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  • Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma

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    Author(s)
    Raninga, Prahlad V
    Di Trapani, Giovanna
    Vuckovic, Slavica
    Bhatia, Maneet
    Tonissen, Kathryn F
    Griffith University Author(s)
    Di Trapani, Jenny
    Tonissen, Kathryn F.
    Bhatia, Maneet K.
    Raninga, Prahlad V.
    Year published
    2015
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    Abstract
    Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM ...
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    Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-?ߠinhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-?ߠsubunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX- 12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-?ߠinhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.
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    Journal Title
    Oncotarget
    Volume
    6
    Issue
    17
    DOI
    https://doi.org/10.18632/oncotarget.3795
    Copyright Statement
    © The Author(s) 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    Subject
    Cancer Cell Biology
    Molecular Targets
    Oncology and Carcinogenesis
    Publication URI
    http://hdl.handle.net/10072/116005
    Collection
    • Journal articles

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