RESUMEN
The quinolinium chloride salt of 8-hydroxyqinolinecarbaldehyde (2-Formyl-8-hydroxy-quinolinium chloride) was prepared as Galipea longiflora alkaloid analogue and its anticancer activity was evaluated both in vitro and in vivo. This chloride salt was found to show certain degree of selectivity between hepatoma cells and normal hepatocytes in vitro. Athymic nude mice Hep3B xenograft model further demonstrated that this 2-Formyl-8-hydroxy-quinolinium chloride could execute strong anti-tumour activity with the identification of extensive necrotic feature from the tumour xenograft and limited adverse toxicological effect.
Asunto(s)
Alcaloides/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Compuestos de Quinolinio/uso terapéutico , Rutaceae/química , Alcaloides/farmacocinética , Alcaloides/farmacología , Animales , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Cloruros/farmacocinética , Cloruros/farmacología , Cloruros/uso terapéutico , Hepatocitos/efectos de los fármacos , Xenoinjertos , Técnicas In Vitro , Ratones Endogámicos C57BL , Ratones Desnudos , Necrosis , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , Compuestos de Quinolinio/farmacocinética , Compuestos de Quinolinio/farmacología , Sales (Química)RESUMEN
Ethanol has been commonly used as a vehicle for drug discovery purpose in vitro. The human breast cancer MCF-7 estrogen dependent cell line is a common in vitro model used for hormonal therapy study. However, special precaution is suggested when ethanol is used in pharmacological tests as solvent in order to evaluate the biological activity of potential drugs especially concerning about the MCF-7. Ethanol was shown to stimulate the proliferation of this estrogen receptor positive cell line. Here, we have further demonstrated that the dose responsive stimulatory effect of ethanol on the MCF-7 cells after pre-incubating the breast carcinoma cells with phenol red-free medium and stripped fetal bovine serum. Our findings open a discussion for the evaluation of ethanol as solvent for drug discovery and screening when using MCF-7 cells as a testing model.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Portadores de Fármacos/farmacología , Etanol/farmacología , Células MCF-7/efectos de los fármacos , Humanos , Receptores de Estrógenos/metabolismo , Solventes/farmacologíaRESUMEN
This work describes the preparation of quinoline compounds as possible anti-bacterial agents. The synthesized quinoline derivatives show anti-bacterial activity towards Staphylococcus aureus. It is interesting to observe that the synthetic 5,7-dibromo-2-methylquinolin-8-ol (4) shows a similar minimum inhibitory concentration of 6.25µg/mL as compared to that of methicillin (3.125µg/mL) against Staphylococcus aureus.
Asunto(s)
Antibacterianos/farmacología , Oxiquinolina/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Muerte Celular/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxiquinolina/síntesis química , Oxiquinolina/química , Relación Estructura-ActividadRESUMEN
We explore the possible cellular cytotoxic activity of an amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B under ambient light experimental environment as well as its in vivo antitumour potential using Hep3B hepatoma cell model. After loading into the Hep3B hepatoma cells, induction of cellular cytotoxicity and cell cycle arrest were detected. Strong growth inhibition of tumour xenograft together with significant tumour necrosis and limited toxicological effects exerted on the nude mice could be identified.
Asunto(s)
Antineoplásicos/farmacología , Indoles/química , Indoles/farmacología , Rodaminas/química , Rodaminas/farmacología , Silicio/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Isoindoles , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Desnudos , Distribución Aleatoria , Silicio/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In this study, a novel green microencapsulation system was used to develop Phyllanthus urinaria (PU) extract containing microcapsules. Agar was used with gelatin as the wall matrix materials of microcapsules to prevent the use of toxic crosslinker formaldehyde. Microencapsulated PU extract was developed to improve the potential antifungal activities of PU water extracts. The active components and surface morphology of PU extract containing microcapsules were analyzed by liquid chromatography/mass spectrometry and scanning electron microscopy, respectively. The in vitro release study demonstrated that approximately 80% of drug was released after 120 h. PU loaded microcapsules were shown to have a stronger anti-Aspergillus niger activity than the free drug.
