Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice.
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.
Bhandarkar
Sulochana S
SS
Department of Dermatology and Atlanta Veterans Administration Medical Center, Emory University, Atlanta, Georgia 30322, USA.
Jaconi
Marisa
M
Fried
Levi E
LE
Bonner
Michael Y
MY
Lefkove
Benjamin
B
Govindarajan
Baskaran
B
Perry
Betsy N
BN
Parhar
Ravi
R
Mackelfresh
Jamie
J
Sohn
Allie
A
Stouffs
Michael
M
Knaus
Ulla
U
Yancopoulos
George
G
Reiss
Yvonne
Y
Benest
Andrew V
AV
Augustin
Hellmut G
HG
Arbiser
Jack L
JL
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
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