RESUMEN
Disrupted cell cycle progression underlies the molecular pathogenesis of multiple diseases. Chronic exposure to inorganic arsenic (iAs) is a global health issue leading to multi-organ cancerous and non-cancerous diseases. Exposure to supratherapeutic concentrations of iAs causes cellular accumulation in G2 or M phase of the cell cycle in multiple cell lines by inducing cyclin B1 expression. It is not clear if iAs exposure at doses corresponding to serum levels of chronically exposed populations (â¼100 nM) has any effect on cell cycle distribution. In the present study we investigated if environmentally relevant iAs exposure induced cell cycle disruption and mechanisms thereof employing two human keratinocyte cell lines (HaCaT and Ker-CT), flow cytometry, immunoblots and quantitative real-time PCR (qRT-PCR). iAs exposure (100 nM; 24 h) led to mitotic accumulation of cells in both cell lines, along with the stabilization of ANAPC11 ubiquitination targets cyclin B1 and securin, without affecting their steady state mRNA levels. This result suggested that induction of cyclin B1 and securin is modulated at the level of protein degradation. Moreover, zinc supplementation successfully prevented iAs-induced mitotic accumulation and stabilization of cyclin B1 and securin without affecting their mRNA levels. Together, these data suggest that environmentally relevant iAs exposure leads to mitotic accumulation possibly by displacing zinc from the RING finger subunit of anaphase promoting complex/cyclosome (ANAPC11), the cell cycle regulating E3 ubiquitin ligase. This early cell cycle disruptive effect of environmentally relevant iAs concentration could underpin the molecular pathogenesis of multiple diseases associated with chronic iAs exposure.
Asunto(s)
Subunidad Apc11 del Ciclosoma-Complejo Promotor de la Anafase , Arsénico , Ciclosoma-Complejo Promotor de la Anafase , Arsénico/toxicidad , Línea Celular , Ciclina B1/genética , Suplementos Dietéticos , Humanos , Queratinocitos , ARN Mensajero , Securina , Ubiquitina-Proteína Ligasas , ZincRESUMEN
The association between selenium and peptide in gastric cancer is an important research topic. The present study reported the facile synthesis of anticancer bioactive peptide (ACBP)functionalized selenium (ACBPSSe) particles with enhanced anticancer activities and a detailed mechanistic evaluation of their ability to regulate oxidative stress in vitro. Structural and chemical characterizations were revealed by ultraviolet absorption, Fourier transform infrared, Xray photoelectron, nuclear magnetic resonance carbon and hydrogen, energy dispersive Xray spectroscopy and inductively coupled plasma mass spectrometry, as well as scanning electron microscopy. Sulfhydrylation modifications of ACBP were achieved with Sacetylmercaptosuccinic anhydride via chemical absorption. After the polypeptide was modified by sulfhydrylation, the ACBP chain was linked to sulfhydryl groups by amide bonds to form the ACBPchelated selenium complex. Two gastric cancer cell lines (MKN45 and MKN74 cells) demonstrated high susceptibility to ACBPSSe particles and displayed significantly decreased proliferation ability following treatment. The results suggested that the bioactive peptidechelated selenium particles effectively inhibited the proliferation of MKN45 and MKN74 cells in vitro. The genes encoding CDK inhibitor 1A (CDKN1A), cyclin B1, thioredoxin (TXN) and mitogenactivated protein kinase kinase kinase 5 are associated with regulation of oxidative stress, while CDKN1A and TXN protect cells by decreasing oxidative stress and promoting cell growth arrest. Therefore, ACBPSSe may be an ideal chemotherapeutic candidate for human cancer, especially gastric cancer.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Péptidos/farmacología , Selenio/farmacología , Neoplasias Gástricas/genética , Antineoplásicos/química , Línea Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Ciclina B1/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Redes Reguladoras de Genes , Humanos , MAP Quinasa Quinasa Quinasa 5/genética , Péptidos/química , Selenio/química , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Tiorredoxinas/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese herbal formulas have been proven to exert an inhibitory effect on tumor. Compound mylabris capsules (CMC) has been used for treating cancer, especially hepatocellular carcinoma (HCC), for years in China. However, its therapeutic mechanisms on HCC remain unclear. AIM OF THE STUDY: This research aimed to elucidate the molecular targets and mechanisms of CMC for treating HCC. MATERIALS AND METHODS: First, the bioactive ingredients and potential targets of CMC, as well as HCC-related targets were retrieved from publicly available databases. Next, the overlapped genes between potential targets of CMC and HCC-related targets were determined using bioinformatics analysis. Then, networks of ingredient-target and gene-pathway were constructed. Finally, cell experiments were carried out to examine