Asunto(s)
Aspergillus niger , Composición de Medicamentos , Phyllanthus/química , Extractos Vegetales , Agar/química , Antifúngicos/química , Antifúngicos/farmacología , Aspergillus niger/efectos de los fármacos , Aspergillus niger/patogenicidad , Cápsulas/química , Cápsulas/farmacología , Gelatina/química , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
We have investigated the potential in vivo anti-tumour activity of corilagin using the Hep3B hepatocellular carcinoma cell line and an athymic nude mice xenograft model. The purity of corilagin was confirmed by high performance liquid chromatographic analysis. Corilagin was administrated intraperitoneally for a continuous period of 7 days at a concentration of 15 mg/kg of body weight per day. A significant inhibition of tumour growth was observed when treated mice are compared with control groups. Furthermore, analysis of enzymes markers of liver function, including alanine aminotransferase and asparate aminotransferase, suggested that current therapeutic dosage of corilagin did not exert adverse effect on liver. Our observations support the view that corilagin is considerably effective to retard the in vivo growth of xenografted Hep3B hepatocellular carcinoma.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Glucósidos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Glucósidos/administración & dosificación , Glucósidos/farmacología , Humanos , Taninos Hidrolizables , Hígado/efectos de los fármacos , Hígado/enzimología , Ratones , Ratones Desnudos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Acetaminophen is a commonly used drug for the treatment of patients with common cold and influenza. However, an overdose of acetaminophen may be fatal. In this study we investigated whether mice, administered intraperitoneally with a lethal dose of acetaminophen, when followed by oral administration of Phyllanthus urinaria extract, may be prevented from death. Histopathological analysis of mouse liver sections showed that Phyllanthus urinaria extract may protect the hepatocytes from acetaminophen-induced necrosis. Therapeutic dose of Phyllanthus urinaria extract did not show any toxicological phenomenon on mice. Immunohistochemical staining with the cytochrome P450 CYP2E1 antibody revealed that Phyllanthus urinaria extract reduced the cytochrome P450 CYP2E1 protein level in mice pre-treated with a lethal dose of acetaminophen. Phyllanthus urinaria extract also inhibited the cytochrome P450 CYP2E1 enzymatic activity in vitro. Heavy metals, including arsenic, cadmium, mercury and lead, as well as herbicide residues were not found above their detection limits. High performance liquid chromatography identified corilagin and gallic acid as the major components of the Phyllanthus urinaria extract. We conclude that Phyllanthus urinaria extract is effective in attenuating the acetaminophen induced hepatotoxicity, and inhibition of cytochrome P450 CYP2E1 enzyme may be an important factor for its therapeutic mechanism.
Asunto(s)
Acetaminofén/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Inhibidores del Citocromo P-450 CYP2E1 , Hígado/metabolismo , Phyllanthus , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/mortalidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Ácido Gálico/aislamiento & purificación , Ácido Gálico/farmacología , Ácido Gálico/uso terapéutico , Glucósidos/aislamiento & purificación , Glucósidos/farmacología , Glucósidos/uso terapéutico , Hepatocitos/efectos de los fármacos , Taninos Hidrolizables , Hígado/patología , Metales Pesados/análisis , Ratones , Ratones Endogámicos C57BL , Necrosis/tratamiento farmacológico , Phyllanthus/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plantas Medicinales/químicaRESUMEN
A series of 2,6-dimethoxylpyridinyl phosphine oxides have been synthesized and examined for their antitumor activity. 2,6-Dimethoxy-3-phenyl-4-diphenylphosphinoylpyridine 2 has been employed as the lead compound for this study. We found out that the presence of phosphine oxide on the 2,6-dimethoxylpyridine ring is important for the antitumor activity; the presence of bromine on this core leads to a further enhancement of its antitumor activity. This is the first reported work on the antitumor activity of the 2,6-dimethoxy-3,5-dibromopyridinyl phosphine oxide 5b towards MDAMB-231 breast cancer and SKHep-1 hepatoma cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Óxidos/síntesis química , Fosfinas/síntesis química , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Óxidos/uso terapéutico , Fosfinas/uso terapéuticoRESUMEN
The 'one pot' condensation reaction for the synthesis and potent antiproliferative inhibition of alpha-phthalimide based ketones is reported here. 2-Phthalimide-1-(4-fluoro-phenyl)ethanone (5) showed the best growth inhibition on human MDAMB-231 breast carcinoma and SKHep-1 hepatoma cell lines. Preliminary studies showed that the reported bioactivity may be due to the presence of strong electronegative fluorine group at the para-position of the aryl ring.
