RESUMO
Carotenoids have been shown to exhibit antiangiogenic activities. Several studies have indicated that carotenoids used in combination were more effective on antioxidation and anticancer actions than carotenoids used singly. However, it is unclear whether multi-carotenoids have antiangiogenic effects. We investigated the effects of multi-carotenoids at physiological plasma levels of Taiwanese (abbreviated as MCT, with a total of 1.4 µM) and Americans (abbreviated as MCA, with a total of 1.8 µM), and of post-supplemental plasma levels (abbreviated as HMC with a total of 3.55 µM) on vascular endothelial growth factor (VEGF)-induced tube formation in human umbilical vein endothelial cells (HUVECs) and rat aortic rings. MCT, MCA, and HMC inhibited VEGF-induced migration, invasion, and tube formation of HUVECs as well as new vessels formation in rat aortic rings. MCT, MCA, and HMC inhibited activities o\f matrix metalloproteinase (MMP)-2, urokinase plasminogen activator, and phosphorylation of VEGF receptor 2 induced by VEGF. Moreover, MCT, MCA, and HMC significantly upregulated protein expression of tissue inhibitors of MMP-2 and plasminogen activator inhibitor-1. These results demonstrate the antiangiogenic effect of multi-carotenoids both in vitro and ex vivo with possible mechanistic actions involving attenuation of VEGF receptor 2 phosphorylation and extracellular matrix degradation.
Assuntos
Inibidores da Angiogênese/farmacologia , Aorta/efeitos dos fármacos , Carotenoides/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Carotenoides/sangue , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Antrodan, a unique protein-bound polysaccharide derived from the fungal mycelia of Antrodia cinnamomea, has been reported to exhibit antitumor and anti-metastatic effects on Lewis lung carcinoma (LLC) cells through direct action and immunomodulation in vitro. In this study, we investigated the combined treatment of antrodan with an anti-cancer drug-cisplatin-and its underlying molecular mechanisms of action in a mouse xenograft tumor model. C57BL/6 mice were implanted (s.c.) with LLCs for nine days, before administration with only antrodan (20 mg/kg and 40 mg/kg; p.o.) daily, only cisplatin (1 mg/kg; i.p.) twice per week, or a combination of both for an additional 28 days. As expected, antrodan on its own significantly inhibited metastasis of lung and liver tissues, while treatment with cisplatin only merely inhibited metastasis of the liver. Antrodan exhibited efficient adjuvant therapy in combination with cisplatin, by inhibiting the activities of the plasma urokinase plasminogen activator (uPA) and the liver matrix metalloproteinase 9 (MMP-9), as well as by inhibiting the phosphorylation of p38 and extracellular signal-regulated kinase 2 (ERK2) in lung and liver tissues. In addition, antrodan effectively ameliorated cisplatin-induced kidney dysfunction when treated combinatorially, as evidenced by a decrease in cisplatin-induced blood urea nitrogen (BUN) levels in plasma and in the level of p38 phosphorylation in the kidney. Mechanistically, the actions of antrodan on its own involved (i) reducing the activities of uPA and MMP-2 and -9 in plasma; (ii) reducing protein expression of MMP-2/9, and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 in lung and liver tissues; and (iii) enhancing immune system functions resulting in the promotion of an anti-metastatic response through immunomodulation, by increasing interferon-γ (IFN-γ) levels and decreasing interleukin-6 (IL-6) levels in plasma. These results demonstrated that antrodan provides a novel, complementary therapeutic strategy against cancer metastasis, by attenuating the activities of MMP-2 and -9 through the modulation of STAT3/MAPK/ERK/JNK signaling pathways, and of the host's immune system.
