The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects.

摘要: Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable inhibitor PX-478 reduces protein levels signaling vitro dose-dependent manner provides direct radiosensitization of hypoxic cancer cells clonogenic survival assays using C6 glioma, HN5 UMSCCa10 squamous cells, Panc-1 pancreatic adenocarcinoma lines. However, yields striking vivo sensitization single-dose irradiation, which cannot be explained by incremental improvement killing. show prevents postradiation abrogates downstream stromal reporter xenografts measured serial ultrasound, vascular magnetic resonance imaging, hypoxia response element-specific micro-positron emission tomography imaging. The primacy indirect effects was corroborated our findings (a) either concurrent or early sequencing roughly equivalent (b) constitutive endothelial growth factor expression maintains refractory vessel function progression following combined radiation PX-478. These results confirm disruption adaptive imparts increased therapeutic efficacy through blockade HIF-1-dependent reconstitution function. Successful translation targeted clinical setting will require specific consideration mechanisms.