title: WM130 preferentially inhibits hepatic cancer stem-like cells by suppressing AKT/GSK3β/β-catenin signaling pathway.
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.
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors: Chen-Xu
authors: CX
authors: Ni
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors: Yang
authors: Y
authors: Qi
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.|Department of Pharmacy, Shanghai East Hospital, Tongji University, Shanghai 310000, China.
authors: Jin
authors: J
authors: Zhang
authors: Department of Pharmacy, Shanghai East Hospital, Tongji University, Shanghai 310000, China.
authors: Ying
authors: Y
authors: Liu
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors: Wei-Heng
authors: WH
authors: Xu
authors: Department of Pharmacy, Shanghai East Hospital, Tongji University, Shanghai 310000, China.
authors: Jing
authors: J
authors: Xu
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors: Hong-Gang
authors: HG
authors: Hu
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors: Qiu-Ye
authors: QY
authors: Wu
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors: Yan
authors: Y
authors: Wang
authors: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors: Jun-Ping
authors: JP
authors: Zhang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000066673:Cell Self Renewal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000071858:Epithelial Cell Adhesion Molecule / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011807:Quinolizines / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D011807:Quinolizines; C000602836:WM130 compound; D051176:beta Catenin; D004317:Doxorubicin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; GSK3β; cancer stem-like cells; hepatocellular carcinoma; matrine derivative