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Métodos Terapêuticos e Terapias MTCI
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1.
Surgery ; 146(6): 1196-207, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19958949

RESUMO

BACKGROUND: Heat shock protein 90 (HSP90) is a chaperone protein regulating several client proteins involved in thyroid cancer development. The purpose of this study was to mechanistically evaluate a novel, natural product drug with anticancer activity in thyroid cancer cell lines in vitro for future translational applications. METHODS: A total of 285 natural plant extracts and compounds were evaluated for anticancer activity by MTS assay. Apoptosis and cell cycle arrest were characterized by annexin V-propidium iodide (PI) flow cytometry. HSP90 and client protein modulation, as well as apoptosis confirmation, as demonstrated by Western blot analysis. RESULTS: Of the 285 compounds and products tested, 45 demonstrated antiproliferative activity in thyroid cancers by MTS assay. BTIMNP_D004 demonstrated the greatest inhibition (IC(50) = 155-2,890 nM in thyroid cancers). Activity was cancer-cell selective compared to fibroblasts, with increased potency over 17-AAG in BCPAP, FTC133, and DRO81-1 cells. D004 modulated cell cycle arrest after 18 hours (G(1)/G(0) --> S and G(2)/M) with 30% FTC133 cells shifted, 22% BCPAP cells shifted, and 15% SW1736 cells shifted versus controls (P < .01, P < .01, and P < .05, respectively). A total of 1 muM D004 induced significant apoptosis, with 76% BCPAP cells gated after 18 hours (annexin V-PI staining vs <3% in controls, P < .01; and 80% FTC133 cells vs 4% controls; P < .01). Western blot analysis demonstrated modulation of HSP90 expression levels, with inhibition of HSF-1, AKT, and caspase-3 expression, and cleavage of PARP in both BCPAP and FTC133 cells. CONCLUSION: BTIMNP_D004 is a novel natural product drug with anticancer activity against thyroid cancers in vitro, and may act through induction of apoptosis, modulation of cell cycle arrest, and modulation of heat shock chaperone proteins including HSP90. These preliminary in vitro data support future preclinical studies for translational applications.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Fitoterapia , Extratos Vegetais/farmacologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
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