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    Ascochlorin enhances the sensitivity of doxorubicin leading to the reversal of epithelial-to-mesenchymal transition in hepatocellular carcinoma

    Access Status
    Fulltext not available
    Authors
    Dai, X.
    Ahn, K.
    Wang, L.
    Kim, C.
    Deivasigamni, A.
    Arfuso, Frank
    Um, J.
    Kumar, Alan Prem
    Chang, Y.
    Kumar, D.
    Kundu, G.
    Magae, J.
    Goh, B.
    Hui, K.
    Sethi, G.
    Date
    2016
    Type
    Journal Article
    
    Metadata
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    Citation
    Dai, X. and Ahn, K. and Wang, L. and Kim, C. and Deivasigamni, A. and Arfuso, F. and Um, J. et al. 2016. Ascochlorin enhances the sensitivity of doxorubicin leading to the reversal of epithelial-to-mesenchymal transition in hepatocellular carcinoma. Molecular Cancer Therapeutics. 15 (12): pp. 2966-2976.
    Source Title
    Molecular Cancer Therapeutics
    DOI
    10.1158/1535-7163.MCT-16-0391
    ISSN
    1535-7163
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/4098
    Collection
    • Curtin Research Publications
    Abstract

    Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo- and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3-Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma.

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