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dc.contributor.authorGrogan, Patrick T.
dc.contributor.authorSarkaria, Jann N.
dc.contributor.authorTimmermann, Barbara N.
dc.contributor.authorCohen, Mark S.
dc.identifier.citationGrogan, P.T., Sarkaria, J.N., Timmermann, B.N. et al. Invest New Drugs (2014) 32: 604. doi:10.1007/s10637-014-0084-7en_US
dc.description.abstractTemozolomide (TMZ) has remained the chemotherapy of choice in patients with glioblastoma multiforme (GBM) primarily due to the lack of more effective drugs. Tumors, however, quickly develop resistance to this line of treatment creating a critical need for alternative approaches and strategies to resensitize the cells. Withaferin A (WA), a steroidal lactone derived from several genera of the Solanaceae plant family has previously demonstrated potent anti-cancer activity in multiple tumor models. Here, we examine the effects of WA against TMZ-resistant GBM cells as a monotherapy and in combination with TMZ. WA prevented GBM cell proliferation by dose-dependent G2/M cell cycle arrest and cell death through both intrinsic and extrinsic apoptotic pathways. This effect correlated with depletion of principle proteins of the Akt/mTOR and MAPK survival and proliferation pathways with diminished phosphorylation of Akt, mTOR, and p70 S6K but compensatory activation of ERK1/2. Depletion of tyrosine kinase cell surface receptors c-Met, EGFR, and Her2 was also observed. WA demonstrated induction of N-acetyl-L-cysteine-repressible oxidative stress as measured directly and through a subsequent heat shock response with HSP32 and HSP70 upregulation and decreased HSF1. Finally, pretreatment of TMZ-resistant GBM cells with WA was associated with O6-methylguanine-DNA methyltransferase (MGMT) depletion which potentiated TMZ-mediated MGMT degradation. Combination treatment with both WA and TMZ resulted in resensitization of MGMT-mediated TMZ-resistance but not resistance through mismatch repair mutations. These studies suggest great clinical potential for the utilization of WA in TMZ-resistant GBM as both a monotherapy and a resensitizer in combination with the standard chemotherapeutic agent TMZ.en_US
dc.publisherSpringer Verlagen_US
dc.rights© Springer Science+Business Media New York 2014en_US
dc.subjectWithaferin Aen_US
dc.subjectGlioblastoma multiformeen_US
dc.subjectTemozolomide resistanceen_US
dc.subjectOxidative stressen_US
dc.subjectHeat shock responseen_US
dc.subjectAkt/mTOR pathwayen_US
dc.subjectO6-methylguanine-DNA methyltransferaseen_US
dc.titleOxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulationen_US
kusw.kuauthorTimmermann, Barbara N.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer SHERPA/RoMEO 6/14/2017: uthor's Pre-print: green tick author can archive pre-print (ie pre-refereeing) Author's Post-print: green tick author can archive post-print (ie final draft post-refereeing) Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions:

Author's pre-print on pre-print servers such as Author's post-print on author's personal website immediately Author's post-print on any open access repository after 12 months after publication Publisher's version/PDF cannot be used Published source must be acknowledged Must link to publisher version Set phrase to accompany link to published version (see policy) Articles in some journals can be made Open Access on payment of additional charge
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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