Nutlin-3,An Antagonist Of MDM2,Enhances The Radiosensitivity Of Esophageal Squamous Cancer With Wild-type P53

Murine double minute 2(MDM2)negatively regulates the activity of the p53 and plays a vital role in cell cycle arrest,apoptosis,and senescence mediated by p53.Nutlin-3,an antagonist of MDM2,is frequently used in anti-cancer studies.In many human tumors,nutlin-3 stabilizes p53 status and enhances p53 expression in cells with wild-type p53.However,the effect of nutlin-3 combined with ionizing radiation(IR)on esophageal squamous cancer(ESCC)has not been reported.In this study,we examined whether nutlin-3 increases the radiosensitivity of ESCC in vitro and in vivo.We chose two cell lines,ECA-109(wild-type p53)and TE-13(p53 mutated),for the following experiments.Cell proliferation and clonogenic survival experiments showed that nutlin-3 inhibits the cell growth and colony formation of ECA-109 cells in a dose-dependent manner.The apoptosis rate of ECA-109 cells co-treated with nutlin-3 and irradiation detected by the flow cytometry analysis showed that was significantly increased compared with cells treated with irradiation or nutlin-3 alone.Western blotting detected the expression of apoptosis-associated proteins in ECA-109 cells in response to nutlin-3 and irradiation.These effects were not evident in TE-13 cells.Xenograft mouse models indicated that nutlin-3 suppresses tumor growth and promotes radiosensitivity in the ESCC cell line ECA-109 in vivo.We have demonstrated that co-treatment of nutlin-3 with irradiation can significantly inhibit the growth and improve the radiosensitivity of ESCC cells with wild-type p53.The study suggests that nutlin-3 may be a potent therapeutic agent in conjunction with radiotherapy in ESCC.