Journal Article

DNA-PKcs Inhibition Sensitizes Human Chondrosarcoma Cells to Carbon Ion Irradiation via Cell Cycle Arrest and Telomere Capping Disruption

Eck, Nicole, Leithner, Andreas, Georg, Dietmar, Glänzer, Dietmar, Lohberger, Birgit, Barna, Sandra

2024

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Bone Neoplasms - drug therapy / Bone Neoplasms - genetics / Bone Neoplasms - metabolism / Bone Neoplasms - pathology / Carbon / Cell cycle / Cell Cycle Checkpoints - drug effects / Cell Cycle Checkpoints - radiation effects / Cell division / Cell growth / Cell Line, Tumor / Cell Proliferation - drug effects / Chemotherapy / Chondrosarcoma - drug therapy / Chondrosarcoma - genetics / Chondrosarcoma - metabolism / Chondrosarcoma - radiotherapy / Cyclin-dependent kinases / DNA / DNA damage / DNA repair / DNA Repair - drug effects / DNA-Activated Protein Kinase - antagonists & inhibitors / DNA-Activated Protein Kinase - genetics / DNA-Activated Protein Kinase - metabolism / Ethylenediaminetetraacetic acid / Flow cytometry / G2 Phase Cell Cycle Checkpoints - drug effects / G2 Phase Cell Cycle Checkpoints - radiation effects / Genes / Heavy Ion Radiotherapy / Humans / Investigations / Kinases / Medical prognosis / Protein expression / Proteins / Pyrazoles - pharmacology / Radiation therapy / Radiation Tolerance - drug effects / Telomerase / Telomere - drug effects / Telomere - metabolism / Telomeres / Tumors / X-rays