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dc.contributor.authorSubramanian, Chitra
dc.contributor.authorGrogan, Patrick T.
dc.contributor.authorOpipari, Valerie P.
dc.contributor.authorTimmermann, Barbara N.
dc.contributor.authorCohen, Mark S.
dc.date.accessioned2018-06-13T18:52:02Z
dc.date.available2018-06-13T18:52:02Z
dc.date.issued2018-02-07
dc.identifier.citationSubramanian, C., Grogan, P. T., Opipari, V. P., Timmermann, B. N., & Cohen, M. S. (2018). Novel natural withanolides induce apoptosis and inhibit migration of neuroblastoma cells through down regulation of N-myc and suppression of Akt/mTOR/NF-κB activation. Oncotarget, 9(18), 14509–14523. http://doi.org/10.18632/oncotarget.24429en_US
dc.identifier.urihttp://hdl.handle.net/1808/26509
dc.description.abstractDespite recent advances in intensive chemotherapy treatments, long-term success is achieved in less than 30% of children with high-risk neuroblastoma (NB). Key regulatory pathways including the PI3K/Akt, mTOR and NF-κB are implicated in the pathogenesis of NB. Although drugs targeting these individual pathways are in clinical trials, they are not effective due to the activation of compensatory mechanisms. We have previously reported that natural novel withanolides from Physalis longifolia can potently inhibit these key regulatory pathways simultaneously. In the present study, we examined the efficacy and mechanisms through which novel withanolides and their acetate derivatives (WGA-TA and WGB-DA) from P.longifolia kill NB cells. The results from the study demonstrated that our novel acetate derivatives are highly effective in inhibiting the proliferation, shifting the cell cycle and inducing apoptosis in a dose dependent manner. Analysis of oncogenic pathway proteins targeted by withanolides indicated induction of heat shock response due to oxidative stress. Dose dependent decrease in clients of HSP90 chaperone function due to suppression of Akt, mTOR, and NF-κB pathways led to decrease in the expressions of target genes such as cyclin D1, N-myc and Survivin. Additionally, there was a dose dependent attenuation of the migration and invasion of NB cells. Furthermore, the lead compound WGA-TA showed significant reduction in tumor growth of NB xenografts. Taken together, these results suggest that withanolides are an effective therapeutic option against NBs.en_US
dc.publisherImpact Journalsen_US
dc.rightsCopyright © 2018 Subramanian et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en_US
dc.subjectNeuroblastomaen_US
dc.subjectWithanolidesen_US
dc.subjectN-mycen_US
dc.subjectAkt/mToR/NFKBen_US
dc.subjectApoptosisen_US
dc.titleNovel natural withanolides induce apoptosis and inhibit migration of neuroblastoma cells through down regulation of N-myc and suppression of Akt/mTOR/NF-κB activationen_US
dc.typeArticleen_US
kusw.kuauthorTimmermann, Barbara N.
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.18632/oncotarget.24429en_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccessen_US


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Copyright © 2018 Subramanian et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as: Copyright © 2018 Subramanian et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.