RESUMEN
Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.
Asunto(s)
Antineoplásicos/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/metabolismo , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Sorafenib/efectos adversos , Sorafenib/uso terapéutico , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/mortalidadRESUMEN
Background: Vitamin C has been demonstrated to kill BRAF mutant colorectal cancer cells selectively. BRAF mutation is the most common genetic alteration in thyroid tumor development and progression; however, the antitumor efficacy of vitamin C in thyroid cancer remains to be explored. Methods: The effect of vitamin C on thyroid cancer cell proliferation and apoptosis was assessed by the MTT assay and flow cytometry. Xenograft and transgenic mouse models were used to determine its in vivo antitumor activity of vitamin C. Molecular and biochemical methods were used to elucidate the underlying mechanisms of anticancer activity of vitamin C in thyroid cancer. Results: Pharmaceutical concentration of vitamin C significantly inhibited thyroid cancer cell proliferation and induced cell apoptosis regardless of BRAF mutation status. We demonstrated that the elevated level of Vitamin C in the plasma following a high dose of intraperitoneal injection dramatically inhibited the growth of xenograft tumors. Similar results were obtained in the transgenic mouse model. Mechanistically, vitamin C eradicated BRAF wild-type thyroid cancer cells through ROS-mediated decrease in the activity of EGF/EGFR-MAPK/ERK signaling and an increase in AKT ubiquitination and degradation. On the other hand, vitamin C exerted its antitumor activity in BRAF mutant thyroid cancer cells by inhibiting the activity of ATP-dependent MAPK/ERK signaling and inducing proteasome degradation of AKT via the ROS-dependent pathway. Conclusions: Our data demonstrate that vitamin C kills thyroid cancer cells by inhibiting MAPK/ERK and PI3K/AKT pathways via a ROS-dependent mechanism and suggest that pharmaceutical concentration of vitamin C has potential clinical use in thyroid cancer therapy.
Asunto(s)
Ácido Ascórbico/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/patología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Ratones Desnudos , Ratones Transgénicos , Mutación/genética , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/genética , Ubiquitinación/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Drosophila provides an inexpensive and quantitative platform for measuring whole animal drug response. A complementary approach is virtual screening, where chemical libraries can be efficiently screened against protein target(s). Here, we present a unique discovery platform integrating structure-based modeling with Drosophila biology and organic synthesis. We demonstrate this platform by developing chemicals targeting a Drosophila model of Medullary Thyroid Cancer (MTC) characterized by a transformation network activated by oncogenic dRetM955T. Structural models for kinases relevant to MTC were generated for virtual screening to identify unique preliminary hits that suppressed dRetM955T-induced transformation. We then combined features from our hits with those of known inhibitors to create a 'hybrid' molecule with improved suppression of dRetM955T transformation. Our platform provides a framework to efficiently explore novel kinase inhibitors outside of explored inhibitor chemical space that are effective in inhibiting cancer networks while minimizing whole body toxicity.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Neuroendocrino , Evaluación Preclínica de Medicamentos/métodos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas , Neoplasias de la Tiroides , Animales , Carcinoma Neuroendocrino/enzimología , Carcinoma Neuroendocrino/metabolismo , Biología Computacional/métodos , Drosophila , Modelos Biológicos , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/metabolismo , Proteínas Quinasas/efectos de los fármacos , Proteínas Quinasas/metabolismo , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/metabolismoRESUMEN
BACKGROUND Shikonin is a component of Chinese herbal medicine. The aim of this study was to investigate the effects of shikonin on cell migration of papillary thyroid cancer cells of the TPC-1 cell line in vitro and expression levels of the phosphate and tensin homolog deleted on chromosome 10 (PTEN) and DNA methyltransferase 1 (DNMT1) genes. MATERIAL AND METHODS The Cell Counting Kit-8 (CCK-8) assay was performed to evaluate the proliferation of TPC-1 papillary thyroid cancer cells, and the normal thyroid cells, HTori-3, in vitro. A transwell motility assay was used to analyze the migration of TPC-1 cells. Western blot was performed to determine the expression levels of PTEN and DNMT1 genes. A methylation-specific polymerase chain reaction (PCR) (MSP) assay was used to evaluate the methylation of PTEN. RESULTS Following treatment with shikonin, the cell survival rate of TPC-1 cells decreased in a dose-dependent manner; the inhibitory effects on HTori-3 cells were less marked. Shikonin inhibited TPC-1 cell migration and invasion in a dose-dependent manner. The methylation of PTEN was suppressed by shikonin, which also reduced the expression of DNMT1 in a dose-dependent manner, and increased the expression of PTEN. Overexpression of DNMT1 promoted the migration of TPC-1 cells and the methylation of PTEN. Levels of protein expression of PTEN in TPC-1 cells treated with shikonin decreased, and were increased by DNMT1 knockdown. CONCLUSIONS Shikonin suppressed the expression of DNMT1, reduced PTEN gene methylation, and increased PTEN protein expression, leading to the inhibition of TPC-1 cell migration.
