RESUMEN
Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths worldwide. It has a very poor prognosis with over a 5-year survival rate of only 50%. Thus, it is important to identify effective therapeutic interventions against oral cancer. Apoptosis and autophagy have reported genetically regulated in physiology and diseases, which close relationship. Many natural compound study objects anticancer effect have been studied between apoptosis and autophagy relationship. The present study was designed to evaluate the effect of erianin on human oral cancer cell proliferation. Results of the study revealed that treatment with erianin significantly reduced the viability of different OSCC cell lines. Erianin exerted its cytotoxic effect by inducing cell cycle arrest and caspase-dependent apoptotic pathways. Both intrinsic and extrinsic pathways were found to be involved in erianin-mediated cell death. In addition, treatment with erianin also increased autophagy in OSCC cells. With further analysis, it was found that erianin induced both apoptosis and autophagy by regulating MAPK signaling pathways. Taken together, our study indicates that erianin plays an important role in reducing oral cancer cell viability, and thus, can be considered as a potential anticancer agent.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Bibencilos/farmacología , Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/tratamiento farmacológico , Fenol/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Humanos , Estructura MolecularRESUMEN
Licochalcone A is widely studied in different fields and possesses antiasthmatic, antibacterial, anti-inflammatory, antioxidative, and anticancer properties. Its antimalignancy activity on renal, liver, lung, and oral cancer has been explored. However, limited studies have been conducted on the inhibitory effects of licochalcone A in human nasopharyngeal carcinoma cells. We determined cell viability using MTT assay. Cell cycle distribution and apoptotic cell death were measured via flow cytometry. Caspase activation and mitogen-activated protein kinase-related proteins in nasopharyngeal cancer cells in response to licochalcone A were identified by Western blot analysis. Results indicated that licochalcone A reduces cell viability and induces apoptosis, as evidenced by the upregulation of caspase-8 and caspase-9, caspase-3 activation, and cleaved-poly ADP-ribose polymerase expression. Treatment with licochalcone A significantly increases ERK1/2, p38, and JNK1/2 activation. Co-administration of a JNK inhibitor (JNK-IN-8) or p38 inhibitor (SB203580) abolishes the activation of caspase-9, caspase-8, and caspase-3 protein expression during licochalcone A treatment. These findings indicate that licochalcone A exerts a cytostatic effect through apoptosis by targeting the JNK/p38 pathway in human nasopharyngeal carcinoma cells. Therefore, licochalcone A is a promising therapeutic agent for the treatment of human nasopharyngeal cancer cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Chalconas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Antineoplásicos/farmacología , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Humanos , Imidazoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
Oral cancer is causally associated with environmental carcinogens, and the susceptibility to carcinogen-mediated tumorigenesis is proposed to be genotype-dependent. Leptin (LEP) and leptin receptor (LEPR) both play a crucial role in the mediation of physiological reactions and carcinogenesis and may serve as a candidate biomarker of oral cancer. The current case-control study aimed to examine the effects of LEP -2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) single-nucleotide polymorphisms (SNPs) with or without interacting to environmental carcinogens on the risk for oral squamous cell carcinoma. The SNPs of three genetic allele, from 567 patients with oral cancer and 560 healthy controls in Taiwan were analyzed. The results shown that the patients with polymorphic allele of LEP -2548 have a significant low risk for the development of clinical stage (A/G: adjusted odds ratio [AOR] = 0.670, 95% confidence interval [CI] = 0.454-0.988, P < 0.05; A/G + G/G: AOR = 0.676, 95% CI = 0.467-0.978, P < 0.05) compared to patients with ancestral homozygous A/A genotype. In addition, an interesting result was found that the impact of LEP -2548 G/A SNP on oral carcinogenesis in subjects without tobacco consumption is higher than subjects with tobacco consumption. These results suggest that the genetic polymorphism of LEP -2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) were not associated to the susceptibility of oral cancer; SNP in LEP -2548 G/A showed a poor clinicopathological development of oral cancer; population without tobacco consumption and with polymorphic LEP -2548 G/A gene may significantly increase the risk to have oral cancer.
