RESUMEN
To develop novel therapies for aggressive thyroid cancers, we have synthesized a collection of histone deacetylase (HDAC) inhibitor analogs named AB1 to AB13, which have different linkers between a metal chelating group and a hydrophobic cap. The purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy. AB2, AB3 and AB10 demonstrated the lowest half-maximal inhibitory concentration (IC50) values in one metastatic follicular and two anaplastic thyroid cancer cell lines. Treatment with each of the three ABs resulted in an increase in apoptosis markers, including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3. Additionally, the expression of cell-cycle regulatory proteins p21(WAF1) and p27(Kip1) increased with the treatment of ABs while cyclin D1 decreased. Furthermore, AB2, AB3 and AB10 were able to induce thyrocyte-specific genes in the three thyroid cancer cell lines indicated by increased expression levels of sodium iodide symporter, paired box gene 8, thyroid transcription factor 1 (TTF1), TTF2 and thyroid-stimulating hormone receptors. AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell-cycle arrest and apoptosis. They also induce cell re-differentiation, which could make aggressive cancer cells more susceptible to radioactive iodine therapy.
Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Terapia Molecular Dirigida/métodos , Neoplasias de la Tiroides/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Ensayos de Selección de Medicamentos Antitumorales/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patologíaRESUMEN
The intrinsic sizes of the field galaxies with I-19) galaxies is skewed with respect to the CDM predictions, and an excess of small-size disks (Rd<2 kpc) is already present at z approximately 0.5. The excess persists up to z approximately 3 and involves brighter galaxies. Such an excess may be reduced if luminosity-dependent effects, like starburst activity in interacting galaxies, are included in the physical mechanisms governing the star formation history in CDM models.