Back to Search
Start Over
Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2009 Aug; Vol. 119 (8), pp. 2359-65. Date of Electronic Publication: 2009 Jul 13. - Publication Year :
- 2009
-
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.
- Subjects :
- Angiopoietin-2 physiology
Animals
Endothelial Cells metabolism
Hemangioma pathology
Intracellular Signaling Peptides and Proteins
Mice
NADPH Oxidase 4
NADPH Oxidases genetics
NADPH Oxidases physiology
Proteins genetics
Vascular Endothelial Growth Factor A antagonists & inhibitors
Cyclopentanes pharmacology
Enzyme Inhibitors pharmacology
Hemangioma drug therapy
NADPH Oxidases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 119
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 19620773
- Full Text :
- https://doi.org/10.1172/JCI33877