Assuntos
Antineoplásicos/uso terapêutico , Antrodia/química , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Polissacarídeos Fúngicos/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Polissacarídeos Fúngicos/administração & dosagem , Interferon gama/sangue , Interleucina-6/sangue , Fígado/metabolismo , Pulmão/metabolismo , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Metástase Neoplásica , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Postherpetic neuralgia is the most common complication of herpes zoster. Identifying predictors for postherpetic neuralgia may help physicians screen herpes zoster patients at risk of postherpetic neuralgia and undertake preventive strategies. Peptic ulcer has been linked to immunological dysfunctions and malnutrition, both of which are predictors of postherpetic neuralgia. The aim of this retrospective case-control study was to determine whether adult herpes zoster patients with peptic ulcer were at greater risk of postherpetic neuralgia. Adult zoster patients without postherpetic neuralgia and postherpetic neuralgia patients were automatically selected from a medical center's electronic database using herpes zoster/postherpetic neuralgia ICD-9 codes supported with inclusion and exclusion criteria. Consequently, medical record review was performed to validate the diagnostic codes and all pertaining data including peptic ulcer, Helicobacter pylori (H. pylori) infection and ulcerogenic medications. Because no standard pain intensity measurement exists, opioid usage was used as a proxy measurement for moderate to severe pain. In total, 410 zoster patients without postherpetic neuralgia and 115 postherpetic neuralgia patients were included. Multivariate logistic regressions identified 60 years of age and older, peptic ulcer and greater acute herpetic pain as independent predictors for postherpetic neuralgia. Among etiologies of peptic ulcer, H. pylori infection and usage of non-selective nonsteroidal anti-inflammatory drugs were significantly associated with the increased risk of postherpetic neuralgia; conversely, other etiologies were not significantly associated with the postherpetic neuralgia risk. In conclusion, 60 years of age and older, peptic ulcer and greater acute herpetic pain are independent predictors for postherpetic neuralgia in adult herpes zoster patients.
Assuntos
Infecções por Helicobacter/complicações , Herpes Zoster/complicações , Neuralgia Pós-Herpética/epidemiologia , Úlcera Péptica/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
Several studies have demonstrated that single carotenoid, including lycopene, ß-carotene, and α-carotene, exhibits antimetastatic effects; however, little is known whether multicarotenoids have similar effects. Herein, we investigated the antimetastatic effect of multicarotenoids at physiological serum levels in Taiwanese (MCT at 1.4 µM) and American (MCA at 1.8 µM) populations using human hepatocarcinoma SK-Hep-1 cells in comparison with single carotenoid, such as lycopene (0.3 or 0.6 µM, respectively), α-carotene (0.1 µM), ß-carotene (0.4 µM), lutein (0.4 or 0.5 µM, respectively), and ß-cryptoxanthin (0.2 µM). Results reveal that MCA treatment exhibited an additive inhibition on invasion, migration and adhesion at 24 and 48 h of incubation, whereas MCT treatment possessed additive inhibition at 48 h of incubation. The antimetastatic action of MCT and MCA involved additive reduction on activities of matrix metalloproteinase (MMP)-2, -9, and protein expression of Rho and Rac 1 but additive promotion on protein expression of tissue inhibitor of MMP (TIMP)-1 and -2. All of these effects were stronger in MCA than in MCT at 24 and 48 h of incubation. These results demonstrate that multi-carotenoids effectively inhibit metastasis of human hepatocarcinoma SK-Hep-1 cells. More in vivo studies are needed to confirm these findings.
Assuntos
Carcinoma Hepatocelular/patologia , Carotenoides/farmacologia , Criptoxantinas/farmacologia , Luteína/farmacologia , beta Caroteno/farmacologia , Carcinoma Hepatocelular/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Licopeno , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metástase Neoplásica , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismoRESUMO
Calorie restriction (CR) extends lifespan in a remarkable range of organisms. However, the mechanisms of CR related to the longevity effects are not fully elucidated to date. Using human fibroblast Hs68 (Hs68) cells cultured at a lower level of medium glucose (i.e., glucose restriction; GR) to mimic CR, we investigated the crucial role of nicotinamide phosphoribosyltransferase (Nampt), nicotinamide adenine dinucleotide (NAD(+)), and nicotinamide (NAM) in GR-extended replicative lifespan of Hs68 cells. We found that GR extended the lifespan of Hs68 cells, in parallel to significantly increased expression of Nampt, intracellular NAD(+) levels, and SIRT1 activities, and to significantly decreased NAM levels. The lifespan-extending effects of GR were profoundly diminished by FK866 (a noncompetitive inhibitor of Nampt) and blocked by sirtinol (a noncompetitive inhibitor of sirtuins). However, the steady-state intracellular NAM level (averaged 2.5 µM) was much lower than the IC50 of NAM on human SIRT1 (about 50 µM). All these results suggest that up-regulation of Nampt play an important role in GR-extended lifespan of Hs68 cells by increasing the intracellular NAD(+) levels followed by activating SIRT1 activity in Hs68 cells. In contrast, the role of NAM depletion is limited.
Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Citocinas/metabolismo , Fibroblastos/citologia , Glucose/farmacologia , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Regulação para Cima/efeitos dos fármacos , Acrilamidas/farmacologia , Benzamidas/farmacologia , Linhagem Celular , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Senescência Celular/fisiologia , Citocinas/antagonistas & inibidores , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Naftóis/farmacologia , Niacinamida/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piperidinas/farmacologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismoRESUMO
Vitamin B3 (niacin) deficiency can cause pellagra with symptoms of dermatitis, diarrhea and dementia. However, it is unclear whether the vitamin B3 deficiency causes human aging. FK866 (a Nampt inhibitor) can reduce intracellular NAD(+) level and induce senescence of human Hs68 cells. However, the mechanisms underlying FK866-induced senescence of Hs68 cells are unclear. In this study, we used FK866 to mimic the effects of vitamin B3 deficiency to reduce the NAD(+) level and investigated the mechanisms of FK866-induced senescence of Hs68 cells. We hypothesized that FK866 induced the senescence of Hs68 cells via an attenuation of NAD(+)-silent information regulator T1 (SIRT1) signaling. We found that FK866 induced cell senescence and diminished cellular NAD(+) levels and SIRT1 activity (detected by acetylation of p53), and these effects were dramatically antagonized by co-treatment with nicotinic acid, nicotinamide, or NAD(+). In contrast, the protein expression of SIRT1, AMP-activated protein kinase, mammalian target of rapamycin, and nicotinamide phosphoribosyltransferase (Nampt) was not affected by FK866. In addition, the role of GSH in the FK866-induced cells senescence may be limited, as N-acetylcysteine did not antagonize FK866-induced cell senescence. These results suggest that FK866 induces cell senescence via attenuation of NAD(+)-SIRT1 signaling. The effects of vitamin B3 deficiency on human aging warrant further investigation.
Assuntos
Acrilamidas/farmacologia , Senescência Celular/efeitos dos fármacos , Citocinas/antagonistas & inibidores , NAD/metabolismo , Niacinamida/deficiência , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piperidinas/farmacologia , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Senescência Celular/fisiologia , Inibidores Enzimáticos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Glutationa/metabolismo , Humanos , NAD/farmacologia , NADP/metabolismo , Niacina/farmacologia , Niacinamida/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 µM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression.
Assuntos
Inibidores da Angiogênese/farmacologia , Endotélio Vascular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Tocoferóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antimetabólitos Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Nucleosídeo NM23 Difosfato Quinases/química , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/agonistas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Vitamin C (vit C) has been shown to diminish cisplatin (CP)-induced nephrotoxicity and oxidative damage in healthy rats and mice. However, little is known whether vit C has similar actions and enhances the anticancer effect of CP in tumor-bearing mice. Herein, C57BL/6 mice were implanted (s.c.) with Lewis lung carcinoma (LLC) for 9 days before intraperitoneal administration with CP (5 mg/kg) in the presence or absence of low- (200 mg/kg) and high- (1000 mg/kg) dose vit C twice a week for an additional 28 days. Results reveal that vit C or CP treatment alone significantly inhibited tumor growth, although vit C in combination with CP did not further inhibit tumor growth, as compared to CP treatment alone. In addition, CP significantly induced nephrotoxicity and oxidative damage, as evidenced by increased plasma levels of blood urea nitrogen and creatinine as well as levels of lipid peroxidation and carbonyls, decreased ratios of GSH/GSSG in liver and kidney. Vit C significantly reversed these undesirable side effects induced by CP, and most of these actions of vit C were dose-dependent. Overall, we conclude that vit C can protect against CP-induced nephrotoxicity and damage without reducing CP's effectiveness in LLC-bearing mice.