the effects of CMC-medicated serum on HCC and validate the core molecular targets. RESULTS: In total, 151 bioactive ingredients and 255 potential targets of CMC were selected, 982 differentially expressed genes of HCC were identified. Among them, 34 overlapped genes were finally selected. In addition, 20 pathways and 429 GO terms were significantly enriched. Protein-protein interaction and gene-pathway networks indicated that Cyclin B1(CCNB1) and Cyclin Dependent Kinase 1(CDK1) were the core gene targets for the treatment of CMC on HCC. Moreover, in vitro studies showed that CMC-medicated serum significantly inhibited the viability of HepG2 cells. Furthermore, CMC downregulated CCNB1 and CDK1 expressions and induced G2/M phase cell cycle arrest. CONCLUSIONS: CMC plays a therapeutic role in HCC via multi-component, -target and -pathway mechanisms, in which CCNB1 and CDK1 may be the core molecular targets. This study indicates that the integration of network pharmacology and bioinformatics analysis, followed by experimental validation, can serves as an effective tool for studying the therapeutic mechanisms of traditional Chinese medicine.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Medicamentos Herbarios Chinos/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Biología Computacional , Ciclina B1/genética , Ciclina B1/metabolismo , Bases de Datos Genéticas , Bases de Datos Farmacéuticas , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Redes Reguladoras de Genes/efectos de los fármacos , Células Hep G2 , Humanos , Masculino , Mapas de Interacción de Proteínas/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
As a plant medicine, Oxalidaceae has been used to treat various diseases in Korea. However, there is little data on the anti-cancer efficacy of Oxalidaceae, particularly O. obtriangulata. This study aimed to investigate the anti-cancer effect of O. obtriangulata methanol extract (OOE) and its regulatory actions on pancreatic carcinoma. OOE showed anti-proliferative effects and induced cell death in the colony formation and cell viability assays, respectively. The Fluorescence-activated cell sorting (FACS) data confirmed that OOE significantly induced cell cycle accumulation at the G2/M phase and apoptotic effects. Additionally, OOE inhibited the activated ERK (extracellular-signal-regulated kinase)/Src (Proto-oncogene tyrosine-protein kinase Src)/STAT3 (signal transducers and activators of transcription 3) pathways including nuclear translocation of STAT3. Furthermore, suppression of Ki67, PARP(Poly ADP-ribose polymerase), caspase-3, P27(Cyclin-dependent kinase inhibitor 1B), and c-Myc as well as the STAT3 target genes CDK(cyclin-dependent kinase)1, CDK2, Cyclin B1, VEGF-1(vascular endothelial growth factor-1), MMP-9(Matrix metallopeptidase 9), and Survivin by OOE was observed in BxPC3. We speculate that these molecular actions might support an anti-cancer effect of OOE. In this study, we demonstrated that OOE may be a promising anti-cancer material and may serve as a natural therapy and alternative remedy for pancreatic cancer treatment.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Magnoliopsida/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina B1/genética , Ciclina B1/metabolismo , Humanos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Páncreas/metabolismo , Páncreas/patología , Extractos Vegetales/química , Plantas Medicinales , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas pp60(c-src)/genética , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Pancreatic cancer has a high mortality rate due to poor rates of early diagnosis. One tumor suppressor gene in particular, p53, is frequently mutated in pancreatic cancer, and mutations in p53 can inactivate normal wild type p53 activity and increase expression of transcription factor forkhead box M1 (FoxM1). Overexpression of FoxM1 accelerates cellular proliferation and cancer progression. Therefore, inhibition of FoxM1 represents a therapeutic strategy for treating pancreatic cancer. Broussoflavonol B (BF-B), isolated from the stem bark of Broussonetia kazinoki Siebold has previously been shown to inhibit the growth of breast cancer cells. This study aimed to investigate whether BF-B exhibits anti-pancreatic cancer activity and if so, identify the underlying mechanism. BF-B reduced cell proliferation, induced cell cycle arrest, and inhibited cell migration and invasion of human pancreatic cancer PANC-1 cells (p53 mutated). Interestingly, BF-B down-regulated FoxM1 expression at both the mRNA and protein level. It also suppressed the expression of FoxM1 downstream target genes, such as cyclin D1, cyclin B1, and survivin. Cell cycle analysis showed that BF-B induced the arrest of G0/G1 phase. BF-B reduced the phosphorylation of extracellular signal-regulated kinase ½ (ERK½) and expression of ERK½ downstream effector c-Myc, which regulates cell proliferation. Furthermore, BF-B inhibited cell migration and invasion, which are downstream functional properties of FoxM1. These results