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 hepatocell...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.展开更多
基金supported by National Natural Science Foundation of China(81270508)National Major Special Science and Technology Project(2012ZX09103101-043)
文摘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.
