Asunto(s)
Odorantes , Perfumes , Butiratos/toxicidad , Perfumes/toxicidad , Sistema de Registros , Medición de RiesgoAsunto(s)
Butiratos , Perfumes , Pruebas de Toxicidad , Animales , Femenino , Humanos , Masculino , Ratones , Ratas , Butiratos/química , Butiratos/toxicidad , Células Cultivadas , Bases de Datos de Compuestos Químicos , Pruebas de Micronúcleos , Perfumes/química , Perfumes/toxicidad , Reproducción/efectos de los fármacos , Absorción Cutánea , Pruebas CutáneasAsunto(s)
Butiratos , Monoterpenos , Octanoles , Perfumes , Pruebas de Toxicidad , Animales , Femenino , Humanos , Masculino , Ratas , Butiratos/química , Butiratos/toxicidad , Células Cultivadas , Bases de Datos de Compuestos Químicos , Pruebas de Micronúcleos , Monoterpenos/química , Monoterpenos/toxicidad , Octanoles/química , Octanoles/toxicidad , Perfumes/química , Perfumes/toxicidad , Reproducción/efectos de los fármacos , Absorción Cutánea , Pruebas CutáneasAsunto(s)
Butiratos/toxicidad , Odorantes , Animales , Butiratos/química , Seguridad de Productos para el Consumidor , Bases de Datos de Compuestos Químicos , Vías de Administración de Medicamentos , Determinación de Punto Final , Humanos , Estructura Molecular , Nivel sin Efectos Adversos Observados , Perfumes , Medición de Riesgo , Pruebas de ToxicidadRESUMEN
Melanoma is known to aggressively metastasize and is one of the prominent causes of skin cancer mortality. This study was designed to assess the molecular mechanism of decursinol angelate (DA) against murine melanoma cell line (B16F10 cells). Treatment of DA resulted in growth inhibition and cell cycle arrest at G0/G1 (p < 0.001) phase, evaluated through immunoblotting. Moreover, autophagy-related proteins such as ATG-5 (p < 0.0001), ATG-7 (p < 0.0001), beclin-1 (p < 0.0001) and transition of LC3-I to LC3-II (p < 0.0001) were markedly decreased, indicating autophagosome inhibition. Additionally, DA treatment triggered apoptotic events which were corroborated by the occurrence of distorted nuclei, elevated reactive oxygen species (ROS) levels and reduction in the mitochondrial membrane potential. Subsequently, there was an increase in the expression of pro-apoptotic protein Bax in a dose-dependent manner, with the corresponding downregulation of Bcl-2 expression and cytochrome C expression following 24 h DA treatment in A375.SM and B16F10 cells. We substantiated our results for apoptotic occurrence through flow cytometry in B16F10 cells. Furthermore, we treated B16F10 cells with N-acetyl-L-cysteine (NAC). NAC treatment upregulated ATG-5 (p < 0.0001), beclin-1 (p < 0.0001) and LC3-I to LC3-II (p < 0.0001) conversion, which was inhibited in the DA treatment group. We also noticed a systematic upregulation of important markers for progression of G1 cell phase such as CDK-2 (p < 0.029), CDK-4 (p < 0.036), cyclin D1 (p < 0.0003) and cyclin E (p < 0.020) upon NAC treatment. In addition, we also observed a significant fold reduction (p < 0.05) in ROS fluorescent intensity and the expression of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase-9 (p > 0.010) and cleaved caspase-3 (p < 0.0001). NAC treatment was able to ameliorate DA-induced apoptosis and cell cycle arrest to support our finding. Our in vivo xenograft model also revealed similar findings, such as downregulation of CDK-2 (p < 0.0001) and CDK-4 (p < 0.0142) and upregulation of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase 3 (p < 0.0001) and cleaved caspase 9 (p < 0.0001). In summary, our study revealed that DA is an effective treatment against B16F10 melanoma cells and xenograft mice model.
Asunto(s)
Apoptosis , Benzopiranos/farmacología , Butiratos/farmacología , Melanoma/patología , Neoplasias Cutáneas/patología , Acetilcisteína/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Benzopiranos/toxicidad , Butiratos/toxicidad , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Melanoma Experimental/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Membranas Mitocondriales/efectos de los fármacos , Membranas Mitocondriales/metabolismo , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Many bony features of the face develop from endochondral ossification of preexisting collagen-rich cartilage structures. The proper development of these cartilage structures is essential to the morphological formation of the face. The developmental programs governing the formation of the pre-bone facial cartilages are sensitive to chemical compounds that disturb histone acetylation patterns and chromatin structure. We have taken advantage of this fact to develop a quantitative morphological assay of craniofacial developmental toxicity based on the distortion and deterioration of facial cartilage structures in zebrafish larvae upon exposure to increasing concentrations of several well-described histone deacetylase inhibitors. In this assay, we measure the angle formed by the developing ceratohyal bone as a precise, sensitive and quantitative proxy for the overall developmental status of facial cartilages. Using the well-established developmental toxicant and histone deacetylase-inhibiting compound valproic acid along with 12 structurally related compounds, we demonstrate the applicability of the ceratohyal angle assay to investigate structure-activity relationships.