suggested that BF-B could repress pancreatic cancer cell proliferation by inactivation of the ERK/c-Myc/FoxM1 signaling pathway. Broussoflavonol B from Broussonetia kazinoki Siebold may represent a novel chemo-therapeutic agent for pancreatic cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Broussonetia/química , Flavonoles/farmacología , Proteína Forkhead Box M1/genética , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Cámaras de Difusión de Cultivos , Flavonoles/aislamiento & purificación , Proteína Forkhead Box M1/antagonistas & inhibidores , Proteína Forkhead Box M1/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Páncreas/metabolismo , Páncreas/patología , Corteza de la Planta/química , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Survivin/genética , Survivin/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Pyropia yezoensis, rich in porphyran, is a medicine-edible red alga. In the present study, the physicochemical characteristics, conformational states and antitumor activities of a novel porphyran extracted from the high-yield algal strain Pyropia yezoensis Chonsoo2 and its two degraded derivatives by gamma irradiation were investigated. RESULTS: Pyropia yezoensis porphyran is a water-soluble, triple-helical sulfated hetero-galactopyranose, named PYP. PYP was degraded by gamma irradiation at 20 kGy and 50 kGy, giving two low molecular weight derivatives comprising PYP-20 and PYP-50, respectively. PYP with a higher molecular weight has a solution conformation different from PYP-20 and PYP-50. Three porphyrans had no toxicity in normal human liver cells (HL-7702) and showed antitumor effects on Hep3B, HeLa and MDA-MB-231. They had better antitumor against HeLa cells, exhibiting a similar inhibition ratio compared to 5-fluorouracil, with PYP especially exhibiting a higher inhibition ratio than 5-fluorouracil. With respect to HeLa cells, the different antitumor activities might be related to porphyran molecular weight and solution conformation. Furthermore, the HeLa cell cycle was blocked in the G2/M phase after PYP treatment, leading to cell proliferation inhibition. The induction of cell cycle arrest was related to the changes in the expression of p21, p53, Cyclin B1 and cyclin-dependent kinase 1. CONCLUSION: Pyropia yezoensis porphyran, as applied to medicine and functional food, could potentially be used as a non-toxic natural adjuvant in cancer therapy. © 2019 Society of Chemical Industry.
Asunto(s)
Antineoplásicos/farmacología , Extractos Vegetales/farmacología , Rhodophyta/química , Sefarosa/análogos & derivados , Antineoplásicos/aislamiento & purificación , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina B1/genética , Ciclina B1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Extractos Vegetales/aislamiento & purificación , Sefarosa/aislamiento & purificación , Sefarosa/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Scutellaria altissima L. is a common traditional Chinese medicine used to treat inflammation in some countries. Scutellarin, an active major flavone glycoside isolated from the traditional Chinese medicine Scutellaria altissima L., has been shown to offer various beneficial biochemical effects on cerebrovascular diseases and inflammation. However, the antiproliferative effects of Scutellarin in prostate cancer and the underlying mechanism are not fully elucidated. In the present study, we aimed to ascertain whether Scutellarin inhibits cancer cell growth and to further explore the molecular mechanism. Scutellarin enhanced the sensitivity of prostate cancer cells to cisplatin. MTT assays revealed that cell viability was significantly decreased in the prostate cancer cells treated with Scutellarin. Flow cytometric analysis indicated that Scutellarin suppressed cell proliferation by promoting G2/M arrest and inducing apoptosis. We employed western blotting to delineate the underlying mechanisms involved in the G2/M arrest and apoptosis. Comet assay and γH2AX immunocytochemistry were used to detect levels of DNA damage in PC3 cells exposed to Scutellarin and/or cisplatin. Our data revealed that Scutellarin significantly induced prostate cancer cell apoptosis by activating the caspase cascade. An increase in the Bax/Bcl-2 ratio, depolarization of mitochondrial membrane potential and cell cycle arrest at G2/M phase were accompanied by the apoptosis induction. Additionally, Scutellarin altered the protein expression of cell cycle and apoptosis regulatory genes by downregulating Cdc2, cyclin B1 and Bcl-2 and upregulating caspase-3, caspase-9 and Bax in prostate cancer cells. Furthermore, Scutellarin sensitized PC3 cells to cisplastin treatment in a dose-dependent manner. Taken together, our data confirmed the cytotoxicity of Scutellarin against prostate cancer PC3 cells and provide new findings in regards to Scutellarin sensitizing prostate cancer cells to chemotherapy. Our findings suggest that Scutellarin has potential to be used as a novel antineoplastic therapeutic candidate for prostate cancer patients.
