RESUMO
BACKGROUND/AIM: The polyphenol curcumin is produced in the rhizome of Curcuma longa and exhibits potent anti-inflammatory, antioxidant, and chemopreventive activities. Due to the fact that curcumin is poorly soluble in water, many delivery systems have been developed to improve its solubility and bioavailability achieving optimum therapeutic application. In this study, we evaluated the biological effects of a liposomal curcumin formulation (Lipocurc™) on human synovial fibroblasts (SW982) and mouse macrophages (RAW264). MATERIAL AND METHODS: Cellular uptake of liposomes was studied using calcein-loaded liposomes. Effects of Lipocurc™ on cell viability and proliferation were determined with Celltox green cytotoxicity assay and 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay, respectively. To induce cytokine/chemokine expression, the cells were stimulated with interleukin (IL)1ß or lipopolysaccharide (LPS). The release of IL6, IL8, and tumor necrosis factor-alpha (TNFα) was quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Data showed that the liposomal curcumin formulation Lipocurc™ was significantly less toxic to synovial fibroblasts and macrophages compared to non-encapsulated, free curcumin. Furthermore, Lipocurc™ effectively reduced pro-inflammatory cytokine/chemokine expression in synovial fibroblasts as well as in macrophages without affecting cell viability, suggesting that this curcumin nanoformulation might be a promising tool for the treatment of inflammatory diseases.
Assuntos
Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Fibroblastos/patologia , Lipossomos/química , Macrófagos/patologia , Líquido Sinovial/química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Técnicas In Vitro , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismoRESUMO
BACKGROUND/AIM: Resveratrol, a natural polyphenol, possesses many beneficial health properties but its therapeutic application is limited due to its low water solubility and instability against oxidative processes. To improve the stability and lipophilicity of the natural compound, we synthesized a resveratrol prodrug, termed FEHH4-1. In the present study, we compared the antiproliferative and pro-apoptotic effects of resveratrol with FEHH4-1 on Jurkat T-cells. MATERIALS AND METHODS: Cell proliferation and viability were monitored by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay, annexin-V/7-amino-actinomycin D staining and western blot. To induce interleukin-2 (IL2) expression, cells were stimulated with phorbol 12-myristate 13-acetate/phytohemagglutinin. IL2 production was quantified by enzyme-linked immunosorbent assay. IL2 promoter activity was studied by a Jurkat T-cell line containing an IL2 promoter luciferase reporter construct. RESULTS: Both polyphenols inhibited proliferation, induced apoptotic cell death and blocked IL2 synthesis in Jurkat T-cells. Most importantly, FEHH4-1 was three-to four-times more potent than resveratrol. CONCLUSION: FEHH4-1 had improved antiproliferative and pro-apoptotic potential against Jurkat T-cells compared to resveratrol.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Leucemia de Células T/tratamento farmacológico , Pró-Fármacos/farmacologia , Estilbenos/farmacologia , Antineoplásicos/síntese química , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Células Jurkat , Leucemia de Células T/genética , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Pró-Fármacos/síntese química , Regiões Promotoras Genéticas , Resveratrol , Estilbenos/síntese química , TransfecçãoRESUMO
Genistein, a naturally occurring isoflavone, possesses many beneficial health effects. To improve the bioactivity of the natural compound, we designed and synthesized the genistein prodrug FEHH6-1. In the present study, we evaluated the biological effects of FEHH6-I on mouse RAW264.7 macrophages and compared them with those obtained with the parent drug genistein. The characteristics of FEHH6-1 were determined by melting point, nuclear magnetic resonance spectroscopy (NMR), and mass spectrometric analysis. The effects of FEHH6-I on cell proliferation, apoptosis, and pro-inflammatory cytokine expression were monitored by XTT-assay, Annexin-V/7-AAD staining, Western blotting, and ELISA. FEHH6-1 showed NMR spectra and relative molecular mass in agreement with the designed structure. In mouse RAW264.7 macrophages, FEHH6-1 inhibited proliferation, induced apoptotic cell death and blocked interleukin 6 and tumor necrosis factor alpha synthesis. At low concentrations, FEHH6-1 induced phosphorylation of AKT1, a kinase involved in cell proliferation and survival. Our data demonstrate that the genistein prodrug FEHH6-1 is a bioactive molecule but its solubility and therefore also its efficacy was significantly lower compared with genistein.
