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Title: Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity
Authors: Leite de Oliveira, Rodrigo
Deschoemaeker, Sofie
Henze, Anne-Theres
Debackere, K
Finisguerra, Veronica
Takeda, Yukiji
Roncal, Carmen
Dettori, Daniela
Tack, Evelyne
J├Ânsson, Yannick
Veschini, Lorenzo
Anisimov, Andrey
Hofmann, Matthias
Alitalo, Kari
Baes, Myriam
D'hooge, Jan
Carmeliet, Peter
Mazzone, Max # ×
Issue Date: Aug-2012
Publisher: Cell Press
Series Title: Cancer Cell vol:22 issue:2 pages:263-277
Article number: 10.1016/j.ccr.2012.06.028
Abstract: The success of chemotherapy in cancer treatment is limited by scarce drug delivery to the tumor and severe side-toxicity. Prolyl hydroxylase domain protein 2 (PHD2) is an oxygen/redox-sensitive enzyme that induces cellular adaptations to stress conditions. Reduced activity of PHD2 in endothelial cells normalizes tumor vessels and enhances perfusion. Here, we show that tumor vessel normalization by genetic inactivation of Phd2 increases the delivery of chemotherapeutics to the tumor and, hence, their antitumor and antimetastatic effect, regardless of combined inhibition of Phd2 in cancer cells. In response to chemotherapy-induced oxidative stress, pharmacological inhibition or genetic inactivation of Phd2 enhances a hypoxia-inducible transcription factor (HIF)-mediated detoxification program in healthy organs, which prevents oxidative damage, organ failure, and tissue demise. Altogether, our study discloses alternative strategies for chemotherapy optimization.
URI: 
ISSN: 1535-6108
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Cell Metabolism
Cardiovascular Imaging and Dynamics
Laboratory of Angiogenesis and Neurovascular Link (Vesalius Research Center) (+)
Laboratory of Molecular Oncology and Angiogenesis (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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