Asunto(s)
Apigenina/administración & dosificación , Citotoxinas/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Glucuronatos/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Apigenina/química , Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina B1/genética , Citotoxinas/química , Resistencia a Antineoplásicos/efectos de los fármacos , Medicamentos Herbarios Chinos/química , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucuronatos/química , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Scutellaria/químicaRESUMEN
Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia, for which radiotherapy and/or chemotherapy are the primary treatment methods. Many herbs are known to have potential uses in chemotherapy; however, the mechanisms underlying the observed antitumor activity of Ajuga bracteosa (AB) against NPC remain unclear. We explored the antitumor effects of AB, which was shown specifically to induce mitotic delay in pharyngeal (Detroit 562) and nasopharyngeal (Hone-1) cancer cells. Proliferation of cancer cells after exposure to aqueous extract of A. bracteosa (AEAB) was assessed using the MTT assay. DNA content and cell cycle arrest induction were analyzed using flow cytometry. The expression of checkpoint kinase 2 (CHK2), cell division control protein 2 (CDC2), and cyclin B1 was investigated using qRT-PCR and Western blot analysis. Results indicated the inhibition of cancer cell growth following exposure to AEAB. In addition, AEAB induced the accumulation of G2/M-phase cells in cancer cell through the disassociation of CDC2/cyclin B1 complex. Our findings suggested that, in addition to the known effects of AEAB in NPC prevention, it may have antitumor activities against NPC cells. In conclusion, AEAB inhibits the growth of and induces mitotic delay in cancer cells, supporting its use as an anticancer agent.
Asunto(s)
Ajuga/química , Carcinoma/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Faríngeas/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Apoptosis/efectos de los fármacos , Carcinoma/genética , Carcinoma/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa de Punto de Control 2/genética , Ciclina B1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mitosis/efectos de los fármacos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patología , Extractos Vegetales/química , Agua/químicaRESUMEN
Besides being traditionally used to relieve hepatobiliary disorders, Cynara cardunculus L. has evidenced anticancer potential on triple-negative breast cancer (TNBC). This study highlights the antiproliferative effects of lipophilic extracts from C. cardunculus L. var. altilis (DC) leaves and florets, and of their major compounds, namely cynaropicrin and taraxasteryl acetate, against MDA-MB-231 cells. Our results demonstrated that MDA-MB-231 cells were much less resistant to leaves extract (IC50 10.39 µg/mL) than to florets extract (IC50 315.22 µg/mL), during 48 h. Moreover, leaves extract and cynaropicrin (IC50 6.19 µg/mL) suppressed MDA-MB-231 cells colonies formation, via an anchorage-independent growth assay. Leaves extract and cynaropicrin were also assessed regarding their regulation on caspase-3 activity, by using a spectrophotometric assay, and expression levels of G2/mitosis checkpoint and Akt signaling pathway proteins, by Western blotting. Leaves extract increased caspase-3 activity, while cynaropicrin did not affect it. Additionally, they caused p21Waf1/Cip1 upregulation, as well as cyclin B1 and phospho(Tyr15)-CDK1 accumulation, which may be related to G2 cell cycle arrest. They also downregulated phospho(Ser473)-Akt, without changing total Akt1 level. Cynaropicrin probably contributed to leaves extract antiproliferative action. These promising insights suggest that cultivated cardoon leaves lipophilic extract and cynaropicrin may be considered toward a natural-based therapeutic approach on TNBC.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Cynara/química , Lactonas/farmacología , Extractos Vegetales/farmacología , Sesquiterpenos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2 , Línea Celular Tumoral , Ciclina B1/genética , Ciclina B1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Humanos , Lactonas/química , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sesquiterpenos/químicaRESUMEN
BACKGROUND: Carnosic acid (CA) is a diterpenoid found in Rosmarinus officinalis L. and Salvia officinalis L. as well as in many other Lamiaceae. This compound is reported to have antioxidant and antimicrobial properties. In addition, a number of reports showed that CA has a cytotoxic activity toward several cancer cell lines. PURPOSE: The aim of this study was to establish whether CA has any specific antiproliferative effect toward human glioblastoma (GBM) cells and to analyze the molecular mechanisms involved. METHODS: We evaluated cell survival by MTT assay, apoptosis and DNA content by flow cytometry, protein expression and phosphorylation by immunoblot analyses. RESULTS: Our results showed that CA inhibited cell survival on both normal astrocytes and GBM cells. In GBM cells, in particular, CA caused an early G2 block, a reduction in the percentage of cells expressing Ki67, an enhanced expression of p21(WAF) and induced apoptosis. Furthermore, we showed that CA promoted proteasomal degradation of several substrate proteins, including Cyclin B1, retinoblastoma (RB), SOX2, and glial fibrillary acid protein (GFAP), whereas MYC levels were not modified. In addition, CA dramatically reduced the activity of CDKs. CONCLUSION: In conclusion, our findings strongly suggest that CA promotes a profound deregulation of cell cycle control and reduces the survival of GBM cells via proteasome-mediated degradation of Cyclin B1, RB and SOX2.
