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dc.contributor.authorSamadi, Abbas K.
dc.contributor.authorLoo, Peter
dc.contributor.authorO'Donnell, Gemma
dc.contributor.authorTong, Xiaqin
dc.contributor.authorTimmermann, Barbara N.
dc.contributor.authorCohen, Mark S.
dc.date.accessioned2017-04-19T20:47:47Z
dc.date.available2017-04-19T20:47:47Z
dc.date.issued2009-12
dc.identifier.citationSamadi, Abbas et al. “A Novel HSP-90 Inhibitor with Highly Selective Activity against Papillary and Anaplastic Thyroid Cancers.” Surgery 146.6 (2009): 1196–1207.en_US
dc.identifier.urihttp://hdl.handle.net/1808/23746
dc.description.abstractBackground

HSP90 is a chaperone protein regulating several client proteins involved in thyroid cancer development. The purpose of this study is to mechanisticially evaluate a novel natural-product HSP90 inhibitor in thyroid cancer cell lines for future translational applications.

Methods

285 plant-extracts/compounds were evaluated for anti-cancer activity by MTS assay. Apoptosis and cell-cycle-arrest were characterized by annexinV-PI flow cytometry. HSP90 and client-protein inhibition along with apoptosis confirmation was demonstrated by Western blot analysis.

Results

45 of 285extracts/compounds demonstrated anti-proliferative activity in thyroid cancers by MTS assay. BTIMNP_D004 demonstrated the highest inhibition [IC50(NPA)=0.19±0.02mM, IC50(DRO)=0.26±0.03mM]vs. 17-AAG [IC50(NPA)=0.51±0.02mM; IC50(DRO)=0.75±0.04mM;p<0.001]. D004 induced cell-cycle-arrest after 18hours (G1/G0→S and G2/M) with 26%DRO cells shifted and 23%NPA cells shifted vs. controls (p<0.001 and <0.01 respectively). 1mM D004 induced significant apoptosis with 76%DRO cells gated after 18hrs. (Annexin V/PI staining) vs <2% in controls;p<0.001 and 80%NPA cells vs. 4%controls(p<0.001). Western analysis demonstrated inhibition of HSP90, HSF-1, AKT, and cleavage of procaspase3 and PARP in both NPA and DRO cells.

Conclusion

BTIMNP_D004 is a potent, novel HSP90inhibitor with selective activity against papillary and anaplastic thyroid cancers through modulation of client proteins, induction of apoptosis and cell cycle arrest. These data support future pre-clinical studies for translational applications.
en_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/
dc.titleA novel HSP-90 inhibitor with highly selective activity against papillary and anaplastic thyroid cancersen_US
dc.typeArticleen_US
kusw.kuauthorTimmerman, Barbara N.
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.1016/j.surg.2009.09.028en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccess


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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.