Asunto(s)
Carcinogénesis/genética , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Leptina/genética , Neoplasias de la Boca/genética , Polimorfismo de Nucleótido Simple/genética , Fumar/genética , Carcinogénesis/patología , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Receptores de Leptina/genéticaRESUMEN
From several decades ago to now, cancer continues to be the leading cause of death worldwide, and metastasis is the major cause of cancer-related deaths. For health benefits, there is a great desire to use non-chemical therapy such as nutraceutical supplementation to prevent pathology development. Over 10,000 different natural bioactives or phytochemicals have been known that possessing potential preventive or supplementary effects for various diseases including cancer. Previously, the in vitro and in vivo anti-invasive and anti-metastatic activities of phenolic acids, monophenol, polyphenol and their derivatives and flavonoids and their derivatives have been reviewed. However, a vast number of natural dietary compounds other than phenolics have been demonstrated to potentially possess the ability to inhibit the invasion and metastasis of various cancers. In this review, we summarize the studies in recent decade on in vitro and in vivo effects and molecular mechanisms of natural bioactives, excluding the phenolics in food, in cancer invasion and metastasis. By combining this review of non-phenolics with the previous phenolics reviews, the puzzle for the contribution of natural dietary bioactives on cancer invasive or/and metastatic progress will be almost complete and more clear.
Asunto(s)
Suplementos Dietéticos/análisis , Neoplasias/tratamiento farmacológico , Fitoquímicos/administración & dosificación , Animales , Humanos , Metástasis de la Neoplasia , Neoplasias/patologíaRESUMEN
Glabridin, a flavonoid extracted from licorice (Glycyrrhiza glabra), possesses various biological properties, including anticancer activities. However, the effect of glabridin on oral cancer cell apoptosis and the underlying molecular mechanisms has not been elucidated. In this study, we demonstrated that glabridin treatment significantly inhibits cell proliferation in human oral cancer SCC-9 and SAS cell lines. Flow cytometric assays demonstrated that glabridin induced several features of apoptosis, such as sub-G1 phase cell increase and phosphatidylserine externalization. Furthermore, glabridin induced apoptosis dose-dependently in SCC-9 cells through caspase-3, -8, and -9 activation and poly (ADP-ribose) polymerase cleavage. Moreover, glabridin increased the phosphorylation of the extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase (JNK) pathways in a dose-dependent manner. Moreover, the inhibition of the JNK1/2 inhibitor significantly reversed the glabridin-induced activation of the caspase pathway. In conclusion, our findings suggest that glabridin induces oral cancer cell apoptosis through the JNK1/2 pathway and is a potential therapeutic agent for oral cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Isoflavonas/farmacología , Neoplasias de la Boca/patología , Fenoles/farmacología , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Neoplasias de la Boca/metabolismo , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Allergic airway disorder is characterized by an increase in the level of reactive oxygen species (ROS). The induction of inflammation and hyperresponsiveness by an allergen was ameliorated by antioxidants in vivo. This study investigated the protective effects and underlying mechanism of diallyl sulfide (DAS) on ovalbumin (OVA)-induced allergic asthma of BALB/c mice. The animals were intraperitoneally sensitized by inhaling OVA to induce chronic airway inflammation. By administering DAS, a decrease of the infiltrated inflammatory cell counts and the levels of IL-4 and IL-10 in bronchoalveolar lavage fluid as well as the OVA-specific immunoglobulin E levels in sera were observed. DAS also effectively inhibited OVA-induced inflammatory cell infiltration and mucus hypersecretion in lung tissue. Several OVA-induced inflammatory factors (ROS, 8-hydroxy-2'-deoxyguanosine, 8-iso-prostaglandin F2α, and NF-κB) were inhibited by DAS. In addition, DAS increased OVA inhalation-reduced levels of Nrf2 activation by regulating microRNA-144, -34a and -34b/c. Together, the pathogenesis of OVA-induced asthma is highly associated with oxidative stress, and DAS may be an effective supplement to alleviate this disease.