Asunto(s)
Movimiento Celular/efectos de los fármacos , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Naftoquinonas/farmacología , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Amplificación de Genes/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Metilación , Invasividad Neoplásica , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
Berberine, an important natural isoquinoline alkaloid from traditional Chinese medicine, is reported to exhibit multiple pharmacological properties, including anti-microbial, anti-diabetes, anti-obesity, anti-inflammatory and anti-carcinogenic activities. Although studies have shown that a wide range of carcinoma cells could be inhibited by berberine, few studies involved thyroid carcinoma. We therefore examined the effect of berberine on papillary thyroid carcinoma (PTC, the most common subtype) and anaplastic thyroid carcinoma (ATC, the most malignant and aggressive subtype). Three thyroid carcinoma cell lines with different aberrant genotypes and one normal thyroid cell line were selected, including C643 (ATC, with H-RAS mutation), OCUT1 (ATC, with BRAFV600E and PIK3CA mutations), TPC1 (PTC, with RET/PTC1 rearrangement) and Htori3 (normal). We found that berberine inhibited the proliferation of C643, OCUT1 and TPC1 thyroid carcinoma cells in a dose- and time-dependent manner (p<0.01, compared with the control), while normal human thyroid cells showed less sensitivity to the cytotoxicity of berberine. Berberine-induced significant mitochondrial apoptosis, G0/G1 cell cycle arrest and inhibitive migration in thyroid carcinoma cells were also observed (p<0.05 or p<0.01, compared with the control). Increased Bax/Bcl-2, cleaved Caspase 3, P21 and decreased Cyclin E1, CDK2 and Vimentin were verified by western blot. Additionally, berberine caused markedly decreased p-AKT1 expression and disturbances in classic ERK MAPK as well as P38 and JNK MAPK pathways in diverse thyroid carcinoma cells. Therefore, berberine could modulate PI3K-AKT and MAPK signaling pathways in thyroid carcinoma cells, which leads to mitochondrial apoptosis, G0/G1 cell cycle arrest and suppressive migration. Berberine may represent a promising chemotherapy for the treatment of thyroid carcinoma.
Asunto(s)
Apoptosis/efectos de los fármacos , Berberina/farmacología , Movimiento Celular/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Tiroides/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Fosfatidilinositol 3-Quinasas/metabolismo , Glándula Tiroides/patología , Neoplasias de la Tiroides/enzimologíaRESUMEN
BACKGROUND: Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC. METHODS: This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400 mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib. RESULTS: The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity. CONCLUSIONS: Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Carcinoma Neuroendocrino/enzimología , Carcinoma Neuroendocrino/mortalidad , Carcinoma Neuroendocrino/secundario , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Sorafenib , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Bencenosulfonatos/uso terapéutico , Carcinoma Medular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Administración Oral , Bencenosulfonatos/administración & dosificación , Biomarcadores de Tumor/metabolismo , Calcitonina/metabolismo , Antígeno Carcinoembrionario/metabolismo , Carcinoma Medular/enzimología , Carcinoma Medular/genética , Carcinoma Medular/mortalidad , Carcinoma Medular/secundario , Ensayos Clínicos Fase II como Asunto , Supervivencia sin Enfermedad , Humanos , Escisión del Ganglio Linfático , Metástasis Linfática , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Sorafenib , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Resultado del TratamientoRESUMEN
PURPOSE: Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. PATIENTS AND METHODS: In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. RESULTS: Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD >or= 15 months, four patients had SD Asunto(s)
Bencenosulfonatos/uso terapéutico
, Carcinoma Medular/tratamiento farmacológico
, Inhibidores de Proteínas Quinasas/uso terapéutico
, Piridinas/uso terapéutico
, Neoplasias de la Tiroides/tratamiento farmacológico
, Administración Oral
, Adulto
, Anciano
, Bencenosulfonatos/administración & dosificación