Asunto(s)
Abietanos/farmacología , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ciclina B1/efectos de los fármacos , Glioblastoma/patología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Proteína de Retinoblastoma/efectos de los fármacos , Factores de Transcripción SOXB1/efectos de los fármacos , Astrocitos/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Ciclina B1/genética , ADN de Neoplasias/biosíntesis , ADN de Neoplasias/genética , Relación Dosis-Respuesta a Droga , Fase G2/efectos de los fármacos , Humanos , Complejo de la Endopetidasa Proteasomal/genética , Proteína de Retinoblastoma/genética , Factores de Transcripción SOXB1/genéticaRESUMEN
Despite state of the art cancer diagnostics and therapies offered in clinic, prostate cancer (PCa) remains the second leading cause of cancer-related deaths. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of Andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on cell cycle phases in LNCaP, C4-2b and PC3 cells compared to retinoblastoma protein (RB(-/-)) and CDKN2A lacking DU-145 cells. G2/M transition was blocked in LNCaP, C4-2b and PC3 after AG treatment whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to differential activation of cell cycle regulators in these cell lines. Levels of cyclin A2 after AG treatment increased in all PCa cells line. Cyclin B1 levels increased in LNCaP and PC3, decreased in C4-2b and showed no difference in DU-145 cells after AG treatment. AG decreased cyclin E2 levels only in PC3 and DU-145 cells. It also altered Rb, H3, Wee1 and CDC2 phosphorylation in PCa cells. Intriguingly, AG reduced cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggests its potential use as a therapeutic and/or preventive agent for PCa.
Asunto(s)
Andrographis/química , Antineoplásicos Fitogénicos/farmacología , Diterpenos/farmacología , Células Epiteliales/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Receptores CXCR3/genética , Receptores CXCR/genética , Antineoplásicos Fitogénicos/aislamiento & purificación , Proteína Quinasa CDC2 , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quimiocina CXCL11/genética , Quimiocina CXCL11/metabolismo , Ciclina B1/genética , Ciclina B1/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Diterpenos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Células Epiteliales/metabolismo , Células Epiteliales/patología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilación , Extractos Vegetales/química , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Receptores CXCR/antagonistas & inhibidores , Receptores CXCR/metabolismo , Receptores CXCR3/antagonistas & inhibidores , Receptores CXCR3/metabolismo , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Transducción de SeñalRESUMEN
The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell) was selected for comparison. A high-performance liquid chromatography (HPLC) method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 µg/mL), demethoxycurcumin (1,147.4 µg/mL), and bisdemethoxycurcumin (190.2 µg/mL). A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 µg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells.
