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A novel HSP-90 inhibitor with highly selective activity against papillary and anaplastic thyroid cancers
Samadi, Abbas K. Loo, Peter O'Donnell, Gemma Tong, Xiaqin Timmermann, Barbara N. Cohen, Mark S.
Samadi, Abbas K.
Loo, Peter
O'Donnell, Gemma
Tong, Xiaqin
Timmermann, Barbara N.
Cohen, Mark S.
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Abstract
Background
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.
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Date
2009-12
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Elsevier
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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.