, Bencenosulfonatos/efectos adversos
, Biomarcadores de Tumor/metabolismo
, Carcinoma Medular/enzimología
, Carcinoma Medular/genética
, Carcinoma Medular/mortalidad
, Carcinoma Medular/secundario
, Supervivencia sin Enfermedad
, Femenino
, Humanos
, Estimación de Kaplan-Meier
, Imagen por Resonancia Magnética
, Masculino
, Persona de Mediana Edad
, Mutación
, Niacinamida/análogos & derivados
, Compuestos de Fenilurea
, Tomografía de Emisión de Positrones
, Inhibidores de Proteínas Quinasas/administración & dosificación
, Inhibidores de Proteínas Quinasas/efectos adversos
, Proto-Oncogenes Mas
, Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores
, Proteínas Proto-Oncogénicas c-ret/genética
, Piridinas/administración & dosificación
, Piridinas/efectos adversos
, Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
, Sorafenib
, Neoplasias de la Tiroides/enzimología
, Neoplasias de la Tiroides/genética
, Neoplasias de la Tiroides/mortalidad
, Neoplasias de la Tiroides/patología
, Factores de Tiempo
, Tomografía Computarizada por Rayos X
, Resultado del Tratamiento
, Estados Unidos
, Adulto Joven
RESUMEN
OBJECTIVES: We aimed to evaluate the oxidant/antioxidant status of thyroid tissue in patients with multinodular goiter, papillary carcinoma and to compare with their nonpathologic tissues. METHODS: We studied 41 patients with multinodular goiter who underwent surgical treatment. The patients were divided into three groups according to clinical diagnosis. Malondialdehyde, selenium, total superoxide dismutase and glutathione peroxidase of thyroid tissue samples were determined in 14 toxic multinodular goiters, 18 non-toxic multinodular goiters, and 9 papillary carcinomas. RESULT: Superoxide dismutase and glutathione peroxidase and selenium were found lower but malondialdehyde was higher in both nodule and cancerous tissues compared with those of control ones. The level of malondialdehyde in non-toxic multinodular goiters group was higher than toxic multinodular goiters group in nodule tissues. CONCLUSIONS: It can be stated that the lipid peroxidation is increased and enzymatic free radical defense system was significantly impaired in patients with both multinodular goiters and papillary carcinomas.
Asunto(s)
Antioxidantes/metabolismo , Carcinoma Papilar/metabolismo , Bocio Nodular/metabolismo , Peroxidación de Lípido/fisiología , Neoplasias de la Tiroides/metabolismo , Carcinoma Papilar/enzimología , Femenino , Glutatión Peroxidasa/metabolismo , Bocio Nodular/enzimología , Humanos , Técnicas In Vitro , Masculino , Malondialdehído/metabolismo , Persona de Mediana Edad , Selenio/metabolismo , Superóxido Dismutasa/metabolismo , Neoplasias de la Tiroides/enzimologíaRESUMEN
Patients with anaplastic thyroid carcinoma (ATC) typically succumb to their disease months after diagnosis despite aggressive therapy. A large percentage of ATCs have been shown to harbor the V600E B-Raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase pathway. ATC invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (MMP). The explicit targeting of these two tumor markers may provide a novel therapeutic strategy for the treatment of ATC. The MMP-activated anthrax lethal toxin (LeTx), a novel recombinant protein toxin combination, shows potent mitogen-activated protein kinase pathway inhibition in gelatinase-expressing V600E B-Raf tumor cells in vitro. However, preliminary in vivo studies showed that the MMP-activated LeTx also exhibited dramatic antitumor activity against xenografts that did not show significant antiproliferative responses to the LeTx in vitro. Here, we show that the MMP-activated LeTx inhibits orthotopic ATC xenograft progression in both toxin-sensitive and toxin-resistant ATC cells via reduced endothelial cell recruitment and subsequent tumor vascularization. This in turn translates to an improved long-term survival that is comparable with that produced by the multikinase inhibitor sorafenib. Our results also indicate that therapy with the MMP-activated LeTx is extremely effective against advanced tumors with well-established vascular networks. Taken together, these results suggest that the MMP-activated LeTx-mediated endothelial cell targeting is the primary in vivo antitumor mechanism of this novel toxin. Therefore, the MMP-activated LeTx could be used not only in the clinical management of V600E B-Raf ATC but potentially in any solid tumor.
