RESUMEN
Tocotrienols (T3s) and tocopherols (Tocs) are both members of the vitamin E family. It is known that δ-tocotrienol (δ-T3) has displayed the most potent anti-cancer activity amongst the tocotrienols. On the other hand, γ-tocopherol (γ-Toc) is reported to have a protective effect against prostate cancer. Therefore, we investigated whether the combination of γ-Toc and δ-T3 could strengthen the inhibitory effect of δ-T3 on prostate cancer cell growth. In this study the effect of combined δ-T3 (annatto T3 oil) and γ-Toc (Tmix, γ-Toc-rich oil) therapy was assessed against human androgen-dependent prostate cancer cells (LNCaP). We found that combined treatment of δ-T3 (10 µM) and γ-Toc (5 µM) resulted in reinforced anti-prostate cancer activity. Specifically, cell cycle phase distribution analysis revealed that in addition to G1 arrest caused by the treatment with δ-T3, the combination of δ-T3 with γ-Toc induced G2/M arrest. Enhanced induction of apoptosis by the combined treatment was also observed. These findings indicate that combination of δ-T3 and γ-Toc significantly inhibits prostate cancer cell growth due to the simultaneous cell cycle arrest in the G1 phase and G2/M phase.
Asunto(s)
Anticarcinógenos/metabolismo , Antineoplásicos Fitogénicos/agonistas , Apoptosis , Cromanos/agonistas , Neoplasias de la Próstata/metabolismo , Vitamina E/análogos & derivados , Anticarcinógenos/química , Antineoplásicos Fitogénicos/metabolismo , Bixaceae/metabolismo , Carotenoides/agonistas , Carotenoides/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Cromanos/metabolismo , Fase G1 , Fase G2 , Humanos , Masculino , Concentración Osmolar , Extractos Vegetales/agonistas , Extractos Vegetales/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Vitamina E/agonistas , Vitamina E/metabolismoRESUMEN
The aim of the study was to assess the protective effect of (-)-epigallocatechin gallate (EGCG), a flavonoid abundant in green tea, against ammonium metavanadate (AMV)-induced oxidative stress in male Wistar rats. Four groups of animals have been used, a control group and three test groups. In the first test group, AMV was intra-peritoneally (i.p) injected daily (5 mg/kg body weight for five consecutive days). The second test group of animals was also injected daily with EGCG (5 mg/kg body weight) during the same period. However, the third test group was i.p. injected with both AMV and EGCG (5 mg/kg body weight for five consecutive days). When given alone, AMV induced an oxidative stress evidenced by an increase of lipid peroxidation levels (expressed as TBARS concentration) in kidney. In these animals, activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were significantly decreased, suggesting significant reduction of the antioxidant defense system at the cell level. Kidney histological sections, showed glomerular hypertrophy and tubular dilatation. In AMV-treated animals receiving EGCG, the oxidative stress was much less pronounced and activities of antioxidant enzymes were kept close to control values. Histopathological changes were less prominent. Our results confirm that green tea and other sources of flavonoids might confer a strong protection against ammonium metavanadate-induced oxidative stress.
Asunto(s)
Lesión Renal Aguda/prevención & control , Catequina/análogos & derivados , Intoxicación por Metales Pesados/fisiopatología , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Vanadio/envenenamiento , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Antioxidantes/uso terapéutico , Catequina/administración & dosificación , Catequina/efectos adversos , Catequina/uso terapéutico , Intoxicación por Metales Pesados/etiología , Hipertrofia , Inyecciones Intraperitoneales , Riñón/metabolismo , Riñón/patología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/metabolismo , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/efectos adversos , Ratas Wistar , Vanadatos/administración & dosificación , Vanadio/administración & dosificación , Vitamina A/agonistas , Vitamina A/antagonistas & inhibidores , Vitamina A/sangre , Vitamina E/agonistas , Vitamina E/antagonistas & inhibidores , Vitamina E/sangreRESUMEN
Renal fibroblast proliferation is key in renal fibrosis and chronic kidney disease. Transforming growth factor-ß1 (TGF-ß1) has been demonstrated to be an important factor that induces cell proliferation in renal fibroblasts. Epidermal growth factor receptor (EGFR) is also recognized as a factor promoting renal fibroblast proliferation. In addition, mitogenactivated protein kinase signaling pathways are associated with TGFß1 and EGFRinduced cell proliferation. Gefitinib, an EGFR tyrosine kinase inhibitor, is predominantly used as an antitumor therapeutic agent in clinical therapeutic strategies. However, gefitinib has been suggested to exert antiproliferative effects on renal fibroblasts, however, highdose gefitinib may result in serious side effects. The present study aims to determine whether lowdose gefitinib reduces gefitinibinduced side effects and maintains the antiproliferative effects on renal fibroblasts. TGFß1 promotes cell proliferation in renal fibroblasts, and the current study demonstrates that lowdose gefitinib treatment exhibits antiproliferative effects similar to those of highdose gefitinib treatment. Thus, although highdose gefitinib is a conventional antitumor drug, lowdose gefitinib may be of use in renal fibrosis treatment. Furthermore, the present study demonstrates that a combined treatment with low-dose gefitinib and vitamin E has synergistic effects that reduce TGFß1induced fibroblast proliferation, cell-cycle arrest and the ERK phosphorylation pathway.