Asunto(s)
Antiasmáticos/administración & dosificación , Asma/prevención & control , Pulmón/inmunología , MicroARNs/inmunología , Factor 2 Relacionado con NF-E2/genética , Sulfuros/administración & dosificación , Animales , Asma/inducido químicamente , Asma/genética , Asma/inmunología , Femenino , Humanos , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , Factor 2 Relacionado con NF-E2/inmunología , Ovalbúmina/efectos adversosRESUMEN
Single nucleotide polymorphism (SNP) in some genes is a candidate for having or developing a cancer. Cathepsin B (CTSB) is considered to be the biomarker of cancers. The study aimed to evaluate the impacts of three SNPs in CTSB gene on the risk and progress of hepatocellular carcinoma (HCC). The SNPs of CTSB C76G (rs12338), CTSB A4383C (rs13332), and CTSB A8422G (rs8898) from 135 patients with HCC and 520 control participants in Taiwan were determined by real-time PCR. Through analyzing by statistics, we found that the polymorphism of rs13332 was significantly associated to the risk of HCC cancer; a significantly high frequent tumor size development was observed in HCC patients carrying rs12338 polymorphic genotype than those carrying ancestral genotype. The SNPs of rs12338, rs13332, and rs8898 were irrelevant to the frequencies of HCC clinical status and the levels of HCC clinicopathological markers. In conclusions, CTSB A4383C SNP is observed modestly more often in patients who developed HCC than in healthy controls and might be associated with the risk of HCC. The association between CTSB C76G SNP and greater tumor size may warrant further study in regards to the biology of HCC.
Asunto(s)
Carcinoma Hepatocelular/etiología , Catepsina B/genética , Neoplasias Hepáticas/etiología , Polimorfismo de Nucleótido Simple/genética , Consumo de Bebidas Alcohólicas/efectos adversos , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Riesgo , Uso de Tabaco/efectos adversosRESUMEN
SCOPE: Oxidative stress-aggravated chronic inflammatory diseases of the airway are well documented; hence, treatment with antioxidants to ameliorate oxidative stress might be an effective strategy to reduce airway complications. The aim of this study was to investigate the effect and molecular mechanism of diallyl sulfide (DAS), which is a natural organosulfuric compound found in garlic, on the inhibition of tumor necrosis factor-alpha (TNF-α)- or histamine-induced inflammation in rat aortic smooth muscle A7r5 cells. METHODS AND RESULTS: A7r5 cells were coincubated with DAS before exposure to TNF-α or histamine. DAS significantly blocked the accumulation of the nuclear p65 protein in TNF-α-induced A7r5 cells by attenuating the TNF-α receptor complex through the dissociation of the TNF receptor-associated death domain and TNF receptor-associated factor 2. Moreover, DAS inhibited histamine-induced inflammation by decreasing reactive oxygen species (ROS) levels by enhancing the nuclear factor-erythroid 2-related factor 2-related antioxidative enzyme. DAS also inhibited inflammation by suppressing interleukin-1ß and TNF-α through the inhibition of ROS-induced PI3K/Akt and the downstream NF-κB and activator protein-1. CONCLUSION: Our results demonstrate that DAS is a potential phytochemical to inhibit TNF-α- and histamine-induced inflammation, suggesting that DAS might be an effective dietary agent for the prevention of oxidative stress-induced inflammation of the airway.
