Abstract
Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.
Highlights
The DNA damage response plays a dual role in cancer since it prevents genomic instabilities that can cause cancer, while on the other hand it might protect tumors from therapy-induced DNA damage [1,2,3]
Enhanced PRKDC expression in neuroblastoma patients correlates with poor prognosis For clinical purposes it would be desirable that anticancer agents exert their effects on cancer cells, so unwanted side effects in healthy organs will be limited
Radiosensitization of tumor cells by preventing non-homologous end-joining (NHEJ) of DSBs has successfully been studied for different tumor types, after it was shown that DSB repair by NHEJ is the predominant mechanism by which tumor cells might escape from radiation-induced cell death [8]
Summary
The DNA damage response plays a dual role in cancer since it prevents genomic instabilities that can cause cancer, while on the other hand it might protect tumors from therapy-induced DNA damage [1,2,3]. Cells have a variety of repair pathways for the repair of DNA single- and double-strand breaks (SSBs and DSBs) to maintain genomic. DNA-PK As Target for Radiosensitization of Neuroblastoma Cells. Dutch Children Cancer Free Foundation, Villa Joep and the Tom Voûte Fund
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