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    Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer

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    o'flaherty_et_al_2019(2).pdf (1.478Mb)
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    Publication date
    2019-04-10
    Author
    O'Flaherty, L.
    Shnyder, Steven D.
    Cooper, Patricia A.
    Cross, S.J.
    Wakefield, J.G.
    Pardo, O.E.
    Seckl, M.J.
    Tavare, J.M.
    Keyword
    Tumor growth suppression
    GSK3 inhibition
    Taxol
    Non-small cell lung carcinoma
    Cancer therapy
    Rights
    © 2019 O’Flaherty et al. This is an Open Access article distributed under the terms of the Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0/)
    Peer-Reviewed
    Yes
    
    Metadata
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    Abstract
    Glycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. This makes the enzyme an attractive target for cancer therapy. We examined the effects of a selective cell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel, using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumor xenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered as monotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograft model. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically to inhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignment during metaphase. Our findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer.
    URI
    http://hdl.handle.net/10454/17021
    Version
    Published version
    Citation
    O'Flaherty L, Shnyder SD, Cooper PA et al (2019) Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer. PLoS ONE. 14(4): e0214610.
    Link to publisher’s version
    https://doi.org/10.1371/journal.pone.0214610
    Type
    Article
    Collections
    Life Sciences Publications

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