DNA repair inhibitors sensitize cells differently to high and low LET radiation

The aim of this study was to investigate effects of high LET alpha-radiation in combination with inhibitors of DDR (DNA-PK and ATM) and to compare the effect with the radiosensitizing effect of low LET X-ray radiation. The various cell lines were irradiated with alpha-radiation and with X-ray. Clonogenic survival, the formation of micronuclei and cell cycle distribution were studied after combining of radiation with DDR inhibitors. The inhibitors sensitized different cancer cell lines to radiation. DNA-PKi affected survival rates in combination with alpha-radiation in selected cell lines. The sensitization enhancement ratios were in the range of 1.6-1.85 in cancer cells. ATMi sensitized H460 cells and significantly increased the micronucleus frequency for both radiation qualities. ATMi in combination with alpha-radiation reduced survival of HEK293. A significantly elicited cell cycle arrest in G(2)/M phase after co-treatment of ATMi with alpha-radiation and X-ray. The most prominent treatment effect was observed in the HEK293 by combining alpha-radiation and inhibitions. ATMi preferentially sensitized cancer cells and normal HEK293 cells to alpha-radiation. DNA-PKi and ATMi can sensitize cancer cells to X-ray, but the effectiveness was dependent on cancer cells itself. alpha-radiation reduced proliferation in primary fibroblast without G(2)/M arrest.

Automated summary

This study aimed to investigate the effects of high LET alpha-radiation combined with DDR inhibitors and compare it with the radiosensitizing effect of low LET X-ray radiation. The results showed that the inhibitors sensitized different cancer cell lines to radiation, with sensitization enhancement ratios ranging from 1.6 to 1.85. ATMi preferentially sensitized cancer cells and normal HEK293 cells to alpha-radiation, while DNA-PKi and ATMi could sensitize cancer cells to X-ray depending on the cancer cell type.