Esophageal cancer(EC)is one of the most common malignancies in the world,and there is no specific treatment drug for esophageal cancer yet.Doramectin(DRM)is a broad-spectrum anti-parasitic drug,and it plays an importa...Esophageal cancer(EC)is one of the most common malignancies in the world,and there is no specific treatment drug for esophageal cancer yet.Doramectin(DRM)is a broad-spectrum anti-parasitic drug,and it plays an important role in the treatment of animal diseases,while DRM has not been reported for the treatment of esophageal squamous cell carcinoma(ESCC).The purpose of this study was to investigate the anticancer effects and potential molecular mechanisms of DRM in ESCC.In the present study,the impact of DRM on the viability of ESCC was examined by methylthiazolyldiphenyl-tetrazolium bromide(MTT).Autophagy was measured by transmission electron microscopy(TEM),Western blot and immunohistochemistry.The apoptosis rate was measured by Western blot,flow cytometry and terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL).Meanwhile,autophagy inhibition was achieved by using chloroquine(CQ).After autophagy inhibition,cell proliferation and cloning ability were significantly inhibited,and the expression level of apoptotic protein was significantly changed compared with that of DRM alone.Additionally,Eca109-derived xenografts were established for testing the DRM-induced autophagy in vivo.It was found that DRM significantly inhibited the proliferation of Eca109 and EC9706 cells in vitro and in vivo in a dose-dependent manner by activating autophagy.DRM was able to significantly repress colony formation in Eca109 and EC9706 cells in vitro.At the same time,DRM could induce apoptosis of ESCC in vitro,it was also regulated through mitochondrial pathways.Meanwhile,DRM induced autophagy and inhibited the proliferation of ESCC,and exhibited little toxicity in organs in vivo.Moreover,DRM-induced autophagy could inhibit the apoptosis of EC in vitro and in vivo.Further experiment suggested that DRM might induce autophagy by the Akt/mTOR pathway.In conclusion,the present study was the first to clarify that DRM could inhibit Eca109 and EC9706 cells proliferation through activating autophagy by the Akt/mTOR pathway.DRM might be a potentially effective treatment for EC.展开更多
基金Supported by the Academic Backbone Fund of Northeast Agricultural University(19XG20)the Excellent Young Scholars Fund of Harbin Medical University(HYD2020JQ0016)。
文摘Esophageal cancer(EC)is one of the most common malignancies in the world,and there is no specific treatment drug for esophageal cancer yet.Doramectin(DRM)is a broad-spectrum anti-parasitic drug,and it plays an important role in the treatment of animal diseases,while DRM has not been reported for the treatment of esophageal squamous cell carcinoma(ESCC).The purpose of this study was to investigate the anticancer effects and potential molecular mechanisms of DRM in ESCC.In the present study,the impact of DRM on the viability of ESCC was examined by methylthiazolyldiphenyl-tetrazolium bromide(MTT).Autophagy was measured by transmission electron microscopy(TEM),Western blot and immunohistochemistry.The apoptosis rate was measured by Western blot,flow cytometry and terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL).Meanwhile,autophagy inhibition was achieved by using chloroquine(CQ).After autophagy inhibition,cell proliferation and cloning ability were significantly inhibited,and the expression level of apoptotic protein was significantly changed compared with that of DRM alone.Additionally,Eca109-derived xenografts were established for testing the DRM-induced autophagy in vivo.It was found that DRM significantly inhibited the proliferation of Eca109 and EC9706 cells in vitro and in vivo in a dose-dependent manner by activating autophagy.DRM was able to significantly repress colony formation in Eca109 and EC9706 cells in vitro.At the same time,DRM could induce apoptosis of ESCC in vitro,it was also regulated through mitochondrial pathways.Meanwhile,DRM induced autophagy and inhibited the proliferation of ESCC,and exhibited little toxicity in organs in vivo.Moreover,DRM-induced autophagy could inhibit the apoptosis of EC in vitro and in vivo.Further experiment suggested that DRM might induce autophagy by the Akt/mTOR pathway.In conclusion,the present study was the first to clarify that DRM could inhibit Eca109 and EC9706 cells proliferation through activating autophagy by the Akt/mTOR pathway.DRM might be a potentially effective treatment for EC.
