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: Agnieszka Morgenroth, Andreas T J Vogg, Katja Ermert, Boris Zlatopolskiy, Felix M Mottaghy
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 14 Pg. 5483-93 (Jul 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24978848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-iodo-4'-thio-2'-deoxyuridine
• Hedgehog Proteins
• Iodine Radioisotopes
• Radiopharmaceuticals
• Deoxyuridine

Topics

• Apoptosis (radiation effects)
• Brain Neoplasms (metabolism, pathology, radiotherapy)
• Cell Line, Tumor
• Cell Proliferation (radiation effects)
• Deoxyuridine (administration & dosage, analogs & derivatives)
• Glioblastoma (metabolism, pathology, radiotherapy)
• Hedgehog Proteins (metabolism)
• Humans
• Iodine Radioisotopes (administration & dosage)
• Neoplastic Stem Cells (metabolism, pathology, radiation effects)
• Radiation Tolerance
• Radiopharmaceuticals (administration & dosage)
• Signal Transduction (radiation effects)