Assuntos
Antineoplásicos/efeitos adversos , Ácido Ascórbico/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Cisplatino/efeitos adversos , Nefropatias/prevenção & controle , Animais , Antineoplásicos/administração & dosagem , Nitrogênio da Ureia Sanguínea , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Creatinina/sangue , Glutationa/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cisplain, a platinum-containing anticancer drug, has been shown to enhance DNA repair and to inhibit cell apoptosis, leading to drug resistance. Thus, the combination of anticancer drugs with nutritional factors is a potential strategy for improving the efficacy of cisplatin chemotherapy. In this study, we investigated the anti-proliferative effects of a combination of fucoxanthin, the major non-provitamin A carotenoid found in Undaria Pinnatifida, and cisplatin in human hepatoma HepG2 cells. We found that fucoxanthin (1-10 µΜ) pretreatment for 24 h followed by cisplatin (10 µΜ) for 24 h significantly decreased cell proliferation, as compared with cisplatin treatment alone. Mechanistically, we showed that fucoxanthin attenuated cisplatin-induced NFκB expression and enhanced the NFκB-regulated Bax/Bcl-2 mRNA ratio. Cisplatin alone induced mRNA expression of excision repair cross complementation 1 (ERCC1) and thymidine phosphorylase (TP) through phosphorylation of ERK, p38 and PI3K/AKT pathways. However, fucoxanthin pretreatment significantly attenuated cisplatin-induced ERCC1 and TP mRNA expression, leading to improvement of chemotherapeutic efficacy of cisplatin. The results suggest that a combined treatment with fucoxanthin and cisplatin could lead to a potentially important new therapeutic strategy against human hepatoma cells.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/farmacologia , Reparo do DNA/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , NF-kappa B/metabolismo , Xantofilas/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Endonucleases/genética , Endonucleases/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Timidina Fosforilase/genética , Timidina Fosforilase/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synergistic anti-metastatic efficacy of a combination of sorafenib (SF), a multi-kinase inhibitor, and ß-ionone (BI), a precursor of carotenoids. We found that SF (1 µM) in combination with BI (1 µM) synergistically inhibited cell invasion and additively inhibited cell migration, especially at 48 h of incubation. Mechanistically, the combination of SF and BI was found to decrease the protein expression of focal adhesion kinase (FAK) and Rho, and to enhance the protein expression of tissue inhibitor matrix metalloproteinase (TIMP)-1 and TIMP-2. In addition, the combination of SF and BI inhibited the activity of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased the phosphorylation of FAK and of Rac1 proteins. Importantly, SF enhanced the suppressing effect of BI (1-50 µM) on the viability of SK-Hep-1 cells, but not on murine hepatic BNL CL.2 cells, indicating the selective cytotoxicity of this combination on tumor cells. The combination of SF and BI could be a potential therapeutic strategy against human hepatoma cells.
Assuntos
Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Norisoprenoides/uso terapêutico , Piridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/farmacologia , Carcinoma Hepatocelular/enzimologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Neoplasias Hepáticas/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Niacinamida/análogos & derivados , Norisoprenoides/farmacologia , Compostos de Fenilureia , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Sorafenibe , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Lycopene is primarily metabolized by carotenoid monoxygenase II into apo-8'- and apo-12'-lycopenal in the rat liver. Although lycopene possesses antimetastatic activity in a highly invasive hepatoma SK-Hep-1 cell line, little is known whether its metabolites have a similar effect. In this study, we investigated the antimetastatic effects of apo-8'-lycopenal (1-10 µM) in comparison with lycopene (10 µM) in SK-Hep-1 cells. We found that both apo-8'-lycopenal and lycopene inhibited the invasion and migration of SK-Hep-1 cells, and the effect of apo-8'-lycopenal was stronger than that of lycopene at the same concentration (10 µM). Mechanistically, apo-8'-lycopenal: 1) decreased the activities and protein expression of metalloproteinase-2 (MMP-2) and -9; 2) increased the protein expression of nm23-H1 and the tissue inhibitor of MMP (TIMP)-1 and -2; 3) suppressed protein expression of Rho small GTPases; and 4) inhibited focal adhesion kinase-mediated signaling pathway, such as ERK/p38 and PI3K-Akt axis. Overall, these results demonstrate that apo-8'-lycopenal possesses antimetastatic activity in SK-Hep-1 cells and that this effect is stronger than that of lycopene, suggesting that the antimetastatic effect may be attributed, at least in part, to its metabolites such as apo-8'-lycopenal.
