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1.
Cells ; 11(18)2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36139362

RESUMO

Hypoxia, a typical feature of locally advanced solid tumors including prostate cancer, is a critical contributor to tumor progression and causes resistance to therapy. In this study, we investigated the effects of chrysin on tumor progression in hypoxic PC-3 cells. Chrysin exerted a significant inhibitory effect on 3D cell growth under normoxic and hypoxic conditions. It also decreased the hypoxia-induced vasculogenic mimicry and attenuated the expression of HIF-1α and VE-cadherin. Chrysin inhibited HIF-1α accumulation in a concentration- and time-dependent manner in hypoxic PC-3 cells, while also suppressing the expression of HIF-1α by inhibiting SPHK-1 in both CoCl2 and hypoxic PC-3 cells. At high concentrations of chrysin, there was a greater increase in apoptosis in the hypoxic cells compared to that in normoxic cells, which was accompanied by sub-G1 phase arrest. Chrysin-induced apoptosis inhibited VEGF and Bcl-2 and induced the cleavage of PARP and caspase-3. SPHK-1 knockdown induced apoptosis and inhibited epithelial-mesenchymal transition. Consistent with the in vitro data, 50 mg/kg of chrysin suppressed the tumor growth of PC-3 xenografts by 80.4% compared to that in the untreated control group. The immunohistochemistry of tumor tissues revealed decreased Ki-67, HIF-1α, and VEGF expression in the chrysin-treated group compared to an untreated control. Western blotting data for tumor tissues showed that chrysin treatment decreased SPHK-1, HIF-1α, and PARP expression while inducing caspase-3 cleavage. Overall, our findings suggest that chrysin exerts anti-tumor activity by inhibiting SPHK-1/HIF-1α signaling and thus represents a potent chemotherapeutic agent for hypoxia, which promotes cancer progression and is related to poor prognoses in prostate cancer patients.


Assuntos
Neoplasias da Próstata , Fator A de Crescimento do Endotélio Vascular , Caspase 3/metabolismo , Linhagem Celular Tumoral , Flavonoides , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Células PC-3 , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Mol Biol Rep ; 48(3): 2173-2181, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33630206

RESUMO

BACKGROUND: The pawpaw tree has several beneficial effects. However, no studies have been conducted to address the mechanisms underlying the cytotoxic effects of pawpaw extracts against cancer cells, and no study has investigated the anti-inflammatory effects. Hence, in this study, the growth-inhibitory effects of pawpaw (Asimina triloba [L.] Dunal) extracts against gastric (AGS) and cervical (HeLa) cancer cells and the inhibitory effects of pawpaw extracts against inflammatory factors (NO, TNF-α, IL-6, iNOS, and COX-2) were investigated. METHODS AND RESULTS: The viability of AGS and HeLa cells, the analysis of cell cycle, and the expression of apoptosis marker protein were determined using MTT assay, FACS, western blotting, and TUNEL assays. The inflammatory factors were determined using Griess method, ELISA assay kit, and RAW 264.7 cells. The IC50 values of twig and unripe fruit extracts for AGS cells were 82.01 and 100.61 µg/mL, respectively. For HeLa cells, pawpaw twig extracts exhibited the strongest ability to inhibit cervical cancer cell growth (IC50 = 97.73 µg/mL). Analysis of the cell cycle phase distribution and expression of the apoptosis regulatory proteins BCL-2, BAX, caspase-3, and PARP showed that pawpaw twig, root, and unripe fruit extracts induced Sub G1 cell cycle arrest and apoptosis of AGS and HeLa cells. In addition, the twig, root, and unripe fruit extracts of pawpaw effectively inhibited the inflammatory makers NO, TNF-α, IL-6, and iNOS. Particularly, the twig, root, and unripe fruit extracts at concentrations of 50 µg/mL exhibited > 50% inhibition of TNF-α. CONCLUSIONS: These findings indicate that pawpaw extracts are natural therapeutic agents that may be used for the prevention and treatment of gastric and cervical cancers, and encourage further studies on the anti-inflammatory potential of the pawpaw tree.