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Neoplasias Pulmonares/patología , Nanoestructuras/química , Extractos Vegetales/farmacología , Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2 , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Caspasa 9/genética , Caspasa 9/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Curcuma/química , Curcumina/análogos & derivados , Curcumina/química , Curcumina/farmacología , Ciclina B1/genética , Ciclina B1/metabolismo , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Diarilheptanoides , Relación Dosis-Respuesta a Droga , Emulsiones , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Extractos Vegetales/químicaRESUMEN
The herb Momordica cochinchinensis has been used for a variety of purposes, and been shown to have anticancer properties. The present study assessed the potency and the underlying mechanisms of action of the ethyl acetate extract of seeds of Momordica cochinchinensis (ESMC2) on breast cancer cells. Therefore, the effects of ESMC2 on the cell viability, cell cycle and apoptosis of MDAMB231 cells were investigated. The results showed that ESMC2 exerted a marked growth inhibitory effect on the cells. Cell cycle arrest in G2 phase following treatment with ESMC2 was associated with a marked increase in the protein levels of cyclin B1, cyclin E and cyclin-dependent kinase 1 and a decrease in cyclin D1 expression. In addition, ESMC2 dosedependently induced cell apoptosis, which was mediated via upregulation of the apoptosis-associated proteins p53, B-cell lymphoma 2 (Bcl2)associated X protein, Bcl-2 homologous antagonist killer and Bcl-2-associated death promoter expression, as well as downregulation of nuclear factor kappa B, Bcl2 and myeloid cell leukemia1. Furthermore, the activation of extracellular signal-regulated kinase 1/2, p38, c-Jun N-terminal kinase (JNK) and Akt phosphorylation were decreased by ESMC2 in a dosedependent manner, indicating that ESMC2 exerted its effects via the mitogen-activated protein kinase/JNK pathway. Furthermore, nude mouse xenotransplant models were used to evaluate the tumor growth inhibitory effects of ESMC2. The possible chemical components of ESMC2 were analyzed by gas chromatography-mass spectrometry, and 12 compounds were detected from the major peaks based on the similarity index with entries of a compound database. The results of the present study may aid in the development of novel therapies for breast cancer.
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Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Momordica/química , Extractos Vegetales/química , Proteína Quinasa CDC2 , Línea Celular Tumoral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Fase G2/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Fosforilación , Semillas/química , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Chemotherapy increases the overall survival in colorectal cancer (CRC) patients. 5-Fluorouracil (5-FU) remains as a drug of first choice in CRC therapy over the last four decades. However, only 10-15% of patients with advanced CRC respond positively to 5-FU monotherapy. Therefore, new strategies to enhance the 5-FU effectiveness, overcome the tumor cell resistance and decrease the unspecific toxicity are critically needed. Urolithin A (Uro-A) is the main metabolite produced by the human gut microbiota from the dietary polyphenol ellagic acid. Uro-A targets the colonic mucosa of CRC patients, and preclinical studies have shown the anti-inflammatory and cancer chemopreventive activities of this metabolite. We evaluated here whether Uro-A, at concentrations achievable in the human colorectum, could sensitize colon cancer cells to 5-FU and 5'DFUR (a pro-drug intermediate of 5-FU). We found that both 5-FU and 5'DFUR arrested the cell cycle at the S phase by regulating cyclins A and B1 in the human colon cancer cells Caco-2, SW-480 and HT-29, and also triggered apoptosis through the activation of caspases 8 and 9. Co-treatments with Uro-A decreased IC50 values for both 5-FU and 5'DFUR and additionally arrested the cell cycle at the G2/M phase together with a slight increase in caspases 8 and 9 activation. Overall, we show that Uro-A potentiated the effects of both 5-FU and 5'DFUR on colon cancer cells. This suggests the need for lower 5-FU doses to achieve similar effects, which could reduce possible adverse effects. Further in vivo investigations are warranted to explore the possible role of Uro-A as a chemotherapy adjuvant.
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Antineoplásicos/farmacología , Bacterias/metabolismo , Neoplasias del Colon/microbiología , Cumarinas/metabolismo , Ácido Elágico/metabolismo , Fluorouracilo/farmacología , Microbioma Gastrointestinal , Apoptosis/efectos de los fármacos , Células CACO-2 , Ciclo Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Ciclina A/genética , Ciclina A/metabolismo , Ciclina B1/genética , Ciclina B1/metabolismo , Células HT29 , HumanosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Quisqualis indica is used in traditional Chinese medicine to treat cancer and related syndromes and also known for its anthelminthic effects. AIM OF THE STUDY: Soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential. In this study, we evaluated the cytotoxic, apoptosis inducing and cell cycle arresting effects of 25-O-acetyl-23,24-dihydro-cucurbitacin F which has been isolated from leaves and twigs of Q. indica. MATERIAL AND METHODS: The present study investigates the effects of 25-O-acetyl-23,24-dihydro-cucurbitacin F (1) on cell viability, cell cycle distribution, and apoptotic induction of three human sarcoma cell lines of various origins by using the CellTiter 96(®) AQueous One Solution Cell Proliferation Assay, flow cytometrical experiments, real-time RT-PCR, Western blotting, and the Caspase-Glo(®) 3/7 Assay RESULTS: We could show that 1 reduced cell viability in a dose-dependent manner and arrested the cells at the G2/M interface. The accumulation of cells at the G2/M phase resulted in a significant decrease of the cell cycle checkpoint regulators cyclin B1, cyclin A, CDK1, and CDK2. Interestingly, 1 inhibited survivin expression significantly, which functions as a key regulator of mitosis and programmed cell death, and is overexpressed in many tumor types including sarcomas. Moreover, 1 induced apoptosis in liposarcoma and rhabdomyosarcoma cells caspase-3 dependently. CONCLUSION: Our data strongly support 1 as a very interesting target for further investigation and development of novel therapeutics in sarcoma research.
