RESUMO
Neuroblastoma (NB) is a neuroendocrine tumor derived from neural crest cells. Approximately 90% of cases occur in children less than 5 years old. The amplification of MYCN correlates with high-risk neuroblastoma and patients with MYCN amplified showed poorer prognosis than those without MYCN amplification. In this study, three compounds isolated from Juniperus oblonga showed anti-proliferative activity against NB cell lines with and without tetracycline inducible MYCN over-expression which were identified as (-)-deoxypodophyllotoxin (1), (-)-matairesinol (2) and (+)-isocupressic acid (3). The effects of compounds 2 and 3 in NB cells included a decrease in NB cell viability and induction of apoptosis. Compound 1 was more effective in NB cells over-expressing MycN. Compound 1 also showed almost 2-fold induction of intracellular free calcium levels in M2(+) cells, which may indicate a different mechanism of action for this compound. Cytotoxicity studies against the human embryonic kidney cell (HEK-293) showed compounds 1, 2 and 3 were ineffective in the non-cancer cells at concentrations approximating their IC50 against the NB cell lines. These results may lead to safer and more effective treatment options for NB patients especially for those with high-risk NB.
Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Juniperus/química , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Extratos Vegetais/farmacologia , Antineoplásicos/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Pré-Escolar , Diterpenos/química , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas , Furanos/química , Furanos/farmacologia , Células HEK293 , Humanos , Concentração Inibidora 50 , Lignanas/química , Lignanas/farmacologia , Estrutura Molecular , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Fitoterapia/métodos , Extratos Vegetais/química , Podofilotoxina/análogos & derivados , Podofilotoxina/química , Podofilotoxina/farmacologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologiaRESUMO
A phytochemical investigation of the whole plant of Juniperus oblonga led to the isolationof one previously undescribed labdane diterpenoid, (4R,5S,9S,10R)-13-des-ethyl-13-oxolabda-8(17),11E-dien-19-oic acid (1), together with nine known diterpenoids (2-3, 6-12), two lignans (4, 5),and a coumarin (13). The structures of all the compounds were elucidated on the basis ofspectrometric data, primarily one-dimensional (1D)- and two-dimensional (2D)-NMR and massspectrometry. Electronic circular dichroism (ECD) calculations determined the absoluteconfiguration of 1. In addition, the isolated compounds were evaluated for their cytotoxic activityagainst three human tumor cell lines (HepG2, MCF-7, and HeLa). 6,12-Dihydroxyabieta-5,8,11,13-tetraen-7-one (6) showed moderate cytotoxicity against all three cell lines with IC50 values rangingfrom 24.41 µM to 58.39 µM and trilobinone (10) showed weaker activity with IC50 values rangingfrom 56.93 µM to 79.98 µM. None of the isolated diterpenoids have been previously reported fromJuniperus oblonga, and five compounds are here reported from the genus Juniperus for the first time.
Assuntos
Abietanos/farmacologia , Diterpenos/farmacologia , Juniperus/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Células HeLa , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Espectroscopia de Ressonância Magnética , Espectrometria de MassasRESUMO
Plants represent the best and most extensively studied source of natural antioxidants. The present study investigated the antioxidant and anti-glycation properties of different concentrations of essential oils obtained from fruits and branchlets of Juniperus oblonga M. Bieb., Cupressaceae, using different assays. The essential oils were obtained by steam distillation of the branchlets of male tree (BMT), branchlets of female tree (BFT) and fruits of J. oblonga. Compositional analysis of oils was performed using a gas chromatography-mass method. Antioxidant activity was assessed using linoleic acid peroxidation, peroxyl radical mediated hemolysis of red blood cells (RBC) and low-density lipoprotein (LDL) oxidation assays. Anti-glycation properties of oils were evaluated using hemoglobin and insulin glycation assays. Seventeen, eighteen and fifteen compounds were identified in the BMT, BFT and fruit oil, which represented 82.51, 55.69 and 96.89% of the total oils, respectively. α-Pinene was the major component of all three oils. All three oils possessed antioxidant effects against LDL oxidation, linoleic acid peroxidation and peroxyl radical mediated RBC hemolysis. Anti-glycation activities against hemoglobin and insulin glycation were also observed from all tested oils. Overall, there was no unique pattern of dose-dependence for the antioxidant properties of oils in different employed systems. The findings of this study suggest that essential oils from fruits and branchlets of J. oblonga possess antioxidant and anti-glycation properties. Therefore, these oils might be of therapeutic efficacy against diabetes and cardiovascular disease.