Assuntos
Anti-Inflamatórios/farmacologia , Asimina/química , Frutas/química , Folhas de Planta/química , Raízes de Plantas/química , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Óxido Nítrico/biossíntese , Células RAW 264.7
3.
Int J Mol Sci ; 20(5)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845749

RESUMO

Fomes fomentarius, an edible mushroom, is known to have anti-cancer, anti-inflammatory, and anti-diabetes effects. However, the underlying anti-cancer mechanism of F. fomentarius is unknown. To determine the molecular mechanism of the anti-cancer effects of F. fomentarius, various methods were used including fluorescence-activated cell sorting, Western blotting, migration, and crystal violet assays. F. fomentarius ethanol extract (FFE) decreased cell viability in six cancer cell lines (MDA-MB-231, MCF-7, A549, H460, DU145, and PC-3). FFE decreased the migration of MDA-MB-231 cells without causing cell toxicity. Furthermore, FFE attenuated the expression of matrix metalloproteinase-9 and phosphorylation of Akt as well as increased E-cadherin in MDA-MB-231 cells. FFE arrested the S and G2/M populations by inhibiting the expression of cell cycle regulatory proteins such as cyclin-dependent kinase 2, cyclin A/E, and S-phase kinase-associated protein 2. FFE increased the sub-G1 population and expression of cleaved caspase-9, -3, and cleaved poly adenosine diphosphate (ADP-ribose) polymerase at 72 h and suppressed B-cell lymphoma 2. Interestingly, FFE and AKT inhibitors showed similar effects in MDA-MB-231 cells. Additionally, FFE contained betulin which inhibited p-AKT in MDA-MB-231 cells. Our findings demonstrate that FFE inhibits cell motility and growth and induces apoptosis by inhibiting the phsphoinositide 3- kinase /AKT pathway and caspase activation.


Assuntos
Produtos Biológicos/farmacologia , Neoplasias da Mama/metabolismo , Coriolaceae/química , Etanol/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Metaloproteinase 9 da Matriz/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos
4.
BMC Complement Altern Med ; 18(1): 242, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30165848

RESUMO

BACKGROUND: Rhus verniciflua Stokes is an Asian tree species that is used as a food supplement and traditional medicine in Korea. However, its use is restricted by its potential to cause allergy. Thus, allergen-free R. verniciflua extracts are currently being marketed as a functional health food in Korea. In the present study, three different allergen-free R. verniciflua extracts (DRVE, FRVE, and FFRVE) were produced by detoxification of R. verniciflua, and their properties and constituents were compared. METHODS: The main components and properties (antibacterial, antioxidant, anticancer, and hepatic lipogenesis inhibitory effects) of the three allergen-free extracts were compared. Moreover, the major phenolic constituents of R. verniciflua, including gallic acid, fustin, fisetin, and quercetin, were analyzed in the three extracts. RESULTS: DRVE was superior to the two other extracts with regard to antioxidant activity, while FRVE was superior with regard to antimicrobial activity and suppression of hepatic lipogenesis. FRVE exhibited lipid-lowering effects by lowering sterol regulatory element-binding protein 1 and triglyceride levels, and promoting the activation of peroxisome proliferator-activated receptor and AMP-activated protein kinase in an in vitro model of non-alcoholic fatty liver. CONCLUSIONS: Overall, our findings demonstrate various differences among the three extracts. This suggests that functional and bioactive compounds present in R. verniciflua could be altered by the detoxification process, and this property could be considered in the development of functional health foods in the future.