Assuntos
Carotenoides/metabolismo , Carotenoides/farmacologia , Ácidos Graxos Insaturados/farmacologia , Metástase Neoplásica/prevenção & controle , Carcinoma Hepatocelular , Carotenoides/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas , Licopeno , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/genéticaRESUMO
ß-Ionone (BI), a precursor for carotenoids, is widely distributed in fruit and vegetables. Recent in vitro studies have demonstrated the potential anti-metastatic effects of BI, but the mechanisms underlying such actions are not clear. Because liver cancer is the most endemic cancer in Taiwan and in a large region of the world, we hereby investigate the anti-metastatic effects of BI and its mechanisms of actions in a highly metastatic human hepatocarcinoma SK-Hep-1 cells. We show that incubation of cells with BI (1-50 µm) for 24 and 48 h significantly inhibited cell invasion, migration and adhesion. Mechanistically, incubation of cells with BI (1-50 µm) for 24 h resulted in the following: (1) significant inhibition of matrix metalloproteinase (MMP)-2, MMP-9 and urokinase-type plasminogen activator activities, (2) up-regulation of protein expression of the tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2 and plasminogen activator inhibitor-1, (3) down-regulation of the expression of migration-related proteins, including focal adhesion kinase (FAK), phosphorylated form of FAK, Rho, Rac1 and Cdc42 and (4) up-regulation of the expression of nm23-H1 protein (P < 0·05). Overall, the results show that BI effectively inhibits the metastasis of SK-Hep-1 cells, and this effect involves the regulation of gene expression and signal pathways related to invasion and migration.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Norisoprenoides/farmacologia , Carcinoma Hepatocelular/secundário , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Gelatinases/metabolismo , Humanos , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Inibidores Teciduais de Metaloproteinases/metabolismo , Regulação para Cima/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
Inconsistent expression and regulation of drug-metabolizing enzymes (DMEs) are common causes of adverse drug effects in some drugs with a narrow therapeutic index (TI). An important cytochrome, cytochrome P450 3A4 (CYP3A4), is predominantly regulated by a nuclear receptor, pregnane X receptor (PXR). Sesamin, a major lignan constituent in sesame seeds and oil, exhibits a variety of biological functions; however, the effect of sesamin on the modulation of CYP3A4 is not well understood. In this study, the effects of sesamin on the PXR-CYP3A4 pathway were characterized, as well as the underlying mechanisms of those effects. Sesamin potently attenuated CYP3A4 induction in a dose-dependent manner by blocking the activation of PXR. The PXR inducer-mediated inhibition of CYP3A4 was further evidenced by the ability of sesamin to attenuate the effects of several PXR ligands in the CYP3A4 reporter assay. Further mechanistic studies showed that sesamin inhibited PXR by interrupting the interacting with coregulators. These results may lead to the development of new therapeutic and dietary approaches to reduce the frequency of inducer-drug interaction. Sesamin was established as a novel inhibitor of PXR and may be useful for modulating DMEs expression and drug efficacies. Modification of CYP3A4 expression and activity by consumption of sesamin may have important implications for drug safety.
RESUMO
Pregnane X receptor (PXR) has been reported to regulate the expression of drug-metabolizing enzymes, such as the cytochrome P450 3A (CYP3A) family and transporters, such as multiple drug resistance 1 (MDR1). Fucoxanthin, the major carotenoid in brown sea algae, is a putative chemopreventive agent. In this study, we determined whether fucoxanthin could overcome drug resistance through attenuation of rifampin-induced CYP3A4 and MDR1 gene expression by PXR-mediated pathways in HepG2 hepatoma cells. We found that fucoxanthin (1-10 µM) significantly attenuated rifampin (20 µM)-induced CYP3A4, MDR1 mRNA and CYP3A4 protein expression at 24 h of incubation. Mechanistically, fucoxanthin strongly attenuated the PXR-mediated CYP3A4 promoter activity in HepG2 cells. In addition, fucoxanthin attenuated constitutive androstane receptor (CAR)- and rPXR-mediated CYP3A4 promoter activity in this cell line. Using the mammalian two-hybrid assay, we found that fucoxanthin significantly decreased the interaction between PXR and SRC-1, a PXR co-activator. Thus, fucoxanthin can decrease rifampin-induced CYP3A4 and MDR1 expression through attenuation of PXR-mediated CYP3A4 promoter activation and interaction between PXR and co-activator. These findings could lead to potentially important new therapeutic and dietary approaches to reduce the frequency of adverse drug reactions.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adenocarcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Citocromo P-450 CYP3A/genética , Receptores de Esteroides/fisiologia , Rifampina/farmacologia , Xantofilas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Receptor Constitutivo de Androstano , Células Hep G2 , Humanos , Receptor de Pregnano X , Regiões Promotoras Genéticas , RNA Mensageiro/análise , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Esteroides/antagonistas & inibidores , Ativação TranscricionalRESUMO
