Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity

Rodrigo Leite de Oliveira, Sofie Deschoemaeker, Anne-Theres Henze, Koen Debackere, Veronica Finisguerra, Yukiji Takeda, Carmen Roncal, Daniela Dettori, Evelyne Tack, Yannick Jönsson, Lorenzo Veschini, Annelies Peeters, Andrey Anisimov, Matthias Hofmann, Kari Alitalo, Myriam Baes, Jan D'hooge, Peter Carmeliet, Massimiliano Mazzone

Research output: Contribution to journalArticlepeer-review

110 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)263-77
Number of pages15
JournalCANCER CELL
Volume22
Issue number2
DOIs
Publication statusPublished - 14 Aug 2012

Keywords

  • Alleles
  • Animals
  • Antineoplastic Agents
  • Antioxidants
  • Basic Helix-Loop-Helix Transcription Factors
  • Cisplatin
  • Doxorubicin
  • Gene Targeting
  • Heart Diseases
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Kidney Diseases
  • Mice
  • Neoplasms
  • Organ Specificity
  • Procollagen-Proline Dioxygenase
  • Journal Article
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity'. Together they form a unique fingerprint.

Cite this