Assuntos
Extratos Vegetais , Rhus/química , Anti-Infecciosos/análise , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fermentação , Flavonoides/análise , Flavonoides/química , Flavonóis , Humanos , Lipogênese/efeitos dos fármacos , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica , Fenóis/análise , Fenóis/química , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia
5.
J Food Sci ; 83(5): 1430-1435, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29660776

RESUMO

Pawpaw (Asimina triloba [L.] Dunal) is widely cultivated in Korea for its fruit, which contains bioactive compounds, such as acetogenins. In this study, we investigated the acetogenin content and antiproliferative activity of pawpaw fruit pulp against various cancer cell lines and evaluated the relationship between these two variables at different maturation stages. Unripe fruit had higher antiproliferative activity than ripe fruit, and the activity level depended on acetogenin content. In addition, the presence of specific acetogenins was related to inhibition of certain cancer cell types. The unripe fruit methanol and ethanol extracts (URFM and URFE, respectively) that were rich in acetogenins strongly inhibited the growth of HT-1080, HeLa, and AGS cells by >50% at concentrations of less than 115 µg/mL. These findings indicate that URFM and URFE have therapeutic potential for the treatment of cancer, and our study establishes a basis for further mechanistic studies of the antiproliferative activity of pawpaw fruit. However, it is necessary to further study the anticancer activity of acetogenins from pawpaw fruit using in vivo activity approaches. PRACTICAL APPLICATION: Pawpaw (Asimina triloba) contains acetogenins that can inhibit the growth of cancer cells. In our study, we demonstrate that the antiproliferative activity is higher in unripe than in ripe fruit and depends on acetogenin content. Our results indicate that the extract of unripe pawpaw fruit has value not only as a functional food, but has therapeutic potential for the treatment of cancer as a naturally derived substance that may be less toxic than conventional chemotherapy drugs.


Assuntos
Acetogeninas/análise , Asimina/química , Proliferação de Células/efeitos dos fármacos , Frutas/química , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Extratos Vegetais/análise , Extratos Vegetais/farmacologia , República da Coreia
6.
Int J Mol Sci ; 18(2)2017 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-28165392

RESUMO

Hypoxia enhances cancer development in a solid tumor. Hypoxia-inducible factor-1 α (HIF-1α) is a transcription factor that is dominantly expressed under hypoxia in solid tumor cells and is a key factor that regulates tumor. HIF-1α regulates several target genes involved in many aspects of cancer progression, including angiogenesis, metastasis, anti-apoptosis and cell proliferation as well as imparts resistance to cancer treatment. In this study, we assessed Crataegus Pinnatifida Bunge var. typical Schneider ethanol extract (CPE) for its anti-cancer effects in hypoxia-induced DU145 human prostate cancer cell line. CPE decreased the abundance of HIF-1α and sphingosine kinase-1 (SPHK-1) in hypoxia-induced prostate cancer DU145 cells. CPE decreased HIF-1α and SPHK-1 as well as SPHK-1 activity. Chlorogenic acid (CA) is one of four major compounds of CPE. Compared to CPE, CA significantly decreased the expression of HIF-1α and SPHK-1 as well as SPHK-1 activity in hypoxia-induced DU145 cells. Furthermore, CA decreased phosphorylation AKT and GSK-3ß, which are associated with HIF-1α stabilization and affected SPHK-1 in a concentration-dependent manner. We confirmed the mechanism of CA-induced inhibition of HIF-1α by SPHK-1 signaling pathway using SPHK-1 siRNA and SPHK inhibitor (SKI). CA decreased the secretion and cellular expression of VEGF, thus inhibiting hypoxia-induced angiogenesis. Treatment of DU145cells with SPHK1 siRNA and CA for 48 h decreased cancer cell growth, and the inhibitory action of SPHK siRNA and CA on cell growth was confirmed by decrease in the abundance of Proliferating cell nuclear antigen (PCNA).


