Author/Authors :
Rodrigo Leite de Oliveira، نويسنده , , Rodrigo and Deschoemaeker، نويسنده , , Sofie and Henze، نويسنده , , Anne-Theres and Debackere، نويسنده , , Koen and Finisguerra، نويسنده , , Veronica and Takeda، نويسنده , , Yukiji and Roncal، نويسنده , , Carmen and Dettori، نويسنده , , Daniela and Tack، نويسنده , , Evelyne and Jِnsson، نويسنده , , Yannick and Veschini، نويسنده , , Lorenzo and Peeters، نويسنده , , Annelies and Anisimov، نويسنده , , Andrey and Hofmann، نويسنده , , Matthias and Alitalo، نويسنده , , Kari and Baes، نويسنده , , Myriam and Dʹhooge، نويسنده , , Jan and Carmeliet، نويسنده , , Peter J. Mazzone، نويسنده , , Massimiliano، نويسنده ,
Abstract :
Summary
ccess 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.