Asunto(s)
Compuestos Alílicos/farmacología , Histamina/efectos adversos , Inflamación/prevención & control , Sulfuros/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antioxidantes/farmacología , Línea Celular , Ajo/química , Inflamación/tratamiento farmacológico , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/metabolismo , Miocitos del Músculo Liso , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fitoquímicos/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Proteína de Dominio de Muerte Asociada a Receptor de TNF/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Factor de Transcripción AP-1/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Patients with lung adenocarcinoma are often diagnosed with metastasizing symptoms and die of early and distal metastasis. Metastasis is made up of a cascade of interrelated and sequential steps, including cell adhesion, extracellular matrix degradation, cell movement, and invasion. Hence, substances carrying the ability to stop one of the metastasis-associated steps could be a potential candidate for preventing tumor cells from metastasizing and prolonging the life of cancer patients. Cinnamic acid (CA) was demonstrated to be such a candidate for human lung adenocarcinoma cells. Nevertheless, the effectiveness of CA derivatives on invasion of lung cancer cells is still unclear. The aims of this study were to explore the mechanisms underlying several select CA derivatives against invasion of human lung adenocarcinoma A549 cells. The results revealed that caffeic acid (CAA), chlorogenic acid (CHA), and ferulic acid (FA) can inhibit phorbol-12-myristate-13-acetate (PMA)-stimulated invasion of A549 cells at a concentration of ≥100 µM. The MMP-9 activity was suppressed by these compounds through regulating urokinase-type plasminogen activator (uPA), tissue inhibitor of metalloproteinase (TIMP)-1, plasminogen activator inhibitor (PAI)-1, and PAI-2; the cell-matrix adhesion was decreased by CAA only. The proposed molecular mechanism involved not only decreasing the signaling of MAPK and PI3K/Akt but also inactivating NF-κB, AP-1, and STAT3. In the present study, we selected CAA, CHA, and FA as potential inhibitors for invasive behaviors of human lung adenocarcinoma cells and disclosed the possible mechanisms. The association between structural features and anti-invasive activity of these compounds cannot be determined here and needs to be further verified.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/farmacología , Cinamatos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Antineoplásicos Fitogénicos/química , Ácidos Cafeicos/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Ácido Clorogénico/farmacología , Cinamatos/química , Ácidos Cumáricos/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Transducción de Señal/efectos de los fármacosRESUMEN
Dietary polyphenols have been reported as an effective phytochemical for health protection and cinnamic acid (CA) is one of the polyphenols that has been demonstrated having chemopreventive potential. It was known that the early and distal metastasis might lead to the high mortality of patients with lung adenocarcinoma. We previously compared and verified the inhibitory effect of cis-CA and trans-CA on phorbol-12-myristate-13-acetate (PMA)-induced invasion of human lung adenocarcinoma A549 cells. The aim of this study was to explore the underlying molecular mechanism. By gelatin zymography and semi-quantitative RT-PCR, the activities and mRNA of MMP-9/MMP-2 exerted a significantly (p<.05) dose-dependent reduction by treating with cis-CA and trans-CA. Western blots further showed that the cis-CA- and trans-CA-inhibited MMPs might partly through modulating TIMP-1 and the PAI-2-regulated uPA activity. In molecular level, the AP-1 and NF-κB as well as the downstream of the MAPK pathway might be involved in cis-CA- and trans-CA-inhibited MMPs expression. This study disclosed the molecular mechanism underlying the anti-invasive activity of cis-CA and trans-CA and concluded the cis- and trans-form of CA should be a safe and potential agent to prevent lung tumor cells from metastasizing.