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  • Adenine sulfate mg Previous in vitro studies have demonstrat

    2019-11-01

    Previous in vitro studies have demonstrated that DNA-PK-deficient cell line (MO59J) is approximately 30-fold more sensitive to radiation than DNA-PK-proficient cell line (MO59K) [31]. Moreover, specific DNA-PK inhibitors SU11752 and wortmannin have been shown to sensitize GBM Adenine sulfate mg (MO59K) to radiotherapy [32]. Interestingly, SU11752 alone did not affect GBM cell Adenine sulfate mg survival. However, in combination, SU11752 sensitized cells 5-fold to ionizing radiation at 2Gy with even more pronounced effect at higher radiation doses. Most recent in vitro study confirmed that novel DNA-PK inhibitor NU7741 increased the cytotoxicity of irradiation by 2-fold in MO59-Fus-1 cells (DNA-PK-proficient) whereas it had no effect on MO59J cells [33]. NU7741 decreased the repair of radiation-induced DSB and inhibited also homologous recombination (HR) activity (assessed by Rad51 foci) in a DNA-PK dependent manner. This shows that there is a potential cross talk of DNA-PK with another important DNA repair pathway – HR. Additionally, specific inhibition of DNA-PK with short hairpin RNA (shRNA) has been shown to radiosensitize glioma-initiating cells [34]. Since only high expression of DNA-PK correlated with poor survival of GBM patients, the repair of DSB rather than SSB might have a prognostic value. Similarly, previous experimental studies have shown that the incidence of cell killing, and higher response to radiotherapy do not correlate with the induced number of SSB, but relates better to the incidence of DSB [35]. Radiotherapy has been shown to produce equivalent number of DNA lesions in MO59J (DNA-PK-deficient) and MO59K (DNA-PK-proficient) GBM cell lines [36]. Nevertheless, significant DNA damage repair was evident for MO59K cells with a 5.8-fold increase in relative survival, whereas MO59J GBM cells showed little repair capacity. More DSB were repaired by 30min in MO59K cells than in (MO59) cells, suggesting that deficient DSB repair may be a major determinant of radiosensitivity of GBM cells. Present study measured only baseline (preirradiation) levels of PARP-1 and DNA-PK expression. Due to study design, changes in these proteins that might occur during radiotherapy cannot be described. However, previous in vitro study has shown that there is a radiation-induced increase in the activity of PARP in glioblastoma cell line A172 [37]. Also, in MO59K cell line, both DNA-PK relative protein level and DNA-PK activity have been shown to increase in response to irradiation [38]. In contrast, there was no increase in DNA-PK protein level and no detectable kinase activity in DNA-PK deficient MO59J cells, either with or without irradiation. In the present study, only postoperative radiotherapy was used. However, radiotherapy alone is no longer standard adjuvant treatment of GBM. In countries with access to temozolomide, combined treatment consisting of radiotherapy and concomitant as well as adjuvant chemotherapy (radiochemotherapy) is preferably used [4], [39]. Whether tumor PARP-1 and DNA-PK expression have the prognostic value for patients treated with combined treatment schedule, is not clear. Nevertheless, the effect of DNA repair enzymes on combined treatment results is rather plausible since temozolomide has been shown to produce DNA lesions that are substrates for base excision repair (BER) [40] and homologous recombination (HR) DNA repair pathways [41]. In vivo, mice treated with combined treatment of PARP inhibitor E7016 plus radiotherapy and temozolomide, showed additional growth delay of 6days compared with the combination of radiotherapy and temozolomide [42]. Additionally, previous in vitro studies have reported that in glioblastoma cells (MO59K and MO59J), the sensitivity of temozolomide depends on DSB repair efficiency since DSB are critically involved in drug-induced apoptosis [43]. The present study has several limitations. These include retrospective data collection and small number of patients. Also, some important variables, such as tumor O6-methylguanine-DNA methyltransferase (MGMT) methylation status, isocitrate dehydrogenase 1 (IDH1) gene mutation status, recursive partitioning analysis (RPA) and patient’s quality of life scores were not recorded. However, this hypothesis generating study showed that the survival of GBM patients receiving postoperative radiotherapy depends on the tumor expression of DNA-PK. Further studies are needed to confirm these results and to clarify whether DNA-PK inhibitors might have a potential to radiosensitize GBM and improve the treatment outcome of this devastating disease.