Orateur
Description
Chondrosarcoma is a rare malignant bone tumor characterized by marked radioresistance, frequent hypoxia and enrichment in cancer stem cell populations, which together contribute to poor therapeutic outcomes. This work investigated whether hadrontherapy and PARP inhibition could overcome these resistance mechanisms by comparing the biological responses to X-rays, protons and carbon ions in human chondrosarcoma cell lines with different IDH1 status (OUMS27 and JJ012) and in normal chondrocytes (MC615).
Cells were irradiated under normoxic and chronic hypoxic conditions (20% vs. 1% O₂). Clonogenic survival, cancer stem cell phenotype, hypoxia-associated gene expression and DNA damage response pathways were evaluated. The radiosensitizing effect of the PARP inhibitor olaparib (2 µM) was assessed together with the expression of key DNA repair proteins involved in homologous recombination (ATM, BRCA1) and non-homologous end joining (DNA-PKcs).
Hypoxia promoted stem cell characteristics in OUMS27 cells while reducing the effectiveness of low-LET irradiation. In contrast, carbon ions maintained high biological effectiveness under hypoxic conditions, with only limited oxygen dependence. Clonogenic assays demonstrated that carbon ions consistently produced the highest cell killing, followed by protons and X-rays. Olaparib significantly enhanced radiosensitivity after X-ray and proton irradiation in chondrosarcoma cells, whereas no additional radiosensitization was observed with carbon ions. Similar effects were also detected in normal chondrocytes, indicating that PARP inhibition may increase the response of healthy tissues to low-LET irradiation.
Mechanistically, olaparib efficiently inhibited PARylation without directly activating ATM or BRCA1. Irradiation activated the homologous recombination pathway, whereas olaparib promoted DNA-PKcs activation, suggesting a shift toward NHEJ-dependent repair. These molecular changes are consistent with the observed radiosensitization after low-LET irradiation but not after high-LET carbon ion exposure.
Overall, our results demonstrate that carbon ions efficiently overcome hypoxia-associated radioresistance independently of PARP inhibition, whereas combining olaparib with X-rays or protons represents a promising strategy for enhancing the treatment of chondrosarcoma.