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 language | English |
|---|---|
| Pages (from-to) | 5483-5493 |
| Number of pages | 11 |
| Journal | Oncotarget |
| Volume | 5 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - 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