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/farmacología , Cinamatos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Modelos Biológicos , Adenocarcinoma/inducido químicamente , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Anticarcinógenos/efectos adversos , Anticarcinógenos/química , Anticarcinógenos/farmacología , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/química , Carcinógenos/antagonistas & inhibidores , Carcinógenos/toxicidad , Línea Celular Tumoral , Cinamatos/efectos adversos , Cinamatos/química , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/química , Metaloproteinasa 9 de la Matriz/genética , Invasividad Neoplásica , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Concentración Osmolar , Estereoisomerismo , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/antagonistas & inhibidores , Acetato de Tetradecanoilforbol/toxicidad , Inhibidor Tisular de Metaloproteinasa-1/agonistas , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores , Activador de Plasminógeno de Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Oral cancer is causally associated with environmental carcinogens, and the susceptibility to carcinogen-mediated tumorigenesis is proposed to be genotype-dependent. Cathepsin B (CTSB) is a lysosomal cysteine protease and may serve as a candidate biomarker of oral cancer. The current study aimed to explore the influences of three single nucleotide polymorphisms (SNPs) in CTSB gene, combined with environmental carcinogens on the risk and clinicopathological development of oral cancer. Three SNPs of CTSB, CTSB C76G (rs12338), CTSB A4383C (rs13332), and CTSB A8422G (rs8898), from 444 male patients with oral cancer and 426 control participants (males not diagnosed with cancer) in Taiwan were analyzed. These three CTSB SNPs all exhibited insignificant (P > 0.05) effects on the risk of oral cancer. However, the risk for developing the poor clinical stage of moderately or poorly differentiated cells was significantly (P < 0.001) increased to 3.325-fold in patients with oral cancer carrying the polymorphic genotype of rs8898 compared to patients with the ancestral genotype. Additionally, while considering the exposure of environmental carcinogens, the presence of these three CTSB SNPs, combined with betel quid chewing [adjusted odds ratio (AOR) was 36.570, 21.772, and 43.962 for rs12338, rs13332, and rs8898, respectively] and/or tobacco use (AOR was 3.794, and 8.972 for rs12338 and rs13332, respectively), robustly elevated the susceptibility to oral cancer. These results suggest that the genetic polymorphism of CTSB A8422G (rs8898) was associated with a high risk for the clinicopathological development of oral cancer and CTSB gene polymorphisms may increase the susceptibility to environmental carcinogens-mediated oral cancer.
Asunto(s)
Catepsina B/genética , Neoplasias de la Boca/etiología , Neoplasias de la Boca/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Carcinógenos Ambientales/toxicidad , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Estudios de Casos y Controles , Exposición a Riesgos Ambientales , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/enzimología , Factores de Riesgo , TaiwánRESUMEN
SCOPE: We previously demonstrated that 6-shogaol and 6-gingerol, two active compounds in ginger (Zingiber officinale), possess antiinvasive activity against highly metastatic hepatoma cells. The aims of this study were to evaluate the inhibitory effect and molecular mechanism underlying the transcription and translation of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) in Hep3B cells as well as the antiangiogenic activity of 6-gingerol and 6-shogaol. METHODS AND RESULTS: By gelatin zymography and luciferase reporter gene assays, we found that 6-gingerol and 6-shogaol regulate MMP-2/-9 transcription. Moreover, 6-gingerol directly decreased expression of uPA, but the 6-shogaol-mediated decrease in uPA was accompanied by up-regulation of plasminogen activator inhibitor (PAI)-1. 6-Gingerol and 6-shogaol concentrations of ≥ 10 µM and ≥ 2.5 µM, respectively, significantly inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling, the activation of NF-κB, and the translocation of NF-κB and STAT3. Incubation of 6-gingerol or 6-shogaol with human umbilical vein endothelial cells or rat aortas significantly attenuated tube formation. CONCLUSION: 6-Shogaol and 6-gingerol effectively inhibit invasion and metastasis of hepatocellular carcinoma through diverse molecular mechanisms, including inhibition of the MAPK and PI3k/Akt pathways and NF-κB and STAT3 activities to suppress expression of MMP-2/-9 and uPA and block angiogenesis.
