a normalized vasculature can enhance the efficacy of chemotherapy and radiotherapy
Prolyl hydroxylase domain protein 2 (PHD2; also known as EGLN1) targets the α-subunits of the hypoxia-inducible factors (HIFs) for degradation in the presence of oxygen. To follow up previous data showing that Phd2 haplodeficiency in endothelial cells in mice can normalize tumour vessels, Leite de Oliveira et al. examined whether such changes could also enhance the delivery of chemotherapy. Having found that Phd2+/− mice showed higher intratumoural drug concentrations and increased drug diffusion out of vessels, the authors assessed chemotherapeutic efficacy. Following a suboptimal regimen of cisplatin that had no effect on subcutaneous B16 melanomas growing in wild-type mice, Phd2+/− mice had improved control of melanoma growth. Similar results were evident in Phd2+/− mice with Lewis lung carcinomas (LLCs) that were treated with a suboptimal dose of doxorubicin. Does this effect of Phd2 haplodeficiency on the efficacy of chemotherapy extend to cells other than endothelial cells? Using an inducible Cre expression system to knockout one or both alleles of Phd2 in all tissues, the authors again found a similar improvement in the efficacy of chemotherapy. They also discovered that the mice were protected from renal and cardiac damage following cisplatin or doxorubicin treatment. Why might this be? HIFs have been implicated in the induction of antioxidant enzymes (AOEs), and the toxicity of these chemotherapeutic drugs has been partially attributed to oxidative stress; indeed, the kidneys and hearts of Phd2+/− mice following chemotherapy had reduced oxidative DNA damage and higher levels of AOEs. This pathway is functionally relevant, as pharmacological inhibition of AOEs blocked the toxicity protection conferred by Phd2 loss. Interestingly, this pathway did not seem to operate in PHD2-deficient LLC cells that were treated with doxorubicin.
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