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Hedgehog signaling sensitizes glioma stem cells to endogenous nano-irradiation

Agnieszka Morgenroth1, Andreas T J Vogg1, Katja Ermert1

  • 1Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.

Oncotarget
|July 1, 2014
PubMed

Insights

Targeting therapy-resistant glioma stem cells with Sonic hedgehog ligand sensitizes them to nano-irradiation. This novel approach, using [I-125]ITdU, induces fatal DNA damage and apoptosis, offering a new glioblastoma treatment strategy.

Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Radiotherapy

Background:

  • Therapy-resistant glioma stem cells (GSCs) drive glioblastoma recurrence and incurability.
  • The Hedgehog pathway, particularly Sonic hedgehog (Shh) ligand, is crucial for GSC self-renewal and survival.

Purpose of the Study:

  • To investigate the potential of Shh ligand in sensitizing GSCs to endogenous nano-irradiation.
  • To develop a targeted therapeutic strategy for glioblastoma using Shh pathway modulation and targeted radiotherapy.

Main Methods:

  • Glioma stem cells were treated with Sonic hedgehog ligand to induce cell cycle progression into the radiosensitive G2/M phase.
  • Inhibition of de novo thymidine synthesis with fluorodeoxyuridine followed by treatment with the thymidine analogue 5-[I-125]-Iodo-4'-thio-2'-deoxyuridine ([I-125]ITdU).
  • Analysis of GSC apoptosis induction, DNA repair mechanisms, and in vitro survival following treatment.

Main Results:

  • Sonic hedgehog ligand treatment preferentially sensitized GSCs to nano-irradiation by activating the G2/M phase.
  • [I-125]ITdU incorporation into DNA led to fatal nano-irradiation and invoked apoptosis, overcoming DNA repair.
  • Glioma stem cells demonstrated a differential response to Shh ligand compared to non-stem glioblastoma cells and astrocytes.
  • [I-125]ITdU treatment completely inhibited GSC survival in vitro.

Conclusions:

  • Sonic hedgehog ligand can effectively sensitize glioblastoma stem cells to nano-irradiation.
  • Targeted delivery of [I-125]ITdU to proliferating GSCs offers a potent strategy for inducing apoptosis and eliminating GSCs.
  • This study presents a controllable, single-cell kill therapeutic model for targeting glioblastoma stem cells.

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