Asunto(s)
Antígenos Bacterianos/uso terapéutico , Toxinas Bacterianas/uso terapéutico , Carcinoma/irrigación sanguínea , Metaloproteinasas de la Matriz/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neoplasias de la Tiroides/irrigación sanguínea , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antígenos Bacterianos/farmacología , Toxinas Bacterianas/farmacología , Bencenosulfonatos/farmacología , Carcinoma/tratamiento farmacológico , Carcinoma/enzimología , Carcinoma/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/farmacología , Sorafenib , Análisis de Supervivencia , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/patología , Factores de TiempoRESUMEN
Cancers and hepatoprotective prevention using traditional medicines have attracted increasing interest. The aim of our study was to characterize the putative protective effects of ethanol and chloroform extracts of Peganum harmala on thiourea-induced diseases in adult male rat. We seek to determine the effects of these plant extracts on body weight, thyroid and endocrine cancer parameters. In addition the putative hepatoprotective effect was checked by the determination of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the bilirubin level in the blood. Our data show that ethanol and chloroform extracts of Peganum harmala protected the animal against the carcinogenic effects induced by thiourea since neuron-specific enolase (NSE) and thyroglobulin (TG) levels were back to the normal range. In addition, the observed-hepatocytotoxicity after thiourea treatment was greatly reduced (AST and ALT activities were respectively 270 IU/l and 60 IU/l and in the same order of magnitude as in the untreated rats) as well as the bilirubin levels (6 micromol/l) especially for animals receiving the choroform preparation. Therefore we may suggest that extracts of Peganum harmala are efficient to reduce the toxicity induced by thiourea in male rat as far as the above parameters are concerned.
Asunto(s)
Peso Corporal/efectos de los fármacos , Neoplasia Endocrina Múltiple/tratamiento farmacológico , Peganum/química , Fitoterapia , Extractos Vegetales/uso terapéutico , Tiourea/farmacología , Neoplasias de la Tiroides/tratamiento farmacológico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Cloroformo , Etanol , Masculino , Neoplasia Endocrina Múltiple/sangre , Neoplasia Endocrina Múltiple/inducido químicamente , Neoplasia Endocrina Múltiple/enzimología , Fosfopiruvato Hidratasa/sangre , Ratas , Ratas Wistar , Tiroglobulina/sangre , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/inducido químicamente , Neoplasias de la Tiroides/enzimología , Factores de TiempoRESUMEN
Medullary thyroid carcinoma (MTC) is an uncommon malignancy of hereditary and sporadic presentation. Mutations in the RET proto-oncogene are involved in the pathogenesis of familial MTC and >50% of the sporadic cases. Currently, there is no effective treatment for recurrent or metastatic MTC. We report here a rapid response to a sorafenib (RET and RAF kinase and vascular endothelial growth factor receptor inhibitor)--based regimen in a patient with sporadic MTC who had advanced, progressive disease and a novel RET kinase aberration at exon 11 shown in tumor tissue.
