Effects of niraparib on the radiosensitivity of human esophageal cancer cells and its mechanism
Zhao Fuzhen1, Feng Yue2, Ma Zhaoming1, Hu Lijun3, Sun Fei3, Wang Jianlin3, Yu Jingping2
1Department of Radiotherapy, the second People's Hospital of Lianyungang, Lianyungang 222000 China; 2Department of Radiotherapy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China; 3Department of Radiotherapy, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou 213003, China
Abstract：Objective To evaluate the effect of niraparib, the poly (ADP-ribose) polymerase (PARP) inhibitor, on the radiosensitivity of esophageal squamous cell carcinoma (ESCC) and to preliminarily investigate its mechanism. Methods Human esophageal squamous cell carcinoma cells ECA-109 and KYSE-150 were divided into the control, niraparib, single irradiation, combined (niraparib+irradiation) groups. Cell proliferation was measured by CCK-8 assay. The changes of cell survival rate were detected by colony formation assay. The changes of cell cycle and apoptosis were analyzed by flow cytometry. The number of γH2AX foci was detected by immunofluorescence, and the expression levels of PARP-1, cleaved-PARP, RAD51, mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase 1 and 2 (ERK1/2) ] and p-MAPK (ERK1/2) proteins were determined by Western blot. All data were expressed as Mean±SD. Data between two groups conforming to normal distribution through the normality test were subject to independent sample t-test and multiple groups were analyzed using one-way ANOVA. Results In human ESCC cells ECA-109 and KYSE-150, the proliferation of ESCC cells was significantly inhibited by niraparib combined with irradiation, and the values of average lethal dose (D0), quasi-threshould dose(Dq), survival fraction after 2 Gy irradiation (SF2) in the combined group were decreased compared with those in the single irradiation group. The effect of irradiation alone on apoptosis of ECA-109 and KYSE-150 cells was limited. Compared to single irradiation group, irradiation combined with niraparib further increased the apoptosis rate in ESCC cells (P=0.015, P=0.006). In ECA-109 cells, G2/M phase arrest was significantly increased in combined group compared with irradiation alone group (P<0.001). In ECA-109 cells, the number of γH2AX foci in combined group was higher than that in the single irradiation group after 2 h, and showed a significantly slower decay of γH2AX foci (P<0.001). Moreover, niraparib combined with irradiation enhanced the radiation-induced cleavage of PARP-1 and down-regulated the expression of Rad51 and p-MAPK(ERK1/2). Conclusion Niraparib can increase the radiosensitivity of esophageal cancer cells by inhibiting cell proliferation, promoting cell apoptosis, inhibiting the repair of DNA damage and regulating the MARK-ERK signaling pathway.
Zhao Fuzhen,Feng Yue,Ma Zhaoming et al. Effects of niraparib on the radiosensitivity of human esophageal cancer cells and its mechanism[J]. Chinese Journal of Radiation Oncology, 2023, 32(8): 719-725.
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