Assuntos
Ácido Clorogênico/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ácido Clorogênico/química , Ativação Enzimática/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neovascularização Patológica/metabolismo , Fosforilação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo
7.
BMC Cancer ; 16: 701, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27581969

RESUMO

BACKGROUND: Hypoxia is a typical character of locally advanced solid tumours. The transcription factor hypoxia-inducible factor 1α (HIF-1α) is the main regulator under the hypoxic environment. HIF-1α regulates various genes to enhance tumour progression, angiogenesis, and metastasis. Sphingosine kinase 1 (SPHK-1) is a modulator of HIF-1α. METHODS: To investigate the molecular mechanisms of pristimerin in association with SPHK-1 pathways in hypoxic PC-3 cancer cells. Vascular endothelial growth factor (VEGF) production, cell cycles, and SPHK-1 activity were measured, and western blotting, an MTT assay, and an RNA interference assay were performed. RESULTS: Pristimerin inhibited HIF-1α accumulation in a concentration- and-time-dependent manner in hypoxic PC-3 cells. Pristimerin suppressed the expression of HIF-1α by inhibiting SPHK-1. Moreover, inhibiting SPHK-1 with a sphingosine kinase inhibitor enhanced the suppression of HIF-1α, phosphorylation AKT, and glycogen synthase kinase-3ß (GSK-3ß) by pristimerin under hypoxia. Furthermore, a reactive oxygen species (ROS) scavenger enhanced the inhibition of HIF-1α and SPHK-1 by pristimerin. CONCLUSION: Taken together, these findings suggest that pristimerin can exert an anti-cancer activity by inhibiting HIF-1α through the SPHK-1 pathway.


Assuntos
Antineoplásicos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Triterpenos/farmacologia , Western Blotting , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Triterpenos Pentacíclicos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Int J Mol Sci ; 17(7)2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27399684

RESUMO

Lambertianic acid (LA) is known to have anti-allergic and antibacterial effects. However, the anticancer activities and mechanism of action of LA have not been investigated. Therefore, the anticancer effects and mechanism of LA are investigated in this study. LA decreased not only AR protein levels, but also cellular and secretory levels of PSA. Furthermore, LA inhibited nuclear translocation of the AR induced by mibolerone. LA suppressed cell proliferation by inducing G1 arrest, downregulating CDK4/6 and cyclin D1 and activating p53 and its downstream molecules, p21 and p27. LA induced apoptosis and the expression of related proteins, including cleaved caspase-9 and -3, c-PARP and BAX, and inhibited BCl-2. The role of AR in LA-induced apoptosis was assessed by using siRNA. Collectively, these findings suggest that LA exerts the anticancer effect by inhibiting AR and is a valuable therapeutic agent in prostate cancer treatment.


Assuntos
Antineoplásicos/toxicidade , Ácidos Carboxílicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Naftalenos/toxicidade , Receptores Androgênicos/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Nandrolona/análogos & derivados , Nandrolona/farmacologia , Antígeno Prostático Específico/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
9.
J Agric Food Chem ; 63(32): 7270-6, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26176317

RESUMO

Rhus verniciflua Stokes has been used as a traditional medicine and food supplement in Korea. In the present study, fermented R. verniciflua Stokes extract (FRVE), an allergen-free extract of R. verniciflua Stokes fermented with the yeast Saccharomyces carlsbergensis, was assessed for its lipid-lowering potential in an in vitro non-alcoholic fatty liver disease model. FRVE markedly suppressed lipid accumulation and intracellular triglycerides (TGs) in the presence of oleic acid (OA). Additionally, FRVE decreased both mRNA and protein levels of lipid-synthesis- and cholesterol-metabolism-related factors, such as sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS), glycerol-3-phosphate acyltransferase (GPAT), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), in OA-induced HepG2 cells. Moreover, FRVE activated low-density lipoprotein receptor (LDLR), AMP-activated protein kinase (AMPK), and fatty acid oxidation-related factors peroxisome proliferator activated receptor α (PPARα) and carnitine palmitoyltransferase 1 (CPT-1). Further, the AMPK inhibitor compound C suppressed the increased expression of AMPK phosphorylation induced by FRVE. Phenolics and cosanols in FRVE increased the phosphorylation of AMPK and decreased that of SREBP-1. Taken together, our findings suggest that FRVE has antilipogenic potential in non-alcoholic fatty livers via AMPK upregulation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Ácido Oleico/metabolismo , Extratos Vegetais/farmacologia , Rhus/química , Saccharomyces/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Fermentação , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/metabolismo , Rhus/microbiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
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