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Antineoplásicos/farmacología , Triterpenos/farmacología , Apoptosis/efectos de los fármacos , Proteína Quinasa CDC2 , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclina A/genética , Ciclina B1/genética , Ciclina B1/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Sarcoma , SurvivinRESUMEN
The piperidine alkaloid piperine, a major ingredient in black pepper, inhibits the growth and metastasis of cancer cells both in vivo and in vitro, although its mechanism of action is unclear. Furthermore, its anticancer activity against osteosarcoma cells has not been reported. In this study, we show that piperine inhibited the growth of HOS and U2OS cells in dose- and time-dependent manners but had a weaker effect on the growth of normal hFOB cells. Piperine inhibited osteosarcoma cell proliferation by causing G2/M phase cell cycle arrest associated with decreased expression of cyclin B1 and increased phosphorylation of Cyclin-dependent kinase-1(CDK1) and checkpoint kinase 2 (Chk2). In addition, piperine treatment inhibited phosphorylation of Akt and activated phosphorylation of c-Jun N-terminal kinase (c-JNK) and p38 mitogen-activated protein kinase (MAPK) in HOS and U2OS cells. Piperine induced colony formation in these two cell types. We proved that piperine could suppress the metastasis of osteosarcoma cells using scratch migration assays and Transwell chamber tests. Moreover, gelatin zymography showed that piperine inhibited the activity of matrix metalloproteinase (MMP)-2/-9 and increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1/-2. Taken together, our results indicate that piperine inhibits proliferation, by inducing G2/M cell cycle arrest, and the migration and invasion of HOS and U2OS cells, via increased expression of TIMP-1/-2 and down-regulation of MMP-2/-9. These findings support further study of piperine as a promising therapeutic agent in the treatment of osteosarcoma.
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Alcaloides/uso terapéutico , Benzodioxoles/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Inhibidores de Crecimiento/uso terapéutico , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Osteosarcoma/tratamiento farmacológico , Piper nigrum/química , Piperidinas/uso terapéutico , Alcamidas Poliinsaturadas/uso terapéutico , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/efectos de los fármacos , Quinasa de Punto de Control 2/metabolismo , Ciclina B1/genética , Ciclina B1/metabolismo , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Metástasis de la Neoplasia , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Regulación hacia ArribaRESUMEN
In this study, we used branches Ramulus mori from cultivated mulberry Husang-32 (Morus multicaulis Perry) as the experimental material and anhydrous ethanol as the extraction solution to obtain the crude extract from the branch bark. The ethanolic extract was successively purified through a macroporous resin, Sephadex LH-20, and semipreparative reversed-phase high-performance liquid chromatography (RP-HPLC). The high-purity monomer was identified as morusin by HPLC with diode array detection (HPLC-DAD) and its UV spectrum. The contents of morusin exhibited almost no difference between the root and branch bark in Husang-32, and morusin was not detected in the leaves. Morusin is able to inhibit the tumor growth of transplanted H22 hepatocarcinoma in mice and has no side effects. The fluorescence quantitative real-time PCR (qRT-PCR) results indicate that morusin has a marked inhibitory effect on liver cancer cells through a mechanism that may be related increases in the expression of p53, Survivin, CyclinB1, and Caspase-3 and a decrease in NF-κ B gene expression. The influence of this compound is more apparent in the Caspase-3 and the NF-κ B genes.
