Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lohberger, B; Barna, S; Glänzer, D; Eck, N; Leithner, A; Georg, D.
DNA-PKcs Inhibition Sensitizes Human Chondrosarcoma Cells to Carbon Ion Irradiation via Cell Cycle Arrest and Telomere Capping Disruption.
Int J Mol Sci. 2024; 25(11): 6179
Doi: 10.3390/ijms25116179
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- Führende Autor*innen der Med Uni Graz
- Lohberger Birgit
- Co-Autor*innen der Med Uni Graz
- Eck Nicole
- Glänzer Dietmar
- Leithner Andreas
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- Abstract:
- In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G2/M arrest. The expression of the G2/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- DNA-Activated Protein Kinase - antagonists & inhibitors, metabolism, genetics
- Cell Line, Tumor - administration & dosage
- Chondrosarcoma - metabolism, genetics, radiotherapy, drug therapy
- Heavy Ion Radiotherapy - administration & dosage
- Telomere - drug effects, metabolism
- Cell Cycle Checkpoints - drug effects, radiation effects
- DNA Repair - drug effects
- Radiation Tolerance - drug effects
- Pyrazoles - pharmacology
- Cell Proliferation - drug effects
- Bone Neoplasms - metabolism, genetics, pathology, drug therapy
- G2 Phase Cell Cycle Checkpoints - drug effects, radiation effects
- Find related publications in this database (Keywords)
- carbon ion irradiation
- chondrosarcoma
- AZD7648
- DNA-PKcs inhibitor
- telomere length