RESUMEN
Matrix metalloproteinases (MMPs) play an important role in tissue remodeling during normal physiological situations and pathological implications such as tumor invasion and metastasis. MMP inhibitors were screened from extracts of medicinal herbs by an enzymatic assay using the MMP-14 catalytic domain. Among samples tested, a methanol extract of the root of Dalbergia odorifera T. CHEN (Leguminosae) showed the strongest inhibitory activity. The inhibitory component was purified through fractionation methods and identified as fisetin, abundant in many fruits and vegetables. In addition to inhibition of MMP-14, fisetin inhibits MMP-1, MMP-3, MMP-7, and MMP-9, more efficiently than a naturally occurring MMP inhibitor tetracycline. Fisetin dose-dependently inhibits proliferation of fibrosarcoma HT-1080 cells and human umbilical vascular endothelial cells (HUVECs), MMP-14-mediated activation of proMMP-2 in HT-1080 cells, invasiveness of HT-1080 cells, and in vitro tube formation of HUVECs. Therefore, fisetin could be valuable as a chemopreventive agent against cancer and a lead compound for development of therapeutic MMP inhibitors.
Asunto(s)
Flavonoides/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Metaloproteinasas de la Matriz/metabolismo , Extractos Vegetales/farmacología , Apolipoproteínas E/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimioprevención , Dalbergia/química , Relación Dosis-Respuesta a Droga , Precursores Enzimáticos/genética , Precursores Enzimáticos/metabolismo , Flavonoles , Gelatinasas/genética , Gelatinasas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Invasividad Neoplásica , Raíces de Plantas/químicaRESUMEN
Medicinal herbs are increasingly used in the search for safe and efficient drug candidates for hepatitis C virus infection. In this study, we have investigated the anti-HCV effect of compounds from Mori Cortex Radicis. During a screening for extracts with anti-HCV affinity from medicinal plants (173 species), the methanol extract of Mori Cortex Radicis was selected. Fractionation of the extract by monitoring antiviral activity with a replicon cell-based assay resulted in the isolation of five compounds, mulberroside C ( 1), moracin P ( 2), moracin O ( 3), moracin M ( 4) and mulberrofuran K ( 5) from the ethyl acetate-soluble fraction. Compounds 1 approximately 4 showed significant inhibitory activities. Compounds 2 and 3 showed potent inhibitory activity (IC (50) 35.6 microM, 80.8 microM, respectively) in the replicon cell assay, which was confirmed by NS3 helicase inhibitory activity (IC (50) 42.9 microM, 27.0 microM, respectively).