Hedgehog signaling sensitizes glioma stem cells to endogenous nano-irradiation

Agnieszka Morgenroth, Andreas T J Vogg, Katja Ermert, Boris Zlatopolskiy, Felix M Mottaghy

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The existence of therapy resistant glioma stem cells is responsible for the high recurrence rate and incurability of glioblastomas. The Hedgehog pathway activity plays an essential role for self-renewal capacity and survival of glioma stem cells. We examined the potential of the Sonic hedgehog ligand for sensitizing of glioma stem cells to endogenous nano-irradiation. We demonstrate that the Sonic hedgehog ligand preferentially and efficiently activated glioma stem cells to enter the radiation sensitive G2/M phase. Concomitant inhibition of de novo thymidine synthesis with fluorodeoxyuridine and treatment with the Auger electron emitting thymidine analogue 5-[I-125]-Iodo-4'-thio-2'-deoxyuridine ([I-125]ITdU) leads to a fatal nano-irradiation in sensitized glioma stem cells. Targeting of proliferating glioma stem cells with DNA-incorporated [I-125]ITdU efficiently invokes the intrinsic apoptotic pathway despite active DNA repair mechanisms. Further, [I-125]ITdU completely inhibits survival of glioma stem cells in vitro. Analysis of non-stem glioblastoma cells and normal human astrocytes reveals that glioma stem cells differentially respond to Sonic hedgehog ligand. These data demonstrate a highly efficient and controllable single-cell kill therapeutic model for targeting glioma stem cells.

Original languageEnglish
Pages (from-to)5483-5493
Number of pages11
JournalOncotarget
Volume5
Issue number14
DOIs
Publication statusPublished - 30 Jul 2014

Keywords

  • Apoptosis
  • Brain Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Deoxyuridine
  • Glioblastoma
  • Hedgehog Proteins
  • Humans
  • Iodine Radioisotopes
  • Neoplastic Stem Cells
  • Radiation Tolerance
  • Radiopharmaceuticals
  • Signal Transduction

Cite this