RESUMEN
Naturally occurring flavonoids have been shown to possess anticancer activity. We have previously shown that certain synthetic flavonoids also exert significant antiproliferative potential in MOLT-4, MCF-7, and HepG2 cell lines. To this end, we evaluated eight synthetic flavones for their CDK2 binding by molecular docking. Most flavones showed interaction with Leu 83. Based on docking and antiproliferative activity, we chose 3'-nitroflavone and 3', 5'-dimethoxyflavone for the molecular dynamics (MD) simulation and CDK2 inhibition studies. MD simulation studies confirmed interactions with CDK2 (as observed in docking). Furthermore, the inhibitory activities of CDK2/cyclin A2 enzyme for 3'-nitroflavone and 3', 5'-dimethoxyflavone were found to be 6.17 and 7.19 �M, respectively. 3'-nitroflavone and 3', 5'-dimethoxyflavone displayed moderate activity in colony formation assay, wound-scratch assay, and Leighton tube studies. Based on these data, the synthesized flavones might have clinical potential as potential inhibitors of CDK2.
Asunto(s)
Antineoplásicos/farmacología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Flavonas/química , Flavonas/farmacología , Metástasis de la Neoplasia/prevención & control , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura MolecularRESUMEN
The present study evaluates role of pullulan as hepatic targeting agent. Nanoparticles of silymarin (SIM) a hepatoprotective drug were prepared using polyethylene sebacate (PES) as biodegradable polymer and surface modified with pullulan. PES-SIM nanoparticles (PES-SIM NP) and PES-SIM nanoparticles surface modified with pullulan (PES-SIM-PUL) were prepared by nanoprecipitation. Nanoparticles were evaluated for hepatoprotective activity in a model of carbon-tetrachloride (CCl4) induced hepatotoxicity in rats. Pretreatment of rats with PES-SIM-NP and PES-SIM-PUL revealed reduced levels of SGOT, SGPT and ALKP compared to CCl4 treated group (p < 0.01) whereas levels of LPO and catalase were comparable to vehicle control suggesting enhanced hepatoprotection with nanoparticles. Histopathological evaluation of liver tissues also revealed better hepatoprotection with nanoparticles. Further significant decrease (p < 0.01) in levels of SGOT, SGPT and ALKP with difference PES-SIM-PUL than PES-SIM NP confirms the role of pullulan as hepatic targeting agent.
Asunto(s)
Hígado/efectos de los fármacos , Nanopartículas/química , Poliésteres/química , Sustancias Protectoras/química , Silimarina/química , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas , Femenino , Hígado/patología , Nanopartículas/administración & dosificación , Tamaño de la Partícula , Poliésteres/administración & dosificación , Poliésteres/farmacología , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacología , Ratas , Ratas Sprague-Dawley , Silimarina/administración & dosificación , Silimarina/farmacologíaRESUMEN
BACKGROUND: Many plant-derived products exhibit potent chemopreventive activity against animal tumor models as well as rodent and human cancer cell lines. They have low side effects and toxicity and presumably modulate the factors that are critical for cell proliferation, differentiation, senescence and apoptosis. The present study investigates the effects of some medicinal plant extracts from generally recognized as safe plants that may be useful in the prevention and treatment of cancer. METHODS: Clonogenic assays using logarithmically-growing cells were performed to test the effect. The cytotoxic effects of Curcuma longa and Zingiber officinale were studied using sulforhodamine B assay, tetrazolium dye assay, colony morphology and microscopic analysis. RESULTS: Out of the 13 lyophilized plant-derived extracts evaluated for growth-inhibitory effects on the PC-3M prostate cancer cell line, two extracts derived from C. longa and Z. officinale showed significant inhibitory effects on colony-forming ability. The individual and augmentative effects of these two extracts were tested for their narrow range effective lower concentration on PC-3M in clonogenic assays. At relatively lower concentrations, C. longa showed significant inhibition of colony formation in clonogenic assays; whereas at same concentrations Z. officinale showed only moderate inhibitory effects. However, when both the agents were tested together at the same concentrations, the combined effects were much more significant than their individual ones. On normal prostate epithelial cells both C. longa and Z. officinale had similar effects but at a lower magnitude. These observations were confirmed by several cytotoxicity assays involving the morphological appearance of the colonies, microscopic observations, per cent inhibition in comparison to control by sulforhodamine B and tetrazolium dye assay. CONCLUSIONS: From these observations, it was concluded that the combined effects of C. longa and Z. officinale are much greater than their individual effects, suggesting the role of multiple components and their synergistic mode of actions to elicit stronger beneficial effects.