首页|AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy
AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy
扫码查看
点击上方二维码区域，可以放大扫码查看
原文链接
国家科技期刊平台
NETL
NSTL
万方数据
Background:Radiation(IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvi-ronment(TME).Wee1,a cell cycle regulator,can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1(CDK1).Meanwhile,programed death-1/programed death ligand-1(PD-1/PDL-1)blockade is closely related to TME.This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody(anti-PD-1 Ab)on radiosensitization of hepatoma.Methods:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide(MTT)assay on human and mouse hepatoma cells HepG2,Hepa1-6,and H22.The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro.A hepatoma subcutaneous xenograft mice model was con-structed on Balb/c mice,which were divided into control group,IR group,AZD1775 group,IR+AZD1775 group,IR+anti-PD-1 Ab group,and the IR+AZD1775+anti-PD-1 Ab group.Cytotoxic CD8+T cells in TME were analyzed by flow cytometry.Results:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro.AZD1775 exhibited antitu-mor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage.AZD1775 treatment also reduced the proportion of PD-1+/CD8+T cells in the spleen of hepatoma subcutaneous xenograft mice.Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon y(IFNγ)+or Ki67+CD8 T cells and decreasing the levels of CD8+Tregs cells in the tumor and spleen of the hepatoma mice model,indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression,enhanc-ing CD8+T cells proliferation,and weakening CD8+T cells depletion.Conclusions:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhanc-ing IR-induced DNA damage and improving cytotoxic CD8+T cells in TME.
国家科技期刊平台
NSTL
万方数据
