Gene-Targeting of Phd2 Improves Tumor Response to Chemotherapy and Prevents Side-Toxicity

被引：111

作者：

de Oliveira, Rodrigo Leite ^{[1
,2
,3
,4
]}

Deschoemaeker, Sofie ^{[1
,3
]}

Henze, Anne-Theres ^{[1
,3
]}

Debackere, Koen ^{[1
,3
]}

Finisguerra, Veronica ^{[1
,3
]}

Takeda, Yukiji ^{[1
,2
,3
,4
]}

Roncal, Carmen ^{[1
,2
,3
,4
,5
]}

Dettori, Daniela ^{[1
,2
,3
,4
]}

Tack, Evelyne ^{[1
,3
]}

Jonsson, Yannick ^{[1
,3
]}

Veschini, Lorenzo ^{[1
,3
]}

Peeters, Annelies ^{[6
]}

Anisimov, Andrey ^{[8
]}

Hofmann, Matthias ^{[9
]}

Alitalo, Kari ^{[8
]}

Baes, Myriam ^{[6
]}

D'hooge, Jan ^{[7
]}

Carmeliet, Peter ^{[2
,4
]}

Mazzone, Massimiliano ^{[1
,3
]}

机构：

[1] VIB, Vesalius Res Ctr, Lab Mol Oncol & Angiogenesis, B-3000 Louvain, Belgium

[2] VIB, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium

[3] Katholieke Univ Leuven, Vesalius Res Ctr, Lab Mol Oncol & Angiogenesis, Dept Oncol, B-3000 Louvain, Belgium

[4] Katholieke Univ Leuven, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, Dept Oncol, B-3000 Louvain, Belgium

[5] Univ Navarra, Atherosclerosis Res Lab, CIMA, Pamplona 31008, Spain

[6] Katholieke Univ Leuven, Lab Cell Metab, B-3000 Louvain, Belgium

[7] Katholieke Univ Leuven, Div Cardiovasc Imaging & Dynam, B-3000 Louvain, Belgium

[8] Inst Mol Med, Res Programs Unit, Mol Canc Biol Lab, Helsinki 00014, Finland

[9] Goethe Univ Frankfurt, Dept Dermatol, D-60590 Frankfurt, Germany

来源：

CANCER CELL | 2012年 / 22卷 / 02期

关键词：

INDUCIBLE FACTOR-I; ISCHEMIA-REPERFUSION INJURY; INTERSTITIAL FLUID PRESSURE; OXIDATIVE STRESS; CANCER-THERAPY; TRANSCRIPTIONAL ACTIVATION; OXYGEN SENSORS; HYPOXIA; NORMALIZATION; PATHWAY;

D O I：

10.1016/j.ccr.2012.06.028

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：263 / 277

页数：15

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