Asunto(s)
Carcinoma Hepatocelular/patología , Catecoles/farmacología , Alcoholes Grasos/farmacología , Neoplasias Hepáticas/patología , Inhibidores de la Angiogénesis/farmacología , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Interleucina-8/antagonistas & inhibidores , Interleucina-8/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Factor de Transcripción STAT3/metabolismo , Células Tumorales Cultivadas , Activador de Plasminógeno de Tipo Uroquinasa/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Cancer metastasis refers to the spread of cancer cells from the primary neoplasm to distant sites, where secondary tumors are formed, and is the major cause of death from cancer. Natural phytochemicals containing phenolic compounds have been widely demonstrated to have the capability to prevent cancer metastasis. Among phenolic compounds, flavonoids are a very large subclass, and they are abundant in food and nutraceuticals. The number of reports demonstrating that flavonoids are an effective natural inhibitor of cancer invasion and metastasis is increasing in the scientific literature. Catechin derivatives, (−)-epigallocatechin-3-gallate, (−)-epigallocatechin, (−)-epicatechin-3-gallate,and (−)-epicatechin, are the most studied compounds in this topic so far; genistein/genistin, silibinin, quercetin, and anthocyanin have also been widely investigated for their inhibitory activities on invasion/metastasis. Other flavonoids in dietary vegetable foods that are responsible for anti-invasive and anti-metastatic activities of tumors include luteolin,apigenin, myricetin, tangeretin, kaempferol, glycitein, licoricidin,daidzein, and naringenin. To effectively overcome the metastatic cascade, including cell-cell attachment, tissue barrier degradation, migration, invasion, cell-matrix adhesion,and angiogenesis, it is essential that a bioactive compound prevent tumor cells from metastasizing. This review summarizes the effects of flavonoids on the metastatic cascade and the related proteins, the in vitro anti-invasive activity of flavonoids against cancer cells, and the effects of flavonoids on antiangiogenic and in vivo anti-metastatic models. The available scientific evidence indicates that flavonoids are a ubiquitous dietary phenolics subclass and exert extensive in vitro anti-invasive and in vivo anti-metastatic activities.
Asunto(s)
Flavonoides/uso terapéutico , Metástasis de la Neoplasia/tratamiento farmacológico , Animales , Dieta , Flavonoides/química , Flavonoides/farmacología , Humanos , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia/prevención & controlRESUMEN
BACKGROUND: Matrix metalloproteinase (MMP)-14 is one of the pericellular collagenases to degrade extracellular matrix (ECM), which is involved to the modulation of susceptibility or clinicopathological features of a cancer. The contributions of MMP-14 on the susceptibility or clinicopathological features of certain cancers have been well documented, and the expression of MMP-14 in oral squamous cell carcinoma (OSCC) also has been observed. This study was designed to examine the association of MMP-14 gene polymorphisms with the susceptibility and clinicopathological development of OSCC. METHODS: A total of 363 patients with OSCC and 506 healthy control subjects were recruited. Six single nucleotide polymorphisms (SNPs) of MMP-14 genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism genotyping and haplotype-base analysis. RESULTS: MMP-14 +7096 TC/CC genotypes might lower the risk of OSCC, and MMP-14 +6767 GA/AA genotypes cause a poor clinical status in OSCC patients. The +6727 C: +6767 G: +7096 T: +8153 G haplotype and diplotype increased the risk for OSCC by 1.706-fold (95% confidence interval (CI) 1.383-2.105) and 2.276-fold (95% CI = 1.531-3.384), respectively, compared with the reference. The diplotype with at least one CGTG exhibited a high risk (adjusted odds ratio, 1.639; 95% CI, 1.005-2.673) for developing a poor clinicopathological diagnosis of OSCC compared with the others/other diplotype. CONCLUSIONS: The +7096 and +6767 polymorphic genotypes and haplotype +6727 C: +6767 G: +7096 T: +8153 G of MMP-14 gene might contribute to the prediction of susceptibility and pathological development of OSCC.
Asunto(s)
Carcinoma de Células Escamosas/genética , Predisposición Genética a la Enfermedad/genética , Metaloproteinasa 14 de la Matriz/genética , Neoplasias de la Boca/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Alelos , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Frecuencia de los Genes , Genes Relacionados con las Neoplasias , Haplotipos , Humanos , Masculino , Neoplasias de la Boca/patología , Oportunidad Relativa , Pronóstico , Factores de RiesgoRESUMEN
Cancer metastasis is the major cause of cancer-related death, and chemoprevention is defined as the use of natural or synthetic substances to prevent cancer formation or cancer progress. Evidence that phenolic compounds may have a potential inhibitory effect on cancer invasion and metastasis is increasingly being reported in the scientific literature. Curcumin, resveratrol, and their related derivatives are the most studied compounds in this topic so far; gallic acid, chlorogenic acid, caffeic acid, carnosol, capsaicin, 6-shogaol, 6-gingerol, and their corresponding derivatives are also suggested to be the active members of the phenolic family on anti-invasion and anti-metastasis. Because metastasis occurs through a multistep process, these bioactives might act on a variety of stages of the metastatic process to prevent tumor cells from metastasizing. This review summarizes the common protein targets and signaling pathways for the inhibition of invasion and metastasis as well as past publications on the in vitro and in vivo effects and molecular mechanisms of phenolic acids, monophenol, polyphenol, and their derivatives, except flavonoids, on cancer invasion and metastasis. Based on these data, we conclude that the daily consumption of natural dietary components that are rich in phenolics could be beneficial for the prevention of cancer metastasis.
