Partially blocking an oxygen-sensing enzyme known as prolyl hydroxylase domain protein 2 (PHD2) could increase the effectiveness of chemotherapy and help reduce the toxic side effects of treatment on normal tissues, researchers report. PHD2 is an oxygen/redox-sensitive enzyme that induces cellular adaptations to stress conditions.
Previous work on tumors by a team at the Vesalius Research Center at the Flanders Institute for Biotechnology (VIB) had shown that even a partial block of PHD2 production at the genetic level leads to normalization of the structure of tumor-feeding blood vessels, which increases tumor perfusion. Building on this finding, the researchers have now shown that this translates to much more efficient delivery of chemotherapy directly to the tumor. Encouragingly, PHD2 inhibition in normal tissues had the additional beneficial effects of protecting organs, including the kidneys and heart, from the damaging effects of chemotherapy by triggering antioxidative responses.
The VIB’s Massimiliano Mazzone, Ph.D., and colleagues carried out their work in mice that had been engineered to express only one of two Phd2 alleles (Phd2+/-). Animals received tumor grafts and were then treated with chemotherapy. Initial experiments showed that in comparison with wild-type mice carrying melanoma tumors, cancer-bearing Phd2+/- animals accumulated much more cisplatin in the tumor itself, and tumors in these mice shrank significantly in response to a suboptimal dose of chemotherapy that wasn’t effective at all in the wild-type mice. Tumors in the Phd2+/- mice exhibited tumor cell apoptosis and reduced proliferation in response to cisplatin therapy.
Similar results were observed in Phd2+/- and wild-type mice carrying Lewis lung adenocarcinomas that were treated using a suboptimal dose of doxorubicin. In this case the wild-type animals as well as showing no tumor response to chemotherapy, the wild-type animals also went on to develop metastases, whereas the Phd2+/- mice developed no metastatic tumors. This prevention of metastasis was probably related to the strong inhibition of primary tumor growth in the Phd2+/- animals, the researchers suggest.
Interestingly, the researchers found that partial Phd2 knockdown significantly reduced the toxic effects of chemotherapy on other organs, and in particular the heart and kidneys. In comparison with wild-type chemotherapy-treated mice, the Phd2+/- animals displayed less evidence of nephrotoxicity and kidney tubule necrosis, and significantly reduced evidence of cardiomyopathy. In effect, Phd2 depletion allowed the initiation of a hypoxia-inducible transcription-factor (HIF)-mediated detoxicification program to prevent chemotherapy-related oxidative damage, and resulting organ failure and tissue death.
In summary, Dr. Mazzone et al conclude, “our study provides insight on how PHD2 can regulate drug delivery to the tumor by sensing oxygen availability and re-adapting vessel perfusion and can counter the onset of chemotherapy-associated side-toxicity by working as a gatekeeper for ROS production.” The researchers report their work in Cancer Cell in an paper titled “Gene-Targeting of Phd2 Improves Tumor Response to Chemotherapy and Prevents Side-Toxicity.”