The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects
| Autor: | Garth Powis, Juri G. Gelovani, Junghwan Oh, Uday Mukhopadhay, Mian M. Alauddin, Ryan R. Williams, David L. Schwartz, Robert Lemos, Ryuichi Nishii, James A. Bankson, Zhenghong Peng, Andrei Volgin, Yi He, Arun Thitaikumar, William G. Bornmann, Suren Soghomonyan |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Stromal cell Mustard Compounds Blotting Western Mice Nude Enzyme-Linked Immunosorbent Assay Biology Adenocarcinoma Article Immunoenzyme Techniques chemistry.chemical_compound Mice In vivo Glioma medicine Tumor Cells Cultured Animals Humans Sensitization Tumor Stem Cell Assay Phenylpropionates medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Magnetic Resonance Imaging Cell Hypoxia Vascular endothelial growth factor Pancreatic Neoplasms Vascular endothelial growth factor A medicine.anatomical_structure Oncology chemistry Head and Neck Neoplasms Positron-Emission Tomography Cancer cell Immunology Cancer research Carcinoma Squamous Cell Stromal Cells Whole-Body Irradiation |
| Popis: | 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 HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element–specific micro–positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1–dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms. [Mol Cancer Ther 2009;8(4):947–58] |
| Databáze: | OpenAIRE |
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