Asunto(s)
Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma Medular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Piridinas/uso terapéutico , Quinolonas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Secuencia de Aminoácidos , Carcinoma Medular/enzimología , Línea Celular Tumoral , Exones , Humanos , Masculino , Datos de Secuencia Molecular , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-ret/genética , Sorafenib , Neoplasias de la Tiroides/enzimologíaRESUMEN
We investigated the effects of 1-methoxy-canthin-6-one, isolated from the medicinal plant Ailanthus altissima Swingle, on apoptosis in human leukemia (Jurkat), thyroid carcinoma (ARO and NPA), and hepatocellular carcinoma (HuH7) cell lines. Cultures incubated with the compound showed >50% of sub-G1 (hypodiploid) elements in flow cytometry analysis; the apoptosis-inducing activity was evident at <10 micromol/L and half-maximal at about 40 micromol/L 1-methoxy-canthin-6-one. The appearance of hypodiploid elements was preceded by mitochondrial membrane depolarization, mitochondrial release of cytochrome c, and Smac/DIABLO and procaspase-3 cleavage. We subsequently investigated the effect of 1-methoxy-canthin-6-one in combination with human recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the four cell lines. Suboptimal concentrations (10 micromol/L 1-methoxy-canthin-6-one and 0.25 ng/mL TRAIL, respectively) of the two agents, unable to elicit apoptosis when used alone, induced mitochondrial depolarization, activation of caspase-3, and 45% to 85% of sub-G1 elements when added together to the cells. The synergism seemed to rely partly on the enhanced expression of TRAIL receptor 1 (TRAIL-R1; DR4), analyzed by immunofluorescence, by 1-methoxy-canthin-6-one. Cell incubation with 1-methoxy-canthin-6-one resulted in activating c-Jun NH2-terminal kinase (JNK), as revealed by Western blotting; induction of apoptosis and TRAIL-R1 up-regulation by 1-methoxy-canthin-6-one were >80% prevented by the addition of the JNK inhibitor (JNKI) SP600125JNKI, indicating that both effects were almost completely mediated by JNK activity. On the other hand, synergism with TRAIL was reduced by about 50%, suggesting that besides up-regulating TRAIL-R1, 1-methoxy-canthin-6-one could influence other factor(s) that participated in TRAIL-induced apoptosis. These findings indicate that 1-methoxy-canthin-6-one can represent a candidate for in vivo studies of monotherapies or combined antineoplastic therapies.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/farmacología , Apoptosis/efectos de los fármacos , Indoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Glicoproteínas de Membrana/farmacología , Naftiridinas/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Ailanthus/química , Apoptosis/fisiología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Células Jurkat , Leucemia/tratamiento farmacológico , Leucemia/enzimología , Leucemia/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Ligando Inductor de Apoptosis Relacionado con TNF , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/patologíaRESUMEN
The chemical compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F), isolated from the Chinese herbal medicine plant Pteris semipinnata L, has been known to exert antitumor activity. However, the molecular mechanism of the action is not understood. In this study we demonstrated that apoptotic cell death induced by 5F in FRO cells was concentration- and time-dependent. The rapid increase in intracellular reactive oxygen species (ROS) levels was involved in the mechanism of cell death. c-Jun N-terminal kinase (JNK) activation and G2 block were related to cell death induced by 5F. Extracellular signal-related kinase (ERK) and p38 were also activated, but as survival signals in response to 5F treatment to counteract the induction of cell death. In the process of the induction of apoptotic cell death, Bax translocated into mitochondria, a reduction in Delta psi(m) was observed and a release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria into the cytosol occurred, indicating that cell death induced by 5F was through a mitochondrial-mediated pathway.
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Carcinoma/patología , Diterpenos/farmacología , Medicamentos Herbarios Chinos/farmacología , Neoplasias de la Tiroides/patología , Factor Inductor de la Apoptosis/metabolismo , Carcinoma/enzimología , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fase G2/efectos de los fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias , Poli(ADP-Ribosa) Polimerasas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Tiroides/enzimología , Factores de Tiempo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Hürthle cell carcinomas (HTC) are characterized by mitochondrial amplification and enhanced oxygen metabolism. To clarify if defects in enzymes scavenging reactive oxygen species are involved in the pathogenesis of HTC, we analyzed selenium (Se)-dependent expression of various detoxifying selenoproteins in the HTC cell line XTC.UC1. Glutathione peroxidase and thioredoxin reductase activity was found both in cell lysates and conditioned media of XTC.UC1 cells and was increased by Na(2)SeO(3). Western blot analysis demonstrated the presence of thioredoxin reductase both in cell lysates and conditioned media and of glutathione peroxidase 3 in conditioned media. Type I 5'-deiodinase, another selenoprotein that catalyzes thyroid hormone metabolism, was detectable only in cell lysates by enzyme assay and Western blot, and responded to stimulation by both Na(2)SeO(3) and retinoic acid. A selenoprotein P signal was detected in conditioned media by Western blot, but was not enhanced by Na(2)SeO(3) treatment. In situ hybridization revealed glutathione peroxidase mRNAs in HTC specimen; glutathione peroxidase 3 mRNA levels were reduced. These data suggest adequate expression and Se-dependent regulation of a couple of selenoproteins involved in antioxidant defense and thyroid hormone metabolism in XTC.UC1 cells, so far giving no evidence of a role of these proteins in the pathogenesis of HTCs.
