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: Sulochana S Bhandarkar, Marisa Jaconi, Levi E Fried, Michael Y Bonner, Benjamin Lefkove, Baskaran Govindarajan, Betsy N Perry, Ravi Parhar, Jamie Mackelfresh, Allie Sohn, Michael Stouffs, Ulla Knaus, George Yancopoulos, Yvonne Reiss, Andrew V Benest, Hellmut G Augustin, Jack L Arbiser
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 119 Issue 8 Pg. 2359-65 (Aug 2009) ISSN: 1558-8238 [Electronic] United States
• PMID: 19620773 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietin-2
• Cyclopentanes
• Enzyme Inhibitors
• Intracellular Signaling Peptides and Proteins
• Nrarp protein, mouse
• Proteins
• Vascular Endothelial Growth Factor A
• fulvene-5
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, mouse

Topics

• Angiopoietin-2 (physiology)
• Animals
• Cyclopentanes (pharmacology)
• Endothelial Cells (metabolism)
• Enzyme Inhibitors (pharmacology)
• Hemangioma (drug therapy, pathology)
• Intracellular Signaling Peptides and Proteins
• Mice
• NADPH Oxidase 4
• NADPH Oxidases (antagonists & inhibitors, genetics, physiology)
• Proteins (genetics)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)