WM130 preferentially inhibits hepatic cancer stem-like cells by suppressing AKT/GSK3β/β-catenin signaling pathway  

作　　者：Chen-xu NI Yang QI Jin ZHANG Ying LIU Wei-heng XU Jing XU Hong-gang HU Qiu-ye WU Yan WANG Jun-ping ZHANG 

机构地区：[1]Department of Pharmacy,Shanghai Tenth People's Hospital,Tongji University School of Medicine [2]School of Pharmacy,Second Military Medical University [3]Department of Pharmacy,Shanghai East Hospital,Tongji University

出　　处：《中国药理学与毒理学杂志》2018年第4期299-299,共1页Chinese Journal of Pharmacology and Toxicology

基　　金：supported by National Natural Science Foundation of China(81270508);National Major Special Science and Technology Project(2012ZX09103101-043)

摘　　要：OBJECTIVE The eradication of cancer stem cells(CSCs) is signifcant for cancer therapy and prevention.METHODS In this study,we evaluated WM130,a novel derivative of matrine,for its effect on CSCs using human hepatocellular carcinoma(HCC) cell lines,their sphere cells,and sorted EpCAM+cells.RESULTS We revealed that WM130 could not only inhibit proliferation and colony formation of HCC cells,but also suppress the expression of some stemness-related genes and up-regulate some mature hepatocyte marker genes,indicating a promotion of differentiation from CSCs to hepatocytes.WM130 also suppressed the proliferation of doxorubicin-resistant hepatoma cells,and markedly reduced the cells with CSC biomarker EpCAM.Moreover,WM130 suppressed HCC spheres,not only primary spheres but also subsequent spheres,indicating an inhibitory effect on self-renewal capability of CSCs.Interestingly,WM130 exhibiteda remarkable inhibitory preference on HCC spheres and EpCAM+cells rather than their parental HCC cells and EpCAM-cells respectively.In vivo,WM130 inhibited HCC xenograft growth,decreased the number of sphere-forming cells,and remarkably decreased the levels of EpCAM mRNA and protein in tumor xenografts.Better inhibitory effect was achieved by WM130 in combination with doxorubicin.Further mechanism study revealed that WM130 inhibited AKT/GSK3β/β-catenin signaling pathway.CONCLUSION Collectively,our results suggest that WM130 remark.ably inhibits hepatic CSCs,and this effect may via the down-regulation of the AKT/GSK3β/β-catenin pathway.These findings provide a strong rationale for the use of WM130 as a novel drug candidate in HCC therapy.OBJECTIVE The eradication of cancer stem cells （CSCs） is signifcant for cancer therapy and prevention. METHODS In this study, we evaluated WM130, a novel derivative of matrine, for its effect on CSCs using human hepatocellular carcinoma （HCC） cell lines, their sphere cells, and sorted EpCAM＋ cells. RESULTS We revealed that WM130 could not only inhibit proliferation and colony formation of HCC cells, but also suppress the expression of some sternness-related genes and up-regulate some mature hepatocyte marker genes, indicating a promotion of differentiation from CSCs to hepatocytes. WM130 also suppressed the proliferation of doxorubicin-resistant hepatoma cells, and markedly reduced the cells with CSC biomarker EpCAM. Moreover, WM130 suppressed HCC spheres, not only primary spheres but also subsequent spheres, indicating an inhibitory effect on self-renewal capability of CSCs. Interestingly, WM130 exhibiteda remarkable inhibitory preference on HCC spheres and EpCAM＋ cells rather than their parental HCC cells and EpCAM- cells respectively. In vivo, WM130 inhibited HCC xenograft growth, decreased the number of sphere-forming cells, and remarkably decreased the levels of EpCAM mRNA and protein in tumor xenografts. Better inhibitory effect was achieved by WM130 in combination with doxorubicin. Further mechanism study revealed that WM130 inhibited AKT/ GSK313/13-catenin signaling pathway. CONCLUSION Collectively, our results suggest that WM130 remarkably inhibits hepatic CSCs, and this effect may via the down-regulation of the AKT/GSK313/13-catenin pathway. These findings provide a strong rationale for the use of WM130 as a novel drug candidate in HCC therapy.

关 键 词：肿瘤 干细胞 治疗方法 临床分析 

分 类 号：R730.53[医药卫生—肿瘤] R329.2[医药卫生—临床医学]