Abstract
The aim of this study was to investigate effects of high LET α-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 α-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 α-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 α-radiation reduced survival of HEK293. A significantly elicited cell cycle arrest in G2/M phase after co-treatment of ATMi with α-radiation and X-ray. The most prominent treatment effect was observed in the HEK293 by combining α-radiation and inhibitions. ATMi preferentially sensitized cancer cells and normal HEK293 cells to α-radiation. DNA-PKi and ATMi can sensitize cancer cells to X-ray, but the effectiveness was dependent on cancer cells itself. α-radiation reduced proliferation in primary fibroblast without G2/M arrest.
Highlights
Radiation still remains the most widely utilized treatment modality in the clinical management of c ancer[1]
Repair of complex DNA lesions induced by high LET radiation is still not well understood, it has been proposed that complex double strand breaks (DSBs) generated by high LET irradiation are repaired by HR and not non-homologous end joining (NHEJ) in mammalian cells[9]
In our work we compared the radiobiological effects of combining DNA damage response (DDR) inhibitors (DNA-PK and Ataxia-telangiectasia mutated (ATM)) to alpha particle high LET radiation and X-ray low LET radiation in different cell lines
Summary
Radiation still remains the most widely utilized treatment modality in the clinical management of c ancer[1]. Ra-223 monotherapy in metastatic prostate cancer reported an overall survival benefit of 3.6 months compared to placebo (phase III ALpharadin in SYMPtomatic prostate CAncer patients (ALSYMPCA) s tudy[5] In this patient group with metastatic prostate cancer, the prevalence of germline alterations in DNA repair genes (BRCA1, BRCA2, and ATM) may be as high as 11.8%6. Protection of single stranded DNA upon replication stress[15] Inhibitors of these three PIKKs are in phase I/ II clinical trials as single agent or in combination treatments. Cheng et al.[16] investigated sensitizing effects of inhibitors of ATM and DNA-PK kinase activity towards alpha and gamma radiation in primary lymphocytes, little is known about the combination effects on human tumor cells. Cellular parameters such as cell cycle distribution, clonogenic cell survival and micronucleus formation were investigated to determine the cellular effects of the combination of DDR inhibitors and radiation
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