Hedgehog signaling sensitizes glioma stem cells to endogenous nano-irradiation

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 ligan...

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Bibliographic Details
Published in:Oncotarget 2014-07, Vol.5 (14), p.5483-5493
Main Authors: Morgenroth, Agnieszka, Vogg, Andreas T J, Ermert, Katja, Zlatopolskiy, Boris, Mottaghy, Felix M
Format: Article
Language:English
Subjects:
Apoptosis - radiation effects
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
Brain Neoplasms - radiotherapy
Cell Line, Tumor
Cell Proliferation - radiation effects
Deoxyuridine - administration & dosage
Deoxyuridine - analogs & derivatives
Glioblastoma - metabolism
Glioblastoma - pathology
Glioblastoma - radiotherapy
Hedgehog Proteins - metabolism
Humans
Iodine Radioisotopes - administration & dosage
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Neoplastic Stem Cells - radiation effects
Radiation Tolerance
Radiopharmaceuticals - administration & dosage
Research Paper
Signal Transduction - radiation effects
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2123