Abstract
Repair of radiation-induced dna double-strand breaks is a key mechanism in cancer cell radio-resistance. The synthesized compound NU7026 specifically inhibits dna-dependent protein kinase (dna-pk) within the non-homologous end-joining repair mechanism. Earlier studies demonstrated increased radiosensitivity in dna-pk deficient cells compared with wild-type cells. In chronic leukemia cells, NU7026 appears to enhance the cytotoxic effect of chlorambucil. The radio-modifying effects of NU7026 on cell survival, cell cycle, apoptosis, and dna double-strand break repair have yet to be studied in gastric cancer cells. The gastric cancer cell line N87 was treated with 0 Gy or 4 Gy in the presence of NU7026 at a dose range of 0-20 μmol/L. Clonogenic assays were used to assess cell survival after treatment. Cell-cycle distribution was analyzed using propidium iodide with fluorescence-activated cell sorting. Apoptosis was detected using annexin-V and propidium iodide with fluorescence-activated cell sorting. The γH2AX assay was used to measure dna double-strand breaks. Statistically significant increases in G2/M arrest were observed in N87 cells treated with radiation and NU7026 compared with those treated with radiation alone (p = 0.0004). Combined treatment also led to an increase in apoptosis (p = 0.01). At 24 hours, the γH2AX analysis revealed more dna double-strand breaks in N87 cells treated with radiation and NU7026 than in those treated with radiation alone (p = 0.04). Clonogenic assays demonstrated declining cell survival as both the radiation and the NU7026 dose increased. The dose enhancement factor at 0.1 survival fraction was 1.28 when N87 cells were treated with 4 Gy radiation and 5 μmol/L NU7026. In gastric cancer cells, NU7026 appears to enhance the cytotoxic effect of irradiation as assessed by clonogenic assays. This increased cytotoxicity might be the result of an increase in dna double-strand breaks resulting in G2/M cell arrest and possibly higher levels of apoptosis.
Highlights
The management of gastric cancer patients has evolved since the early 2000s
Significant increases in G2/M arrest were observed in N87 cells treated with radiation and NU7026 compared with those treated with radiation alone (p = 0.0004)
NU7026 appears to enhance the cytotoxic effect of irradiation as assessed by clonogenic assays
Summary
The combination of primary surgical resection with perioperative chemotherapy or adjuvant chemoradiation is the standard of care for most of these patients. Despite advances in primary and adjuvant treatments, 50%–70% of patients with advanced gastric or gastroesophageal junction tumours will relapse and die of their disease[1]. Metaanalyses showed modest survival gains with adjuvant chemotherapy[2], but no benefit was found for postoperative radiotherapy alone[3]. The Intergroup 0116 trial demonstrated that postoperative chemoradiation significantly improves survival in patients with gastric and gastroesophageal cancer, and established one of the standard approaches for these patients[4]. Perioperative chemotherapy and adjuvant chemoradiation have improved overall survival, the results—50% overall survival at 3 years—are still suboptimal and in need of further improvement
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