Oral administration of ß-carotene (BC) was found to exert opposite effects on plasma levels of vascular endothelial growth factor (VEGF) in two animal models. One study in nude mice injected via tail vein with hepatocarcinoma SK-Hep-1 cells showed that BC decreases the plasma VEGF level, whereas the other study in nude mice injected subcutaneously with prostate tumor PC-3 cells showed that BC increases the plasma VEGF level. Herein we investigated whether BC (0.5-20 µM) possesses diverse effects on VEGF secretion in SK-Hep-1, PC-3 and melanoma B16F10 cells. We found that incubation of SK-Hep-1 cells with BC (1-20 µM) for 6 h significantly decreased VEGF secretion, whereas BC (1-10 µM) significantly increased the VEGF secretion in PC-3 cells. However, these effects disappeared at 12 h of incubation. Similar effects occurred in VEGF mRNA and protein expression after treatment of SK-Hep-1 and PC-3 cells with BC for 6 h. In contrast, BC (0.5-20 µM) did not affect mRNA and protein expression and secretion of VEGF in B16F10 cells. We also found that the proliferation of SK-Hep-1 and B16F10 cells was significantly inhibited by 20 µM BC at 6 and 12 h of incubation, whereas the proliferation of PC-3 cells was significantly inhibited by 20 µM BC at 12 h of incubation. In summary, the present study demonstrated the tumor-specific effect of BC on VEGF secretion in different cancer cell lines.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias da Próstata/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , beta Caroteno/farmacologia , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos , Neoplasias da Próstata/genética , RNA Mensageiro/metabolismo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Vitamin C in combination with vitamin K3 (vit CK3) has been shown to inhibit tumor growth and lung metastasis in vivo, but the mechanism of action is poorly understood. Herein, C57BL/6 mice were implanted (s.c.) with Lewis lung carcinoma (LLC) for 9 days before injection (i.p.) with low-dose (100 mg vit C/kg + 1 mg vit K3/kg), high-dose (1,000 mg vit C/kg + 10 mg vit K3/kg) vit CK3 twice a week for an additional 28 days. As expected, vit CK3 or cisplatin (6 mg/kg, as a positive control) significantly and dose-dependently inhibited tumor growth and lung metastasis in LLC-bearing mice. Vit CK3 restored the body weight of tumor-bearing mice to the level of tumor-free mice. Vit CK3 significantly decreased activities of plasma metalloproteinase (MMP)-2, -9, and urokinase plasminogen activator (uPA). In lung tissues, vit CK3 1) increased protein expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, nonmetastatic protein 23 homolog 1 and plasminogen activator inhibitor-1; 2) reduced protein expression of MMP-2 and MMP-9; and 3) inhibited the proliferating cell nuclear antigen (PCNA). These results demonstrate that vit CK3 inhibits primary tumor growth and exhibits antimetastastic potential in vivo through attenuated tumor invasion and proliferation.
Assuntos
Ácido Ascórbico/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , Neoplasias Pulmonares/tratamento farmacológico , Vitamina K 3/farmacologia , Animais , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Neoplasias Pulmonares/patologia , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Transplante Heterólogo , Ativador de Plasminogênio Tipo Uroquinase/sangue , Ativador de Plasminogênio Tipo Uroquinase/genéticaRESUMO
2-Deoxy-D-glucose (2-DG) and dehydroepiandrosterone (DHEA) have been hypothesized to extend lifespan via mimicking calorie restriction (CR). Activation of sirtuins has been proposed to contribute to life extension of CR by increasing intercellular levels of NAD(+) in several organisms. However, it is unclear whether 2-DG and DHEA may affect intracellular NAD(+) levels and human sirtuin 1 (SIRT1) activities. Here, using human fibroblast Hs68 cells we showed that 2-DG increased intracellular NAD(+) levels in both time- and concentration-dependent manners. 2-DG also dose-dependently increased SIRT1 activities and the lifespan (measured as the cumulated growth curve of population doubling levels) of Hs68 cells. In contrast, DHEA at non-cytotoxic concentrations (≤50 µM) did not significantly affect NAD(+) levels, SIRT1 activities or the lifespan of Hs68 cells. These results suggest that 2-DG extends the lifespan of Hs68 cells by increased NAD(+) levels and SIRT1 activities, and that 2-DG has a potential as a CR mimetic.