Asunto(s)
Hidroxibenzoatos/farmacología , Neoplasias/dietoterapia , Fenol/farmacología , Polifenoles/farmacología , Animales , Biomarcadores de Tumor/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Hidroxibenzoatos/uso terapéutico , Invasividad Neoplásica/prevención & control , Metástasis de la Neoplasia/prevención & control , Neoplasias/metabolismo , Neoplasias/patología , Fenol/uso terapéutico , Polifenoles/uso terapéuticoRESUMEN
BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is seldom available because of the lack of reliable markers. Survivin is an anti-apoptotic protein that is implicated in the regulation of apoptosis and cell cycle, and it is undetectable in normal adult tissues but is overexpressed in various types of cancers. Survivin is thus commonly considered to be a marker of malignancy. The aim of this study was to explore the association between survivin gene polymorphisms and the risk and diagnostic progress of HCC. METHODS: A total of 135 patients with HCC and 496 healthy control subjects were recruited. Five single nucleotide polymorphisms (SNPs) of survivin genes were determined by real-time polymerase chain reaction (real-time PCR) and further analyzed statistically. RESULTS: We first found that the -241 C/T and -235 G/A genetic polymorphisms of survivin did not occur frequently enough or even lacked in Taiwanese population. The +9809 C/C polymorphism exhibited a significant (P < .05) low risk of 0.525-fold (95% confidence interval [95% CI] = 0.297-0.930) to have HCC compared with the wild-type homozygotes and a low ratio of 0.214-fold (95% CI = 0.051-0.890) for positive anti-HCV was shown in the individuals with survivin +9809 polymorphic CC allele compared with the TT/TC genotypic subgroup. CONCLUSIONS: Survivin +9809 polymorphic genotype is associated with the risk of HCC, and the HCC patients with survivin +9809 CC homozygotes might have a low risk of developing infected HCV-dependent HCC. The results suggest that the survivin T9809C SNP might contribute to the prediction of susceptibility and pathological development to HCC.
Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Predisposición Genética a la Enfermedad , Proteínas Inhibidoras de la Apoptosis/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Anciano , Alanina Transaminasa/sangre , Pueblo Asiatico/genética , Aspartato Aminotransferasas/sangre , Carcinoma Hepatocelular/sangre , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Intervalos de Confianza , Femenino , Humanos , Neoplasias Hepáticas/sangre , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadísticas no Paramétricas , Survivin , Taiwán , Secuencias Repetidas Terminales/genética , alfa-Fetoproteínas/metabolismoRESUMEN
Lung cancer is the major cause of tumor-related death, and approximately 70% of lung cancer patients die from metastasis. Evidence that phenolic compounds may have a potential inhibitory effect on cancer invasion and metastasis is increasingly being reported in the scientific literature. Cinnamic acid is a member of phenolics which having several isoforms in nature. The trans-cinnamic acid (t-CA) has been investigated extensively for its potential pharmacological effects whereas the study of cis-cinnamic acid (c-CA) is limited because pure c-CA was hard to obtain. We had developed a practicable method previously to transform and obtain pure c-CA, and the pure compound was used to evaluate the anti-invasive effect on human adenocarcinoma A549 cells. The A549 cells were treated with 0-200 µM of c-CA and t-CA in the presence of 200 nM phorbol-12-myristate-13-acetate (PMA) at 37 °C for 24 h, and matrix metalloproteinase (MMP)-2, MMP-9, adhesive, migratory, and invasive activities of the cells were determined. The results showed that the treatment of c-CA and t-CA dose-dependently reduced the PMA-induced MMP-2 and -9 activities but without significant effect on the adhesive activity of cells. The PMA-induced motility was suppressed in a dose-dependent manner by a 24-h treatment with c-CA and t-CA. The invasive ability was significantly (p<0.05) reduced to 68% and 65%, respectively, relative to PMA treatment alone after treatment of PMA-treated A549 cells with either 50 µM c-CA or 100 µM t-CA for 24 h. The results suggest that both of the c-CA and t-CA are inhibitors for invasion of A549 cells and the activity of c-CA seems to be higher than t-CA.