RESUMEN
With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-ß-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Carbolinas , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Fármacos Neuroprotectores , Pez Cebra , Carbolinas/farmacología , Carbolinas/química , Carbolinas/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Animales , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Ratas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Relación Estructura-Actividad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Células PC12 , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Chemotherapy is a commonly used strategy for advanced lung cancer patients. However, its clinical application is restrained due to its toxicity and drug resistance. Ginsenoside Rg3 (Rg3) has a strong anticancer influence on colon cancer, breast cancer, lung cancer, and other malignant tumors. However, it is still unclear whether Rg3 can cooperate with 5-FU to inhibit the tumor growth and angiogenesis of lung adenocarcinoma (LUAD). This study examined the combined treatment of Rg3 and 5-FU in LUAD. It was revealed that the combined treatment could notably enhance the suppression on proliferative, invasive, and migratory abilities and angiogenesis in LUAD cells A549 and SPC-A-1. On the other hand, we also discovered that Rg3 or 5-FU could suppress the activity of the NF-κB signaling pathway and downregulate VEGFA expression in LUAD cells. Collectively, this study suggested that Rg3 combined chemotherapy may perform a more powerful drug efficiency in LUAD cells.