Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity.
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.
Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
Rodrigo
R
Leite de Oliveira
Sofie
S
Deschoemaeker
Anne-Theres
AT
Henze
Koen
K
Debackere
Veronica
V
Finisguerra
Yukiji
Y
Takeda
Carmen
C
Roncal
Daniela
D
Dettori
Evelyne
E
Tack
Yannick
Y
Jönsson
Lorenzo
L
Veschini
Annelies
A
Peeters
Andrey
A
Anisimov
Matthias
M
Hofmann
Kari
K
Alitalo
Myriam
M
Baes
Jan
J
D'hooge
Peter
P
Carmeliet
Massimiliano
M
Mazzone
D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use; D018390:Gene Targeting; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D002945:Cisplatin; D004317:Doxorubicin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C490189:Egln1 protein, mouse