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

• DOI: 10.1016/j.ccr.2012.06.028
• Publication Date: 2012-08-13T15:34:21Z
• Authors: Rodrigo Leite de ...; 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
• Keywords: 0301 basic medicine; Cancer Research; mice; Heart Diseases; Antioxidants/metabolism; Heart Diseases/chemically induced; Procollagen-Proline Dioxygenase; 610; Antineoplastic Agents; alpha Subunit; Research Support; Antioxidants; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; 03 medical and health sciences; Neoplasms; Journal Article; Basic Helix-Loop-Helix Transcription Factors; Animals; Non-U.S. Gov't; Alleles; Basic Helix-Loop-Helix Transcription Factors/metabolism; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Organ Specificity/drug effects; Gene targeting; Antineoplastic Agents/adverse effects; Cell Biology; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms/drug therapy; 3. Good health; Oncology; Doxorubicin; Organ Specificity; Cisplatin/adverse effects; Gene Targeting; Alleles; Animals; Antineoplastic Agents; Antioxidants; Basic Helix-Loop-Helix Transcription Factors; Cisplatin; Doxorubicin; Heart Diseases; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney Diseases; Mice; Neoplasms; Organ Specificity; Procollagen-Proline Dioxygenase; Gene Targeting; Kidney Diseases; Hypoxia-Inducible Factor 1; Doxorubicin/adverse effects; Cisplatin; Procollagen-Proline Dioxygenase/deficiency; Kidney Diseases/chemically induced

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.