Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice

• Type of Material: Article
• Authors: Sulochana S. Bhandarkar, Emory University; Marisa Jaconi, Geneva University; Levi E. Fried, Emory University; Michael Y. Bonner, Emory University; Benjamin Lefkove, Emory University; Baskaran Govindarajan, Emory University; Betsy N. Perry, Emory University; Ravi Parhar, Emory University; Jamie MacKelfresh, Emory University; Allie Sohn, Emory University; Michael Stouffs, Geneva University; Ulla Knaus, The Scripps Research Institute; George Yancopoulos, Regeneron Pharmaceuticals Inc.; Yvonne Reiss, Frankfurt University; Andrew V. Benest, German Cancer Research Centre Heidelberg; Hellmut G. Augustin, German Cancer Research Centre Heidelberg; Jack Arbiser, Emory University
• Language: English
• Date: 2009-08-03
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2009, American Society for Clinical Investigation
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 119
• Issue: 8
• Start Page: 2359
• End Page: 2365
• Grant/Funding Information: H.G. Augustin and Y. Reiss were supported by the Deutsche Forschungsgemeinschaft (SFB-TR23, Vascular Differentiation and Remodeling).; B. Govindarajan was supported by a Dermatology Foundation Career Development award.; J.L. Arbiser was supported by NIH grant R01 AR02030, and grants from the Jamie Rabinowitch-Davis Foundation and the Minsk Foundation.
• Research Categories: Health Sciences, Immunology

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.