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

Mol Cancer Ther. 2009 Apr;8(4):947-58. doi: 10.1158/1535-7163.MCT-08-0981.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma / radiotherapy
  • Animals
  • Blotting, Western
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / radiotherapy
  • Cell Hypoxia / radiation effects
  • Enzyme-Linked Immunosorbent Assay
  • Glioma / metabolism
  • Glioma / pathology
  • Glioma / radiotherapy
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / radiotherapy
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunoenzyme Techniques
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Nude
  • Mustard Compounds / pharmacology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / radiotherapy
  • Phenylpropionates / pharmacology*
  • Positron-Emission Tomography
  • Stromal Cells / radiation effects*
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Vascular Endothelial Growth Factor A / metabolism
  • Whole-Body Irradiation

Substances

  • 2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
  • HIF1A protein, human
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mustard Compounds
  • Phenylpropionates
  • Vascular Endothelial Growth Factor A