Assuntos
Restrição Calórica , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Desidroepiandrosterona/farmacologia , Desoxiglucose/farmacologia , Fibroblastos/efeitos dos fármacos , NAD/metabolismo , Sirtuína 1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibroblastos/enzimologia , Fluorometria , Humanos , Fatores de Tempo , Regulação para CimaRESUMO
Postherpetic neuralgia (PHN) is the most common complication of herpes zoster (HZ). The aim of the present study was to compare the nutritional status of PHN patients with that of healthy controls, and then to identify risk factors for PHN using multivariate multiple logistic regressions. In the present cross-sectional study, we prospectively enrolled fifty PHN patients for at least 3 months and fifty healthy controls. We selected nine circulating nutrients including ionised Ca, Zn, retinol, folic acid, vitamin B12, vitamin C, α-tocopherol, γ-tocopherol and lycopene associated with both immunity and the modulation of neuropathic pain, and measured their concentrations in plasma/serum. Concentrations of ionised Ca, Zn, vitamin C and vitamin B12 were significantly lower in PHN patients than in controls after excluding those patients receiving supplements since the outbreak of HZ. The prevalence of either mild/marginal or severe deficiencies for any of the nine selected circulating nutrients in PHN patients (92 %) was much higher than that in controls (46 %) (P < 0·001). Lower concentrations of vitamin C ( ≤ 45·0 µmol/l), ionised Ca ( ≤ 1·05 mmol/l) and Zn ( ≤ 0·91 g/l) were found to increase independently the risk of PHN using binary variable (dichotomy) analyses with both PHN patients and controls in a multivariate logistic regression analysis. No significant correlations existed between the risks of PHN and the concentrations of retinol, folic acid, vitamin B12, lycopene or α:γ-tocopherol ratios. Thus, lower concentrations of circulating nutrients, namely vitamin C, ionised Ca or Zn, are probably a risk factor in Taiwanese patients with PHN.
Assuntos
Deficiências Nutricionais/epidemiologia , Neuralgia Pós-Herpética/complicações , Idoso , Estudos de Casos e Controles , Deficiências Nutricionais/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Manejo de Espécimes , Taiwan/epidemiologiaRESUMO
Stroke is a major public health problem and ranks third most common cause of death in adults worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury, mainly caused by oxidative/nitrosative stress injury, after revascularization therapy can result in worsening outcomes. For better clinical prognosis, more and more studies have focused on the pharmaceutical neuroprotective therapies against free radical damage. The impact of vitamin C (ascorbic acid) on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. However, recent evidence of the clinical benefit of parenteral vitamin C administration has emerged, especially in critical care. In this study we demonstrated that parenteral administration of vitamin C significantly improved neurological deficits and reduced brain infarction and brain edema by attenuating the transient middle cerebral artery occlusion (tMCAO)-induced nitrosative stress, inflammatory responses, and the resultant disruptions of blood brain barrier and cerebral neuronal apoptosis. These results suggest that parenteral administration of vitamin C has potential as an adjuvant agent with intravenous thrombolysis or endovascular thrombectomy in acute treatment of ischemic stroke.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Apoptose , Ácido Ascórbico/farmacologia , Barreira Hematoencefálica , Encéfalo , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Ratos , Ativador de Plasminogênio TecidualRESUMO
Vitamin C deficiency increases the risk of postherpetic neuralgia (PHN). In this cross-sectional study, the relationships among plasma vitamin C concentrations, pain and Leeds assessment of neuropathic symptoms and signs (LANSS) items were investigated during their first pain clinic visit of 120 PHN patients. The factors associated with vitamin C deficiency were determined. Independent predictors of vitamin C deficiency were presented as adjusted odds ratios (AOR) and 95% confidence intervals (CI). The patients had a high prevalence (52.5%) of vitamin C deficiency. Their plasma vitamin C concentrations were negatively associated with spontaneous pain and tingling, prickling or pins and needles sensation according to the LANSS questionnaire. Based on the receiver operator characteristic curve, the cutoffs for plasma vitamin C to predict moderate-to-severe and severe symptoms of sharp sensation were <7.05 and <5.68 mg/L, respectively. By comparison, the patients well-nourished with vitamin C had lower incidences of sharp sensations, sharp pain, and reddish skin. Multivariate analyses revealed that vitamin C deficiency was associated with the low intake of fruit/vegetables (AOR 2.66, 95% CI 1.09-6.48, p = 0.032), peptic ulcer disease (AOR 3.25, 95% CI 1.28-8.28, p = 0.014), and smoking (AOR 3.60, 95% CI 1.33-9.77, p = 0.010). Future studies are needed to substantiate these findings.