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Cinamatos/química , Cinamatos/farmacología , Adhesión Celular/efectos de los fármacos , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Modelos Biológicos , Invasividad Neoplásica , Estereoisomerismo , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Flavonoids are natural phenolic substances widely found in fruit, vegetables, grains, and wine. Most of these compounds exert health-promoting effects seem to attribute to their antioxidant activity. Metallothioneins (MT) has been suggested to protect against acute heavy metal toxicity in the liver, and the proteins of MT can be induced by various stimuli including antioxidant. Measuring the induction of MT genes may provide an efficient approach to understand the chemopreventive mechanisms of flavonoids. The antioxidant activity of eight flavonoids was determined by TEAC and ORAC assays and their effects on MT protein were also measured. HepG2 cells were employed to explore the mechanisms underlying flavonoid-induced MT induction. Statistical analysis revealed a positive correlation between the antioxidant activity of flavonoids and MT expression. Quercetin-induced MT expression may function by activating the phosphorylation of JNK, p38 and PI3K/Akt as well as by enhancing Nrf2 DNA-binding activity. Moreover, quercetin exhibited a potential protective effect on t-BHP-caused injury in hepatocytes through the induction of MT. These results suggest that quercetin is a natural antioxidant in the diet and the consumption of foods that are rich in quercetin could be beneficial for the prevention of environmental oxidant-induced liver damage.
Asunto(s)
Antioxidantes/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metalotioneína/biosíntesis , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Quercetina/farmacología , Regulación de la Expresión Génica/fisiología , Células Hep G2 , Humanos , MAP Quinasa Quinasa 4/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis. The long course of treatments on TB with a combination of antibiotics leads unfavorable side effects and poor patient compliance which contributes to sustaining multiple-drug resistant tuberculosis (MDR-TB). Therefore, the development of a new effective drug or synergist to reduce the prevalence of MDR-TB is urgent to date. Cinnamic acid (CA) is a natural occurring phenolic compound with anti-microbial activity. Both trans- and cis-isoforms of CA exist in planta, and cis-cinnamic acid (c-CA) can be transformed from trans-cinnamic acid (t-CA) under sunlight. Due to the unavailability of c-CA, the literature regarding the biological functions of c-CA is still limited. We had previously developed a practicable method for the transformation of c-CA from t-CA and the isolation of c-CA. Using the techniques, sufficient c-CA was obtained to evaluate its antituberculosis activity against a MDR M. tuberculosis strain. Moreover, the synergistic effects of c-CA and t-CA with two first-line anti-TB antibiotics, isoniazid (INH) and rifampicin (RIF), were also determined. Although both of c-CA and t-CA decreased the viability of MDR-TB bacilli in a dose-dependent manner, the antituberculosis activity of c-CA was approximately 120-fold of t-CA. Furthermore, the c-CA exhibited higher synergistic effect with INH or RIF against tuberculosis than t-CA. The micrographs of scanning electron microscope (SEM) display that c-CA caused an injury on the out-layer of MDR-TB bacilli. The c-CA might be a potential anti-mycobacterial or synergistic agent that can be developed to against tuberculosis.