RESUMO
Diet polyphenol can reportedly prevent the formation of breast-cancer cells. Nelumbo nucifera leaf extract (NLE) is enriched with polyphenols and has several cellular functions, such as anti-atherosclerosis, anti-inflammation, and antitumor. In this study, we investigated the role of NLE in the prevention of N-methyl-N-nitrosourea (NMU)-induced mammary tumor formation. Cotreatment with NLE significantly reduced the NMU-induced tumor incidence, number, and volume. NLE administration significantly repressed the tumor growth and weight of nude mice upon inoculation with BT-474 cancer cells. Immunohistochemical staining indicated that fatty acid synthetase, estrogen receptor (ER)-α, and phosphorylated ER-α were obviously reduced in the cancer part of BT-474 inoculated nude mice upon administration of 2% NLE. Western blot analysis revealed that NLE and NLPE (polyphenol-rich NLE) repressed ER-α expression and phosphorylation and decreased the phosphorylation of Her-2 without affecting their expression. Overall, NLE and NLPE exhibited more effective antitumor abilities in NMU-induced mammary cancer formation than with tamoxifen and Herceptin.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Receptor alfa de Estrogênio/metabolismo , Ácido Graxo Sintases/genética , Nelumbo/química , Receptor ErbB-2/genética , Animais , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Metilnitrosoureia/efeitos adversos , Camundongos , Camundongos Nus , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2/metabolismoRESUMO
Epidemiological studies have revealed that obesity and being overweight are associated with increased cancer risk. Adipose tissue is regarded as an endocrine organ that secretes proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are related to the progression of hepatocellular carcinoma (HCC). In this study, adipocytes from 3T3-L1 cells were induced and stained with Oil Red O, which revealed marked intracellular lipid accumulation. Adding 15% conditioned medium (CM) from adipogenic -differentiated 3T3-L1 cells, which contained adipocyte-derived factors, to a culture medium of HepG2 cells was discovered to promote cell proliferation by a factor of up to 1.3 compared with the control. Mulberry leaf extract (MLE), with major components including chlorogenic acid and neochlorogenic acid, was revealed to inhibit CM-promoted HepG2 cell proliferation. The inhibitory effect of MLE on the proliferation of the signal network was evaluated. Expression of the CM-activated IκB/NFκB, STAT3, and Akt/mTOR pathways were reduced when MLE was administered. Although adipocyte-derived factors are complex, administrating anti-TNF-α and anti-IL-6 revealed that MLE blocks signal activation promoted by TNF-α and IL-6. Taken together, these results demonstrated that MLE targets the proliferation signal pathway of the inflammatory response of adipocytes in HCC and could be to prevent obesity-mediated liver cancer.
Assuntos
Adipócitos/efeitos dos fármacos , Carcinoma Hepatocelular/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Interleucina-6/metabolismo , Neoplasias Hepáticas/fisiopatologia , Morus/química , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Humanos , Interleucina-6/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
The essential oil from a lemongrass variety of Cymbopogon flexuosus [lemongrass oil (LO)] is used in various food and aroma industry products and exhibits biological activities, such as anticancer and antimicrobial activities. To investigate the effects of 200 LO (200 mg/kg) and 400 LO (400 mg/kg) and its major component, citral (240 mg/kg), on drug-metabolizing enzymes, oxidative stress, and acetaminophen toxicity in the liver, male Sprague-Dawley rats were fed a pelleted diet and administered LO or citral by gavage for 2 weeks. After 2 weeks of feeding, the effects of LO and citral on the metabolism and toxicity of acetaminophen were determined. The results showed that rats treated with 400 LO or citral had significantly reduced hepatic testosterone 6ß-hydroxylation and ethoxyresorufin O-deethylation activities. In addition, NAD(P)H:quinone oxidoreductase 1 activity was significantly increased by citral, and Uridine 5'-diphospho (UDP) glucurosyltransferase activity was significantly increased by 400 LO in the rat liver. Treatment with 400 LO or citral reduced lipid peroxidation and reactive oxygen species levels in the liver. After acetaminophen treatment, however, LO and citral treatment resulted in little or no change in plasma alanine aminotransferase activity and acetaminophen-protein adducts content in the liver. Our results indicate that LO and citral may change the activities of drug-metabolizing enzymes and reduce oxidative stress in the liver. However, LO and citral may not affect the detoxification of acetaminophen.
Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cymbopogon/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Monoterpenos/farmacologia , Óleos de Plantas/farmacologia , Terpenos/farmacologia , Monoterpenos Acíclicos , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Fígado/patologia , Testes de Função Hepática , Masculino , Desintoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Microssomos Hepáticos/efeitos dos fármacos , Monoterpenos/química , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Óleos de Plantas/química , Ratos , Terpenos/químicaRESUMO
Solanum nigrum L., an edible plant and local dish, has been assigned anticancer activities. However, the anticancer mechanisms of S. nigrum are poorly understood. Here, we investigated whether the water or polyphenol extracts of S. nigrum (SNWE or SNPE) could inhibit angiogenesis-mediated tumor growth. In nude mice bearing tumor xenografts, SNWE or SNPE significantly reduced the volume and weight of the tumors, and decreased the expression of CD31, a marker for angiogenesis. SNWE or SNPE was found to inhibit the VEGF-induced capillary structure formation of endothelial cells. The chicken egg chorioallantoic membrane (CAM) and matrigel plug assays showed further that SNWE or SNPE inhibited tumor angiogenesis. In human umbilical vascular endothelial cells (HUVECs), SNWE or SNPE suppressed the VEGF-induced activation of AKT and mTOR. Moreover, SNWE or SNPE inhibited the viability of human hepatoma HepG2 cells, and these effects were correlated with the extent of inhibition of the AKT/mTOR pathway. Taken together, our data imply that SNWE or SNPE downregulated the AKT/mTOR pathway in HUVECs and HepG2 cells, which lead to reduced tumor growth and angiogenesis.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Solanum nigrum/química , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/fisiologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Hepatocelular/irrigação sanguínea , Embrião de Galinha , Modelos Animais de Doenças , Feminino , Células Hep G2 , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Extratos Vegetais/isolamento & purificação , Transdução de Sinais/fisiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Nelumbo nucifera Gaertn (Nymphaeaceae) has been recognized as a medicinal plant, which was distributed throughout the Asia. The aqueous extract of Nelumbo nucifera leaves extract (NLE) has various biologically active components such as polyphenols, flavonoids, oligomeric procyanidines. However, the role of NLE in breast cancer therapy is poorly understood. THE AIM OF THIS STUDY: The purpose of this study was to identify the hypothesis that NLE can suppress tumor angiogenesis and metastasis through CTGF (connective tissue growth factor), which has been implicated in tumor angiogenesis and progression in breast cancer MDA-MB-231 cells. RESULTS: We examined the effects of NLE on angiogenesis in the chicken chorioallantoic membrane (CAM) model. The data showed that NLE could reduce the chorionic plexus at day 17 in CAM and the duration of this inhibition was dose-dependent. In Xenograft model, NLE treatment significantly reduced tumor weight and CD31 (capillary density) over control, respectively. We examined the role of angiogenesis involved restructuring of endothelium using human umbilical vein endothelial cell (HUVEC) in Matrigel angiogenesis model. The results indicated that vascular-like structure formation was further blocked by NLE treatment. Moreover, knockdown of CTGF expression markedly reduced the expression of MMP2 as well as VEGF, and attenuated PI3K-AKT-ERK activation, indication that these signaling pathways are crucial in mediating CTGF function. CONCLUSION: The present results suggest that NLE might be useful for treatment in therapy-resistance triple negative breast cancer.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Fator de Crescimento do Tecido Conjuntivo/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Nelumbo/química , Neovascularização Patológica , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/farmacologia , Folhas de Planta/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inibidores da Angiogênese/isolamento & purificação , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Fator de Crescimento do Tecido Conjuntivo/genética , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Neovascularização Fisiológica/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Interferência de RNA , Fatores de Tempo , Transfecção , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Protocatechuic acid (PCA) has been implicated in the progression of atherosclerosis. The proliferation of vascular smooth muscle cells (VSMC) may play a crucial role in the pathogenesis of atherosclerosis. Adenosine 5'-monophosphate-activated protein kinase (AMPK) additionally exerts several beneficial effects on vascular function and improves vascular abnormalities. The current study sought to determine whether PCA has an inhibitory effect on VSMC proliferation under oleic acid (OA) treatment. A7r5 cells were treated with OA (150 µM) or cotreated with OA and PCA (150 µg/mL) for 24 and 48 h. PCA-treated cells were found to cause an increase in G0/G1 cell cycle arrest. Western blotting showed that PCA increased the expressions of p53 and p21Cip1, subsequently decreasing the expression of cyclin E1 and Cdk2. In addition, PCA induced phosphorylation of AMPK and inhibited the expression of fatty acid synthase, Akt-p, and Skp2 after stimulation with OA. After treatment with AMPK inhibitor, the effects of PCA mentioned above were reversed. Taken together, PCA inhibited OA-induced VSMC proliferation through AMPK activation and down-regulation of FAS and AKT signals, which then blocks G0/G1 phase cell cycle progression. These findings provide a new insight into the protective properties of PCA on VSMC, which may constitute a novel effective antiatherosclerosis agent.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proliferação de Células/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Ácido Oleico/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/enzimologia , Ratos , Fase de Repouso do Ciclo Celular/efeitos dos fármacosRESUMO
Fatty liver may have implications for metabolic syndrome, such as obesity, hypertension, and diabetes. Therefore, the development of pharmacological or natural agents to reduce fat accumulation in the liver is an important effort. The Sechium edule shoots have already been verified to decrease serum lipids and cholesterol and prevent atherosclerosis. However, how Sechium edule shoots modulate hepatic lipid metabolism is unclear. This study was designed to investigate the effects and mechanisms of polyphenol extracts (SPE) of Sechium edule shoots in reducing lipid accumulation in oleic acid-treated HepG2 cells. We found that water extracts (SWE) of Sechium edule shoots could decrease serum and hepatic lipid contents (e.g., triacylglycerol and cholesterol). Furthermore, SWE and SPE through the AMPK (AMP-activating protein kinase) signaling pathway could decrease lipogenic relative enzymes, such as FAS (fatty acid synthase), HMGCoR (HMG-CoA reductase), and SREBPs (sterol regulatory element binding proteins), and increase the expression of CPT-I (carnitine palmitoyltransferase I) and PPARα (peroxisome proliferators activated receptor α), which are critical regulators of hepatic lipid metabolism. These observations suggested that Sechium edule shoots have potential for developing health foods for preventing and remedying fatty liver.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cucurbitaceae/química , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Extratos Vegetais/farmacologia , Brotos de Planta/química , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acil Coenzima A/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR alfa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Previous studies indicate that COX-2 and prostaglandin E(2) (PGE(2)) receptor subtypes are involved in intestinal carcinogenesis and activation of downstream pathways. In this report, we try to understand the association of PGE(2) receptor and K-ras cellular mechanism during the development of colorectal cancer. We collected 21 colorectal cancer patients and compared the protein expression of tumor tissues and normal mucosa tissues by using immunoblot. Furthermore, we transferred empty vector and pcDNA-K-ras into Ras-HT29 colon cancer cells. Result showed that phosphorylation of Akt and EP(1)/EP(4) were over-expressed in the colorectal tumor tissue. K-ras induces HT29 cells proliferation through the expressions of COX-2, EP1/EP4, pAkt, GSK3beta and increases Tcf transcriptional factor activation. Additionally, Ras protein was suppressed when treated with EP(4) inhibitor in Ras-HT29 cell. In cell cycle assay, K-ras mutation causing cell cycle S phase was prolonged with an increase in the G2/M phase ratio. In conclusion, we suggested that Ras overexpression leads to cell proliferation through activating Ras/PI3K/GSK3beta/EP(4) PGE(2) receptor signals and caused a feedback regulation of Ras by EP4 in colorectal tumor progression.