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  • Investigating the Impact of OGT Inhibition on Doxorubicin- and Docetaxel-Induced Cytotoxicity in PC-3 and WPMY-1 Cells

    Author(s)
    Makwana, V
    Dukie, ASA
    Rudrawar, S
    Griffith University Author(s)
    Rudrawar, Santosh
    Makwana, Vivek M.
    Anoopkumar-Dukie, Shailendra
    Year published
    2020
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    Abstract
    Reduction in sensitivity in terms of cytotoxicity is responsible for therapy failure in patients undergoing chemotherapy with first-line anticancer drug molecules. A plethora of literature evidence points out that increased O-linked β-N-acetylglucosamine transferase (OGT) enzyme level/hyper-O-GlcNAcylation has direct implications in development of cancer and interferes with clinical outcomes of chemotherapy via interaction with oncogenic factors. The aim of this research was to evaluate the combination approach of anticancer drugs with an OGT inhibitor (OSMI-1) as an alternative way to resolve issues in the treatment of ...
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    Reduction in sensitivity in terms of cytotoxicity is responsible for therapy failure in patients undergoing chemotherapy with first-line anticancer drug molecules. A plethora of literature evidence points out that increased O-linked β-N-acetylglucosamine transferase (OGT) enzyme level/hyper-O-GlcNAcylation has direct implications in development of cancer and interferes with clinical outcomes of chemotherapy via interaction with oncogenic factors. The aim of this research was to evaluate the combination approach of anticancer drugs with an OGT inhibitor (OSMI-1) as an alternative way to resolve issues in the treatment of prostate cancer and assess the benefits offered by this approach. Effect of combination of doxorubicin and docetaxel with OSMI-1 on drug-induced cell death and synergism/antagonism was investigated using resazurin assay. Reduction in OGT enzyme level was evaluated using ELISA kit. Caspase-3/7 fluorescence assay was performed to detect apoptosis induction in PC-3 cells after treatment with the combinations of doxorubicin and OGT inhibitor to further understand the mechanism of cell death by concomitant treatment. Studies reveal that combination approach is indeed effective in terms of reducing the half-maximum growth inhibition value of doxorubicin when concomitantly treated with OSMI-1 and has synergistic effect in prostate cancer cells. PC-3 cells exhibited elevated levels of OGT enzyme in comparison to WPMY-1, and OSMI-1 has potential to inhibit OGT enzyme significantly. Data show that OSMI-1 alone and in combination with doxorubicin reduces OGT enzyme level significantly accompanied by increased apoptosis in prostate cancer cells. Combination of doxorubicin with OSMI-1 reduced the elevated OGT level which led to a drastic increase in sensitivity of PC-3 cells toward doxorubicin in comparison to doxorubicin alone. This finding provides important insight regarding alternative treatment strategies for effective management of cancer.
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    Journal Title
    International Journal of Toxicology
    DOI
    https://doi.org/10.1177/1091581820948433
    Note
    This publication has been entered in Griffith Research Online as an advanced online version.
    Subject
    Pharmacology and Pharmaceutical Sciences
    OGT enzyme
    apoptosis
    combination approach
    cytotoxicity
    hyper-O-GlcNAcylation
    Publication URI
    http://hdl.handle.net/10072/397509
    Collection
    • Journal articles

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