Phd2 inactivation enhances chemotherapy delivery and protects normal tissues from toxicity.

  • Major finding:Phd2 inactivation enhances chemotherapy delivery and protects normal tissues from toxicity.

  • Mechanism:Phd2 loss increases tumor vessel perfusion and HIF-mediated detoxification in normal organs.

  • Impact: PHD2 is a critical regulator of ROS, and its inhibition may improve chemotherapeutic efficacy.

The effectiveness of chemotherapy is limited by abnormal tumor vessels that impede drug delivery and by toxic side effects in normal tissues that lead to oxidative damage and organ failure. Tumor angiogenesis and scavenging of reactive oxygen species (ROS) are part of an adaptive response to low oxygen tension that is modulated by the prolyl hydroxylase domain-containing proteins (PHD), which negatively regulate hypoxia-inducible factors (HIF). Because haplodeficiency for Phd2 in particular has been shown to promote the normalization of tumor blood vessel structure, Leite de Oliveira and colleagues tested whether inactivation of this gene would also improve responses to chemotherapy. Tumor-bearing mice heterozygous for Phd2 exhibited enhanced tumor vessel perfusion and pericyte coverage that was accompanied by increased intratumoral accumulation of cisplatin and doxorubicin, indicating that Phd2 deficiency enhanced drug delivery and antitumor activity. In support of this observation, partial loss of Phd2 also resulted in decreased tumor growth and greater tumor sensitivity to low-dose chemotherapy. This effect was dependent on stromal deletion of Phd2 in endothelial cells, and equivalent chemosensitization was observed with acute deletion of one or two Phd2 alleles. Furthermore, loss of Phd2 conferred a protective effect against chemotherapy-induced side toxicities and increased survival after acute chemotherapy treatment. Phd2 deficiency in healthy tissues or treatment with the nonspecific prolyl hydroxylase inhibitor dimethyloxaloylglycine preserved kidney and cardiac morphology and suppressed plasma levels of tissue injury markers. This protection was dependent on ROS-mediated stimulation of HIF transcriptional activity following chemotherapy, which led to elevated induction of antioxidative enzymes, such as superoxide dismutases, catalase, and glutathione peroxidase 1, in Phd2-deficient tissues. These results suggest that Phd2 inactivation lowers the threshold for initiation of cellular detoxification mechanisms and that PHD2-specific inhibitors, although not yet available, may augment chemotherapeutic responses.

Leite de Oliveira R, Deschoemaeker S, Henze AT, Debackere K, Finisguerra V, Takeda Y, et al. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer Cell 2012;22:263–77.