RESUMEN
CONTEXT: Coumarin derivatives have been reported to inhibit melanin biosynthesis. OBJECTIVE: The melanogenesis inhibitory activity of osthol, a major coumarin of the fruits of Cnidium monnieri Cusson (Umbelliferae), and optimized extraction conditions for the maximum yield from the isolation of osthol from C. monnieri fruits were investigated. MATERIALS AND METHODS: B16F10 melanomas were treated with osthol at concentration of 1, 3, and 10 µM for 72 h. The expression of melanogenesis genes, such as tyrosinase, TRP-1, and TRP-2 was also assessed. For optimization, extraction factors such as extraction solvent, extraction time, and sample/solvent ratio were tested and optimized for maximum yield of osthol using response surface methodology with the Box-Behnken design (BBD). RESULTS: Osthol inhibits melanin content in B16F10 melanoma cells with an IC50 value of 4.9 µM. The melanogenesis inhibitory activity of osthol was achieved not by direct inhibition of tyrosinase activity but by inhibiting melanogenic enzyme expressions, such as tyrosinase, TRP-1, and TRP-2. The optimal condition was obtained as a sample/solvent ratio, 1500 mg/10 ml; an extraction time 30.3 min; and a methanol concentration of 97.7%. The osthol yield under optimal conditions was found to be 15.0 mg/g dried samples, which were well matched with the predicted value of 14.9 mg/g dried samples. CONCLUSION: These results will provide useful information about optimized extraction conditions for the development of osthol as cosmetic therapeutics to reduce skin hyperpigmentation.
Asunto(s)
Cnidium/química , Cumarinas/aislamiento & purificación , Frutas/química , Extractos Vegetales/aislamiento & purificación , Preparaciones para Aclaramiento de la Piel/aislamiento & purificación , Animales , Línea Celular Tumoral , Fraccionamiento Químico , Cromatografía Líquida de Alta Presión , Cumarinas/farmacología , Relación Dosis-Respuesta a Droga , Oxidorreductasas Intramoleculares/metabolismo , Melaninas/biosíntesis , Melanoma Experimental/enzimología , Ratones , Oxidorreductasas/metabolismo , Fitoterapia , Extractos Vegetales/farmacología , Plantas Medicinales , Preparaciones para Aclaramiento de la Piel/farmacología , Pigmentación de la Piel/efectos de los fármacos , Factores de TiempoRESUMEN
PURPOSE: A sentinel lymph node (SLN) tracer can gain multi-functionality by combining it with additional components. We developed a SLN tracer consisting of iodine and docetaxel and applied it as a theragnostic nanoparticle to simultaneously perform SLN computed tomography (CT) lymphography and locoregional chemotherapy of the draining lymphatic system. RESULTS: Docetaxel could be loaded in iodine emulsions at a drug-to-surfactant weight ratio as high as that in the drug formulation Taxotere®. The particle size and drug concentration were stable during storage for up to 3 months in optimized nanoemulsions. Popliteal LN enhancement on CT was observed in all healthy rabbits (n=3) and VX2 tumor-implanted rabbits (n=6) 12 hours after injection. The rate of SLN metastasis was significantly lower in the treatment group (29.4%, 5/17) than in the non-treatment group (70.6%, 12/17) (P=0.038). MATERIAL AND METHODS: We prepared a nanoemulsion carrying both iodine and docetaxel in a single structure by optimizing the composition of surfactants surrounding the inner iodized oil core. CT was performed 12 hours after subcutaneous injection of the emulsion in healthy rabbits (n=3) and VX2 tumor-implanted rabbits (n=6) for SLN imaging. Next, we tested the effect of treatment by histopathologically assessing the popliteal LN metastasis rate in VX2 tumor-implanted rabbits 7 days after subcutaneous injection of the emulsion (treatment group, n=17) and comparing it with that of non-treatment group rabbits (n=17). CONCLUSIONS: We developed an iodine-docetaxel emulsion and demonstrated that it can be applied to simultaneously achieve CT SLN imaging and local chemotherapy against nodal metastasis.
Asunto(s)
Emulsiones , Yodo , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Ganglio Linfático Centinela/diagnóstico por imagen , Ganglio Linfático Centinela/patología , Taxoides/administración & dosificación , Tomografía Computarizada por Rayos X , Animales , Modelos Animales de Enfermedad , Docetaxel , Estabilidad de Medicamentos , Emulsiones/química , Yodo/química , Metástasis Linfática , Masculino , Estadificación de Neoplasias , Neoplasias/tratamiento farmacológico , Tamaño de la Partícula , Conejos , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
The switch between stem/progenitor cell expansion and differentiation is critical for organ homeostasis. The mammalian Hippo pathway effector and oncoprotein YAP expands undifferentiated stem/progenitor cells in various tissues. However, the YAP-associated transcription factors and downstream targets underlying this stemness-promoting activity are poorly understood. Here we show that the SRF-IL6 axis is the critical mediator of YAP-induced stemness in mammary epithelial cells and breast cancer. Specifically, serum response factor (SRF)-mediated binding and recruitment of YAP to mammary stem cell (MaSC) signature-gene promoters induce numerous MaSC signature genes, among which the target interleukin (IL)-6 is critical for YAP-induced stemness. High SRF-YAP/TAZ expression is correlated with IL6-enriched MaSC/basal-like breast cancer (BLBC). Finally, we show that this high SRF expression enables YAP to more efficiently induce IL6 and stemness in BLBC compared with luminal-type breast cancer. Collectively, our results establish the importance of SRF-YAP-IL6 signalling in promoting MaSC-like properties in a BLBC-specific manner.