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Riñón/metabolismo , Quinazolinas/farmacología , Factor de Crecimiento Transformador beta1/biosíntesis , Vitamina E/farmacología , Animales , Línea Celular , Sinergismo Farmacológico , Fibroblastos/citología , Gefitinib , Riñón/citología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinazolinas/agonistas , Ratas , Vitamina E/agonistasRESUMEN
The study was conducted to investigate the potential of liquorice extract (LE) from Glycyrrhiza uralensis as a dietary supplement for sheep to improve antioxidant capacity of meat. Fifty Tan sheep were randomly allocated to five groups with LE supplementation at levels of 0, 1000, 2000, 3000 and 4000 mg/kg feed. After 120 days, the longissimus thoracis muscle was sampled and conditioned for 0, 2, 4, 6 and 8 days at 4 °C. The results revealed that LE scavenged free radical in a dose-response manner in vitro. Supplementation with LE in animal diet increased (P<0.05) antioxidant content and radical scavenging activity while it decreased (P<0.05) reactive oxygen species (ROS) and thiobarbituric acid reactive substance (TBARS) levels of meat. Dietary LE supplementation can improve antioxidant capacity of meat, and the optimum dosage range of LE supplementation appeared to be 3000 to 4000 mg/kg feed.
Asunto(s)
Antioxidantes/administración & dosificación , Dieta/veterinaria , Glycyrrhiza uralensis/química , Carne/análisis , Músculo Esquelético/metabolismo , Extractos Vegetales/administración & dosificación , Oveja Doméstica/crecimiento & desarrollo , Animales , Animales Endogámicos , Antioxidantes/análisis , Antioxidantes/química , China , Flavonoides/administración & dosificación , Flavonoides/análisis , Flavonoides/química , Conservación de Alimentos , Almacenamiento de Alimentos , Glutatión/agonistas , Glutatión/análisis , Glutatión/metabolismo , Peroxidación de Lípido , Masculino , Músculo Esquelético/química , Músculo Esquelético/crecimiento & desarrollo , Extractos Vegetales/química , Raíces de Plantas/química , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Refrigeración , Oveja Doméstica/fisiología , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Sustancias Reactivas al Ácido Tiobarbitúrico/química , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Vitamina E/agonistas , Vitamina E/análisis , Vitamina E/metabolismoRESUMEN
Statins and gamma-tocotrienol (a rare isoform of vitamin E) both inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase activity and display anticancer activity. However, clinical application of statins has been limited by high dose toxicity. Previous studies showed that combined statin and gamma-tocotrienol treatment synergistically inhibits growth of highly malignant +SA mammary epithelial cells in culture. To investigate the mechanism mediating this growth inhibition, studies were conducted to determine the effect of combination low dose gamma-tocotrienol and statin treatment on +SA mammary tumor cell cycle progression. Treatment with 0.25 microM simvastatin, lovastatin, mevastatin, 10 microM pravastatin or 2.0 microM gamma-tocotrienol alone had no effect, while combined treatment of individual statins with gamma-tocotrienol significantly inhibited +SA cell proliferation during the 4-day culture period. Flow cytometric analysis demonstrated that combined treatment induced cell cycle arrest in G1. Additional studies showed that treatment with 0.25 microM simvastatin or 2 microM gamma-tocotrienol alone had no effect on the relative intracellular levels of cyclin D1, CDK2, CDK4 and CDK6, but combined treatment caused a large reduction in cyclin D1 and CDK2 levels. Combined treatments also caused a relatively large increase in p27, but had no effect on p21 and p15 levels, and resulted in a large reduction in retinoblastoma (Rb) protein phosphorylation at ser780 and ser807/811. Similar effects were observed following combined treatment of gamma-tocotrienol with low doses of lovastatin, mevastatin and pravastatin. These findings demonstrate that combination low dose statin and gamma-tocotrienol treatment induced mammary tumor cell cycle arrest at G1, resulting from an increase in p27 expression, and a corresponding decrease in cyclin D1, CDK2, and hypophosphorylation of Rb protein. These findings suggest that combined treatment of statins with gamma-tocotrienol may provide significant health benefits in the treatment of breast cancer in women, while avoiding myotoxicity associated with high dose statin monotherapy.