UNIGE document Scientific Article
previous document  unige:11152  next document
add to browser collection

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

Bhandarkar, S. S.
Fried, L. E.
Bonner, M. Y.
Lefkove, Benjamin
Govindarajan, Baskaran
Perry, B. N.
Parhar, Ravi
show hidden authors show all authors [1 - 17]
Published in Journal of Clinical Investigation. 2009, vol. 119, no. 8, p. 2359-2365
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.
Keywords Angiopoietin-2/physiologyAnimalsCyclopentanes/ pharmacologyEndothelial Cells/metabolismEnzyme Inhibitors/ pharmacologyHemangioma/ drug therapy/pathologyMiceNADPH Oxidase/ antagonists & inhibitors/genetics/physiologyProteins/geneticsVascular Endothelial Growth Factor A/antagonists & inhibitors
Stable URL http://archive-ouverte.unige.ch/unige:11152
Full text
PMID: 19620773
Research group Mécanismes de différentiation cellulaire des cellules cardiaques (536)
106 hits and 0 download since 2010-08-27
Export document
Format :
Citation style :