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. © 2012 Elsevier Inc.

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

Dettori D.;Mazzone M.
2012-01-01

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. © 2012 Elsevier Inc.
2012
22
2
263
277
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
Leite de Oliveira R.; Deschoemaeker S.; Henze A.-T.; Debackere K.; Finisguerra V.; Takeda Y.; Roncal C.; Dettori D.; Tack E.; Jonsson Y.; Veschini L.; Peeters A.; Anisimov A.; Hofmann M.; Alitalo K.; Baes M.; D'hooge J.; Carmeliet P.; Mazzone M.
File in questo prodotto:
File Dimensione Formato  
109.pdf

Accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 2.01 MB
Formato Adobe PDF
2.01 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1841770
Citazioni
  • ???jsp.display-item.citation.pmc??? 56
  • Scopus 107
  • ???jsp.display-item.citation.isi??? 104
social impact