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Adenoma Oxifílico/metabolismo , Proteínas/metabolismo , Neoplasias de la Tiroides/metabolismo , Adenoma Oxifílico/enzimología , Western Blotting , Línea Celular Tumoral , Medios de Cultivo Condicionados , ADN Complementario/biosíntesis , ADN Complementario/genética , Depuradores de Radicales Libres/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Hibridación in Situ , Yoduro Peroxidasa/metabolismo , Peróxidos/metabolismo , Selenoproteína P , Selenoproteínas , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Neoplasias de la Tiroides/enzimologíaAsunto(s)
Adenocarcinoma Papilar/diagnóstico , Yoduro Peroxidasa/metabolismo , Glándula Tiroides/patología , Neoplasias de la Tiroides/diagnóstico , Adenocarcinoma Papilar/enzimología , Adenocarcinoma Papilar/secundario , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Hipertrofia , Radioisótopos de Yodo/uso terapéutico , Escisión del Ganglio Linfático , Disección del Cuello , Radioterapia Adyuvante , Esclerosis/patología , Glándula Tiroides/enzimología , Glándula Tiroides/cirugía , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/terapia , Tiroxina/uso terapéuticoRESUMEN
Astins, a family of cyclopentapeptides, isolated from the roots of a medicinal plant Aster tataricus (Compositae), show antitumour activity. Their chemical structures consist of a 16-membered ring system containing a unique beta,gamma-dichlorinated proline [Pro(Cl2)], other non-coded amino acid residues, and a cis conformation in one of the peptide bonds. The beta,gamma-dichlorinated proline residue is considered to play an important role in their antineoplastic activities in vitro on nasopharynx carcinoma (KB) cells and in vivo on sarcoma 180 ascites and P388 lymphocytic leukaemia in mice. The acyclic astins without Pro(Cl2) do not show antitumour activity against S-180 ascites in vivo, suggesting that the cyclic nature of astins plays an important role in their antitumour activities. We synthesized new astin-related cyclopeptides differing from the natural product for the presence of some non-proteinogenic amino acid residues: Aib, Abu, -S(beta3)-hPhe and a peptide bond surrogate (-SO2-NH-) and we tested for their antitumour effect. We observed cytotoxic effects of the newly synthesized cyclic astins, but not with the acyclic analogue astins. We also observed that the cyclic astin induced apoptosis in a human papillary thyroid carcinoma cell line (NPA cell line) and that apoptotis was associated with activation of caspases. The caspase family inhibitor, Z-Val-Asp-(OMe)-FMK, protected NPA cells from cyclic analogue astin-induced apoptosis. To determine which caspase was specifically activated, we assayed caspase activity in astin-treated cells in the presence of specific caspase and 8, 9 or 3 inhibitors, i.e. Z-IETD-FMK, Z-LEHD-FMK Z-DEVD-FMK, which inhibit caspases 8, 9 and 3, respectively. The data presented here show selective antineoplastic properties of the newly synthesized cyclic astins, and suggest, for the first time, a mechanism for their antineoplastic action through the activation of apoptotic pathway.
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Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma Papilar/patología , Caspasas/metabolismo , Péptidos Cíclicos/farmacología , Neoplasias de la Tiroides/patología , Aster/química , Carcinoma Papilar/enzimología , Inhibidores de Caspasas , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Neoplasias de la Tiroides/enzimologíaRESUMEN
AIMS: Previous studies have demonstrated that cyclooxygenase-2 (COX-2) plays a role in carcinogenesis and carcinoma development. In this study, we investigated its expression in thyroid neoplasms in order to elucidate its role. METHODS AND RESULTS: COX-2 expression was studied immunohistochemically in 20 anaplastic (undifferentiated) carcinomas, 49 papillary carcinomas, 22 follicular carcinomas and 15 follicular adenomas. Positive staining was only occasionally seen in normal follicles or stromal cells. COX-2 over-expression was found in only 20.0% of follicular adenomas and 40.9% of follicular carcinomas. In papillary carcinomas, the incidence (81.3%) was significantly higher (P < 0.0001) than in follicular carcinomas, although COX-2 expression was reduced in cases with old age (P = 0.0190), large size (P = 0.0028), advanced stage (P = 0.0225), satellite tumours (P = 0.0363), and the presence of solid, scirrhous or trabecular growth patterns (P = 0.0018). Undifferentiated carcinomas less frequently over-expressed COX-2 (P = 0.0004), with an incidence of 40.0%. CONCLUSIONS: These results indicate that the up-regulation of COX-2 may contribute predominantly in the early phase of papillary carcinoma progression, whereas it plays a more adjuvant role in follicular carcinoma progression.
