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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
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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
PMID: 19620773
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Research group Mécanismes de différentiation cellulaire des cellules cardiaques (536)
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BHANDARKAR, S. S. et al. Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice. In: Journal of Clinical Investigation, 2009, vol. 119, n° 8, p. 2359-2365. https://archive-ouverte.unige.ch/unige:11152

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Deposited on : 2010-08-27

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