title: Hedgehog signaling sensitizes glioma stem cells to endogenous nano-irradiation.
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.
authors: Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
authors: Agnieszka
authors: A
authors: Morgenroth
authors: Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
authors: Andreas T J
authors: AT
authors: Vogg
authors: Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
authors: Katja
authors: K
authors: Ermert
authors: Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany. Max Planck Institute for Neurological Research, Cologne, Germany.
authors: Boris
authors: B
authors: Zlatopolskiy
authors: Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany. Department of Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors: Felix M
authors: FM
authors: Mottaghy
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D003857:Deoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D011836:Radiation Tolerance; D019275:Radiopharmaceuticals / Q000008:administration & dosage; D015398:Signal Transduction / Q000528:radiation effects
chemical_list: C465667:5-iodo-4'-thio-2'-deoxyuridine; D053823:Hedgehog Proteins; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D003857:Deoxyuridine