Quinoline Derivative 10E Enhances Radiotherapy Sensitivity In Non-small Cell Lung Cancer By Inhibiting DNA Damage Repair

Objective:Radiotherapy is an important treatment for non-small cell lung cancer.While radiotherapy resistance is the main obstacle to the effectiveness of radiotherapy in NSCLC,this study was conducted to verify the radiotherapy sensitizing effect of quinoline derivative 10 E on NSCLC through in vivo and in vitro experiments,and to investigate the mechanism of 10 E promoting NSCLC radiotherapy sensitizationMethods:A549 and H460 cells were divided into control,radiotherapy,10 E and combination groups,and the effects of 10 E on the proliferation and radiosensitivity of A549 and H460 cells were investigated by CCK8 assay as well as clone formation assay;the apoptosis and cycle distribution of each treatment group were detected by flow cytometry;immunofluorescence assay was performed to detect DNA in each treatment group of A549 and H460 cells The expression of γ-H2 AX,a marker of DNA damage,was detected in A549 and H460 cells.And also by establishing the A549-LUC xenograft of the lotus mouse model,treated with blank control group,radiotherapy group,10 E group and combination group,during which the growth curve of tumor,tumor weight at the end of treatment,KI67 expression of tumor tissue with HE staining and other phase indicators were recorded.Finally,the activation of NUR77 and key proteins for DNA damage repair in different treatment groups were detected by Western blot assay.Results:The proliferative activity of A549 and H460 cells was significantly inhibited by10 E and the radiosensitivity was significantly improved;the combined treatment group increased the proportion of apoptotic cells and increased the G2/M phase block of cell cycle compared with the radiation group;the focal number of γ-H2 AX was significantly increased in the combined group compared with the radiation group,indicating that 10 E enhanced the cellular DNA damage on the basis of radiation.In animal experiments,tumor-bearing mice in the combination treatment group showed a significant reduction in tumor volume,tumor weight and KI67 fluorescence expression;the activation of key DNA damage repair proteins was significantly reduced and NUR77 expression was increased in the combination treatment group compared with the radiation group alone.Conclusions.(1)Quinoline derivative 10 E combined with radiotherapy further inhibited the proliferative activity,increased the apoptosis level and cycle block,and further aggravated the DNA damage level in NSCLC thereby acting as a radiosensitizing effect of radiotherapy.(2)In vivo animal experiments,quinoline derivative 10 E combined with radiotherapy significantly inhibited tumor growth and tumor proliferation activity,demonstrating the radiosensitizing effect of 10 E in vivo.(3)The quinoline derivative 10 E significantly inhibited the activity of DNA repair protein,thus achieving the effect of radiosensitization.