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Carcinoma/enzimología , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Neoplasias de la Tiroides/enzimología , Carcinoma/secundario , Ciclooxigenasa 2 , Humanos , Técnicas para Inmunoenzimas , Proteínas de la Membrana , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de la Tiroides/patología , Regulación hacia ArribaRESUMEN
The aim of the present work was to clarify whether the activities of selenoenzymes can serve as markers for different tumors or goiters, as classified by histological criteria. The following parameters were determined: 1) selenium content of plasma (Se), 2) activities of the selenoenzymes: plasma glutathione peroxidase (plGSHPx), cytosolic glutathione peroxidase (cGSHPx), type I and type II iodothyronine deiodinases (ID-I, ID-II), thioredoxin reductase (THRR) in human thyroid tissues. The material came from follicular neoplasm, papillary carcinoma, struma nodosa, struma lymphomatosis Hashimoto, other thyroid surgery specimens, and normal tissues. There was no difference in Se nor in plGSHPx between patients and healthy volunteers. No significant differences were found for any parameter in thyroid carcinoma versus normal or goitrous thyroid tissue. In the whole group of thyroid surgery specimens the statistically significant correlations were found between ID-I and ID-II and between THRR and selenoperoxidases. Principal components analysis confirmed the above correlation and moreover revealed correlation between Se and plGSHPx, but did not detect any clear distinction between patients with the different diagnoses.
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Proteínas/análisis , Glándula Tiroides/química , Glándula Tiroides/enzimología , Neoplasias de la Tiroides/química , Neoplasias de la Tiroides/enzimología , Adenoma/química , Adenoma/enzimología , Adulto , Anciano , Carcinoma Papilar/química , Carcinoma Papilar/enzimología , Glutatión Peroxidasa/sangre , Glutatión Peroxidasa/metabolismo , Humanos , Yoduro Peroxidasa/metabolismo , Persona de Mediana Edad , Valores de Referencia , Selenio/sangre , Selenoproteínas , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Tiroiditis Autoinmune/enzimología , Tiroiditis Autoinmune/metabolismoRESUMEN
The mechanisms underlying enhanced cell proliferation in thyroid proliferative lesions of rats simultaneously treated with large amounts of vitamin A (VA) and thiourea (TU) were investigated. Male F344 animals were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection). Starting 1 week later, groups received water containing 0.2% TU (TU group), diet containing 0.1% VA (VA group), both 0.2% TU and 0.1% VA (TU + VA group) or tap water/basal diet without supplement (control group) for 10 weeks. The serum levels of triiodothyronine (T3) and thyroxine (T4) were decreased and the thyroid stimulating hormone (TSH) levels were elevated in the TU and TU + VA groups, with the degree of change being significantly greater in the combined treatment group. The induction of P450 isoenzymes by TU was not enhanced by VA supplementation, but uridine diphosphate glucuronosyltransferase (UDP-GT) activity in the liver was significantly increased in the TU + VA group compared to the TU group. Thyroid weights were increased in both the TU and TU + VA groups, this being more pronounced with VA supplementation. Thyroid follicular cell hyperplasias and neoplasias were induced to similar extents in both TU treated groups, but their cell proliferation appeared to be increased by the VA supplementation. The results of the present study suggest that enhanced cell proliferation is due to increased TSH stimulation, resulting from the decrease in serum T3/T4 levels brought about by induction of liver UDP-GT activity with the combined action of TU + VA as well as inhibition by TU of thyroid hormone synthesis in the thyroid.