35 research outputs found
Folate Decorated Dual Drug Loaded Nanoparticle: Role of Curcumin in Enhancing Therapeutic Potential of Nutlin-3a by Reversing Multidrug Resistance
Retinoblastoma is the most common intraocular tumor in children. Malfunctioning of many signaling pathways regulating cell survival or apoptosis, make the disease more vulnerable. Notably, resistance to chemotherapy mediated by MRP-1, lung-resistance protein (LRP) is the most challenging aspect to treat this disease. Presently, much attention has been given to the recently developed anticancer drug nutlin-3a because of its non-genotoxic nature and potency to activate tumor suppressor protein p53. However, being a substrate of multidrug resistance protein MRP1 and Pgp its application has become limited. Currently, research has step towards reversing Multi drug resistance (MDR) by using curcumin, however its clinical relevance is restricted by plasma instability and poor bioavailability. In the present investigation we tried to encapsulate nutlin-3a and curcumin in PLGA nanoparticle (NPs) surface functionalized with folate to enhance therapeutic potential of nutlin-3a by modulating MDR. We document that curcumin can inhibit the expression of MRP-1 and LRP gene/protein in a concentration dependent manner in Y79 cells. In vitro cellular cytotoxicity, cell cycle analysis and apoptosis studies were done to compare the effectiveness of native drugs (single or combined) and single or dual drug loaded nanoparticles (unconjugated/folate conjugated). The result demonstrated an augmented therapeutic efficacy of targeted dual drug loaded NPs (Fol-Nut-Cur-NPs) over other formulation. Enhanced expression or down regulation of proapoptotic/antiapoptotic proteins respectively and down-regulation of bcl2 and NFÎşB gene/protein by Fol-Nut-Cur-NPs substantiate the above findings. This is the first investigation exploring the role of curcumin as MDR modulator to enhance the therapeutic potentiality of nutlin-3a, which may opens new direction for targeting cancer with multidrug resistance phenotype
PPARÎł agonists inhibit growth and expansion of CD133+ brain tumour stem cells
Brain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARγ) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARγ agonist, 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARγ in gliosphere cells. These findings demonstrate that PPARγ agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour
PPARÎł agonists inhibit growth and expansion of CD133+ brain tumour stem cells
Brain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARγ) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARγ agonist, 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARγ in gliosphere cells. These findings demonstrate that PPARγ agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour
Efecto de la combinaciĂłn fungicida protectante y variedad sobre el tizĂłn tardĂo [Phythopthora Infestas (Montagne) De Bary] en el cultivo de papa (Solanum tuberosum L.) en Ă©poca de primera localidad La Tejera, San Nicolás, EstelĂ, 2008
El objetivo principal de este estudio fue el de evaluar el efecto de tres intervalos de aplicaciĂłn del fungicida clorotalonil y tres variedades de papa con diferentes niveles de resistencia sobre la epidemiologĂa y manejo del tizĂłn tardĂo [Phytophthora infestans (Montagne) De Bary] en el cultivo de papa (Solanum tuberosum L.) El trabajo experimental se realizĂł de Julio a Octubre 2008, en la localidad “La Tejera”, municipio de San Nicolás, departamento de EstelĂ, localizado en las coordenadas geográficas 12Âş58'23” latitud norte y 86Âş24'21” longitud oeste, a una altura de 1,328 metros sobre el nivel del mar.
Se evaluaron doce epidemias de tizĂłn tardĂo que resultaron de la combinaciĂłn de tres variedades de papa (Cal White, Granola y Jacqueline Lee) y cuatro tratamientos (tres
intervalos de aplicaciĂłn del fungicida clorotalonil y un testigo en el cual no se aplicĂł fungicida). Los
tratamientos fueron distribuidos en bloques completos al azar. El manejo experimental fue el mismo que realiza el productor convencionalmente. Las variables epidemiológicas evaluadas fueron: severidad, área bajo la curva de progreso de la enfermedad (ABCPE) y la tasa de infección aparente (r). Además, se midieron variables climáticas
como temperatura, humedad relativa y precipitaciones y se determinĂł el rendimiento de las variedades incluidas en el estudio. Las doce epidemias analizadas en este estudio iniciaron con varios dĂas de diferencia, en dependencia del nivel de resistencia de la variedad y del intervalo de aplicaciĂłn del fungicida protectante clorotalonil. La
severidad de la enfermedad alcanzĂł casi el 100% en las variedades susceptibles (Cal White y Granola) en las parcelas donde no se aplicĂł el fungicida clorotalonil, pero el porcentaje de severidad en las parcelas tratadas disminuyĂł conforme el intervalo de aplicaciĂłn se fue
acortando. En la variedad Jacqueline Lee los porcentajes de severidad fueron bajos, incluso en las parcelas que no fueron tratadas con el fungicida clorotalonil, lo cual demuestra que esta variedad es resistente a P. infestans. Ninguno de los intervalos de aplicaciĂłn (cada 4, 7 y 14 dĂas) del fungicida clorotalonil detuvo el avance de las epidemias de tizĂłn tardĂo una vez que Ă©stas iniciaron, principalmente, en las parcelas con variedades susceptibles.
El rendimiento obtenido en cada una de las variedades evaluadas fue menor al compararlo con otro estudio de validaciĂłn llevado a cabo en 2007 en tres localidades de Matagalpa y Jinotega. Los resultados de este estudio const
ituyen una contribuciĂłn muy importante para el desarrollo de futuras estrategias encaminadas, no a la erradicaciĂłn total del tizĂłn tardĂo de los campos de papa y/o tomate de Nicaragua, pero si para lograr mitigar su efecto
devastador sobre tan importantes cultivos tanto desde el punto de vista nutritivo como econĂłmico