bonner
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lefkove
authors.forename: Baskaran
authors.initials: B
authors.lastname: Govindarajan
authors.forename: Betsy N
authors.initials: BN
authors.lastname: Perry
authors.forename: Ravi
authors.initials: R
authors.lastname: Parhar
authors.forename: Jamie
authors.initials: J
authors.lastname: Mackelfresh
authors.forename: Allie
authors.initials: A
authors.lastname: Sohn
authors.forename: Michael
authors.initials: M
authors.lastname: Stouffs
authors.forename: Ulla
authors.initials: U
authors.lastname: Knaus
authors.forename: George
authors.initials: G
authors.lastname: Yancopoulos
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Reiss
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Benest
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
mesh_terms: D042702:Angiopoietin-2 / Q000502:physiology; D000818:Animals; D003517:Cyclopentanes / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006391:Hemangioma / Q000188:drug therapy* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D042702:Angiopoietin-2; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C499040:Nrarp protein, mouse; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; C543098:fulvene-5; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse