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    Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways

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    Timmermann_2013.pdf (4.205Mb)
    Issue Date
    2013-06
    Author
    Grogan, Patrick T.
    Sleder, Kristina D.
    Samadi, Abbas K.
    Timmermann, Barbara N.
    Cohen, Mark S.
    Publisher
    Springer Verlag
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    © Springer Science+Business Media New York 2012
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    Abstract
    Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was found to inhibit proliferation by inducing a dose-dependent G2/M cell cycle arrest and promoting cell death through both intrinsic and extrinsic apoptotic pathways. This was accompanied by an inhibitory shift in the Akt/mTOR signaling pathway which included diminished expression and/or phosphorylation of Akt, mTOR, p70 S6K, and p85 S6K with increased activation of AMPKα and the tumor suppressor tuberin/TSC2. Alterations in proteins of the MAPK pathway and cell surface receptors like EGFR, Her2/ErbB2, and c-Met were also observed. WA induced an N-acetyl-L-cysteinerepressible enhancement in cellular oxidative potential/stress with subsequent induction of a heat shock stress response primarily through HSP70, HSP32, and HSP27 upregulation and HSF1 downregulation. Taken together, we suggest that WA may represent a promising chemotherapeutic candidate in glioblastoma therapy warranting further translational evaluation.
    URI
    http://hdl.handle.net/1808/24497
    DOI
    https://doi.org/10.1007/s10637-012-9888-5
    Collections
    • Medicinal Chemistry Scholarly Works [248]
    Citation
    Grogan, P.T., Sleder, K.D., Samadi, A.K. et al. Invest New Drugs (2013) 31: 545. doi:10.1007/s10637-012-9888-5

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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