Abstract
The eradication of cancer stem cells (CSCs) is significant for cancer therapy and prevention. 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. 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 exhibited a 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. Collectively, our results suggest that WM130 remarkably 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.
Highlights
Liver cancer, including hepatocellular carcinoma (HCC), remains a leading cause of cancer death worldwide [1]
The immortalized human hepatocyte cell line L02 and rat primary hepatocytes were not affected by WM130 at the concentrations tested, which indicated that WM130 exerted a more selective activity against HCC cells than normal cells
By using hepatoma sphere cells and the sorted hepatoma epithelial cell adhesion molecule (EpCAM)+ cells, we evaluated the inhibitory effect of WM130 on HCC cancer stem cells (CSCs)
Summary
Liver cancer, including hepatocellular carcinoma (HCC), remains a leading cause of cancer death worldwide [1]. The existence of CSCs has been shown in liver cancer cell lines and primary HCC specimens [9,10,11,12,13,14,15,16,17,18,19]. HCC CSCs can be isolated and characterized by using various stem cell markers such as EpCAM, CD133, CD90 and CD44. They exhibit stem cell-like characteristics such as spherical colony formation in vitro, self-renewal, differentiation and resistance to chemo- and radiotherapies. Thereby, therapy eradicating CSCs, either alone or in combination with conventional chemotherapies, may provide advantages for cancer eradication
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