RESUMEN
Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPARγ), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21cip and p27kip, and the reduction of hyperphosphorylated retinoblastoma protein (pp-Rb)-E2F1 signaling. Therefore, targeting two pathways involved in lipid metabolism may provide a new direction for treating ATC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cromanos/administración & dosificación , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Sinergismo Farmacológico , Humanos , Lovastatina/administración & dosificación , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Tiazolidinedionas/administración & dosificación , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , TroglitazonaRESUMEN
Malignant human anaplastic thyroid cancer (ATC) is pertinacious to conventional therapies. The present study investigated the anti-cancer activity of simvastatin and its underlying regulatory mechanism in cultured ATC cells. Simvastatin (0-20 µM) concentration-dependently reduced cell viability and relative colony formation. Depletions of mevalonate (MEV) and geranylgeranyl pyrophosphate (GGpp) by simvastatin induced G1 arrest and increased apoptotic cell populations at the sub-G1 phase. Adding MEV and GGpp prevented the simvastatin-inhibited cell proliferation. Immunoblotting analysis illustrated that simvastatin diminished the activation of RhoA and Rac1 protein, and this effect was prevented by pre-treatment with MEV and GGpp. Simvastatin increased the levels of p21cip and p27kip proteins and reduced the levels of hyperphosphorylated-Rb, E2F1 and CCND1 proteins. Adding GGpp abolished the simvastatin-increased levels of p27kip protein, and the GGpp-caused effect was abolished by Skp2 inhibition. Introduction of Cyr61 siRNA into ATC cells prevented the epidermal growth factor (EGF)-enhanced cell migration. The EGF-induced increases of Cyr61 protein expression and cell migration were prevented by simvastatin. Taken together, these results suggest that simvastatin induced ATC proliferation inhibition through the deactivation of RhoA/Rac1 protein and overexpression of p21cip and p27kip, and migration inhibition through the abrogation of Cyr61 protein expression.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Simvastatina/farmacología , Línea Celular Tumoral , Movimiento 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 , Proteína 61 Rica en Cisteína/antagonistas & inhibidores , Proteína 61 Rica en Cisteína/genética , Proteína 61 Rica en Cisteína/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Ácido Mevalónico/farmacología , Fosfatos de Poliisoprenilo/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Simvastatina/uso terapéutico , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
BACKGROUND: Patient handoffs between units can introduce risk and time delays. Verbal communication is the most common mode of handoff, but requires coordination between different parties. OBJECTIVE: We present an asynchronous patient handoff process supported by a structured electronic signout for admissions from the emergency department (ED) to the inpatient medicine service. METHODS: A retrospective review of patients admitted to the medical service from July 1, 2011 to June 30, 2015 at a tertiary referral center with 520 inpatient beds and 57,000 ED visits annually. We developed a model for structured electronic, asynchronous signout that includes an option to request verbal communication after review of the electronic handoff information. RESULTS: During the 2010 academic year (AY) all admissions used verbal communication for signout. The following academic year, electronic signout was implemented and 77.5% of admissions were accepted with electronic signout. The rate increased to 87.3% by AY 2014. The rate of transfer from floor to an intensive care unit within 24 h for the year before and 4 years after implementation of the electronic signout system was collected and calculated with 95% confidence interval. There was no statistically significant difference between the year prior and the years after the implementation. CONCLUSIONS: Our handoff model sought to maximize the opportunity for asynchronous signout while still providing the opportunity for verbal signout when deemed necessary. The process was rapidly adopted with the majority of patients being accepted electronically.