Azithromycin enhances anticancer activity of TRAIL by inhibiting autophagy and up-regulating the protein levels of DR4/5 in colon cancer cells in vitro and in vivo  

作　　者：Xinran Qiao Xiaofei Wang Yue Shang Yi Li Shu-zhen Chen 

机构地区：[1]Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,P.R.China

出　　处：《Cancer Communications》2018年第1期446-458,共13页癌症通讯（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(81373437 and 81621064);CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-02-002).

摘　　要：Background:Azithromycin is a member of macrolide antibiotics,and has been reported to inhibit the proliferation of cancer cells.However,the underlying mechanisms are not been fully elucidated.Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)selectively targets tumor cells without damaging healthy cells.In the present study,we examined whether azithromycin is synergistic with TRAIL,and if so,the underlying mechanisms in colon cancers.Methods:HCT-116,SW480,SW620 and DiFi cells were treated with azithromycin,purified TRAIL,or their combina-tion.A sulforhoddamine B assay was used to examine cell survival.Apoptosis was examined using annexin V-FITC/PI staining,and autophagy was observed by acridine orange staining.Western blot analysis was used to detect protein expression levels.In mechanistic experiments,siRNAs were used to knockdown death receptors(DR4,DR5)and LC-3B.The anticancer effect of azithromycin and TRAIL was also examined in BALB/c nude mice carrying HCT-116 xenografts.Results:Azithromycin decreased the proliferation of HCT-116 and SW480 cells in a dose-dependent manner.Combination of azithromycin and TRAIL inhibited tumor growth in a manner that could not be explained by additive effects.Azithromycin increased the expressions of DR4,DR5,p62 and LC-3B proteins and potentiated induction of apoptosis by TRAIL.Knockdown of DR4 and DR5 with siRNAs increased cell survival rate and decreased the expression of cleaved-PARP induced by the combination of azithromycin and TRAIL.LC-3B siRNA and CQ potentiated the anti-proliferation activity of TRAIL alone,and increased the expressions of DR4 and DR5.Conclusion:The synergistic antitumor effect of azithromycin and TRAIL mainly relies on the up-regulations of DR4 and DR5,which in turn result from LC-3B-involved autophagy inhibition.

关 键 词：AZITHROMYCIN TRAIL Apoptosis AUTOPHAGY Colon cancer 

分 类 号：R73[医药卫生—肿瘤]