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Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Flavonoides/farmacología , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Morus/química , Corteza de la Planta/química , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Caspasa 3/genética , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Ciclina B1/agonistas , Ciclina B1/genética , Ciclina B1/metabolismo , Etanol , Flavonoides/aislamiento & purificación , Proteínas Inhibidoras de la Apoptosis/agonistas , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos ICR , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , FN-kappa B/metabolismo , Extractos Vegetales/química , Raíces de Plantas/química , Proteínas Represoras/agonistas , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Solventes , Survivin , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/agonistas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 µM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G2/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16(INK4a), p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.
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Compuestos de Bifenilo/farmacología , Proteínas de Ciclo Celular/metabolismo , Ciclo Celular/efectos de los fármacos , Lignanos/farmacología , Neoplasias de la Próstata/patología , Antineoplásicos Fitogénicos/farmacología , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Ciclina A/genética , Ciclina A/metabolismo , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Humanos , Magnolia/química , Masculino , Extractos Vegetales/farmacología , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
BACKGROUND: Commelina benghalensis (CB) is a small plant whose fleshy stems are used in South Africa to treat skin conditions (e.g., cancerous skin outgrowths). This study was aimed at evaluating the effect of sub-fractions of acetone extracts of CB stems on growth-associated molecular events of apoptosis and cell division cycle of Jurkat-T (JT) cells. METHODS: Acetone extract of CB stems were subfractioned into n-hexane (F1) and dichloromethane (F2) fractions. After treatment of JT cells with these subfractions, cell proliferation, viability and apoptosis were determined using a haemocytometer, the trypan blue dye exclusion assay, and Hoechst 33258 staining, respectively. Cell division cycle distribution profiles were analysed using an Epics Alba Flow Cytometer and the expression of cell division cycle regulatory genes was analysed using RT-PCR, while immunoreactive proteins were detected on western blots. RESULTS: The F1 and F2 fractions inhibited the proliferation and viability of JT cells in a concentration- and time-dependent manner, with IC50 values of 32.5 µg/mâ and 56 µg/mâ, respectively. The observed cytotoxicity was established to be a consequence of apoptosis. as verified using Hoechst staining method. Both fractions induced a G1/S interphase arrest of the cell division cycle of JT cells.RT-PCR analyses showed an up-regulatory effect by the F1 fraction in the expression of cyclin B1, cdc2 and bax, with a down-regulatory effect in the expression levels of bcl-2. Fraction F1 also increased the protein expression levels of p53 and its downstream regulators, p21 and Cdc2. However, protein Bax and p21 and p53 transcripts were undetectable under the same experimental conditions. On the other hand, fraction F2 increased the mRNA expression levels of bax, bcl-2, cyclin B1 and cdc2. Concomitantly, fraction F2 showed an up-regulation in the protein expression levels of Cdc2, Bcl-2, Cyclin B1 and p21. Despite the up-regulation in protein expression levels by fraction F2, there was no observable expression levels of the p53 protein and p21 and p53 mRNAs under similar experimental conditions. CONCLUSION: These findings suggest that the F1 and F2 fractions of CB may provide a valuable lead for the development of novel and effective anti-neoplastic drug(s).
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Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Commelina , Leucemia de Células T/metabolismo , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Proteína Quinasa CDC2 , Proteínas de Ciclo Celular/genética , Proliferación Celular/efectos de los fármacos , Ciclina B1/genética , Ciclina B1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Humanos , Células Jurkat , Leucemia de Células T/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/metabolismo , Sudáfrica , Linfocitos T/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Moscatilin, a bibenzyl derivative from the orchid Dendrobium loddigesii, has been shown to possess anticancer activity. We examined the effect of moscatilin on human esophageal cancer cells, including squamous cell carcinoma (SCC) and adenocarcinoma (ADC) cells and its possible mechanisms. Moscatilin suppressed the growth of both the histological cell lines in a dose- and time-dependent manner. Morphological changes indicative of apoptosis and mitotic catastrophe were observed following moscatilin treatment. The population of cells in the sub-G1 phase and polyploidy phase significantly increased after treatment. Immunofluorescence revealed multipolar mitosis and subsequent multinucleation in moscatilin-treated cells, indicating the development of mitotic catastrophe. Western blot showed a marked increase in expressions of polo-like kinase 1 and cyclin B1 after exposure to moscatilin. In conclusion, moscatilin inhibits growth and induces apoptosis and mitotic catastrophe in human esophageal SCC- and ADC-derived cell lines, indicating that moscatilin has broad potential against esophageal cancer.