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A novel HSP-90 inhibitor with highly selective activity against papillary and anaplastic thyroid cancers
dc.contributor.author | Samadi, Abbas K. | |
dc.contributor.author | Loo, Peter | |
dc.contributor.author | O'Donnell, Gemma | |
dc.contributor.author | Tong, Xiaqin | |
dc.contributor.author | Timmermann, Barbara N. | |
dc.contributor.author | Cohen, Mark S. | |
dc.date.accessioned | 2017-04-19T20:47:47Z | |
dc.date.available | 2017-04-19T20:47:47Z | |
dc.date.issued | 2009-12 | |
dc.identifier.citation | Samadi, 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.uri | http://hdl.handle.net/1808/23746 | |
dc.description.abstract | BackgroundHSP90 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.Methods285 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.Results45 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.ConclusionBTIMNP_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.publisher | Elsevier | en_US |
dc.rights | 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. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
dc.title | A novel HSP-90 inhibitor with highly selective activity against papillary and anaplastic thyroid cancers | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Timmerman, Barbara N. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1016/j.surg.2009.09.028 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |
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