Asunto(s)
Cetonas/síntesis química , Cetonas/farmacología , Neoplasias/patología , Ftalimidas/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cetonas/química , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Esterification of acetate with generic pharmaceutical compound has been commonly employed to produce ester prodrug for improving its potency when compared with the mother compound. Acetate, on the other hand, has been recognized to have inhibitory effect on the respiratory biochemistry. Here we demonstrate that acetate at a concentration of 400 microM exhibited significant growth inhibitory activity on two human cancer cell lines, the MDAMB-231 breast cancer and the SKHep-1 hepatoma cell lines. To establish the ester prodrug with multi-acetate ester conjugates as our experimental model, one molecule of (-)-epigallocatechin gallate was required to conjugate with eight molecules of acetate forming the corresponding (-)-epigallocatechin gallate octaacetate prodrug. Chemical structure of this epigallocatechin gallate octaacetate ester prodrug was confirmed by both 13C and 1H nuclear magnetic resonance spectra and mass spectrometry. Further cytotoxic assay using both MDAMB-231 and SKHep-1 human carcinoma cell lines showed that acetate at a concentration of 400 microM exhibits an additional cytotoxic effect with (-)-epigallocatechin gallate at a concentration of 50 microM, although the additional effect was not as high as (-)-epigallocatechin gallate octaacetate ester prodrug alone at a concentration of 50 microM. Our results thus raise a pharmacological consideration of using multi-acetate conjugate as the ester prodrug where the release of free acetate by esterase could be part of the explanation for the improved in vitro cytotoxicity.
Asunto(s)
Acetatos/farmacología , Neoplasias de la Mama/patología , Carcinoma Hepatocelular/patología , Catequina/análogos & derivados , Profármacos/farmacología , Acetatos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Catequina/química , Catequina/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Profármacos/síntesis química , Profármacos/químicaRESUMEN
Phthalic anhydride is a highly toxic substance, facing, however, the problem of hydrolysis. In fact, it is rapidly hydrolyzed in aqueous medium, generating phthalic acid as the final product, which is almost harmless to viable cells. Here we describe the 'one pot' condensation reaction for the synthesis of phthalic imide derivative (benzothiazole containing phthalimide), exhibiting in vitro cytotoxic potential on human cancer cell lines. We further demonstrated that both caspase-dependent and -independent pathways are involved in our novel benzothiazole containing phthalimide induced apoptosis on cancer cells.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzotiazoles/química , Carcinoma/patología , Ftalimidas/síntesis química , Ftalimidas/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Línea Celular Tumoral , Fenómenos Químicos , Química Física , Humanos , Estructura Molecular , Ftalimidas/química , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
There are several scientific approaches for the determination of cellular growth influences of known or novel substances under in vitro conditions, among which colourimetric absorption measurement is considered to be one of the convenient methods. [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay is one of the commonly used colourimetric absorption assays based on the ability of dehydrogenase from viable cells to produce the brown soluble formazan detectable at 490 nm. Here we have tested the possible growth influence of iron (II) sulphate on two human cancer cell lines, the K562 chronic myelogenous leukaemia and T47D breast carcinoma cells, based on the MTS assay. We found that iron (II) sulphate possessed an inhibitory effect when added at 16- to 125-microM concentrations, but iron (II) sulphate became growth stimulatory when its concentration was further increased to 1000 microM. In addition, a dose-dependent increase in absorbance at the same wavelength was observed when we repeated the experiments without the addition of MTS and phenazine methosulfate. When we further repeated the cell growth determinations using adenosine triphosphate content assay for K562 and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for T47D, iron (II) sulphate showed a consistent dose-dependent growth inhibitory effect. Morphological investigation after methylene blue staining clearly demonstrated that iron (II) sulphate, at a concentration of 1000 microM, is cytotoxic to T47D cells. Interestingly, a consistent increment for the absorbance at 490 nm was further observed with increased iron (II) sulphate concentration either in the presence or absence of MTS even in a cell-free environment. Thus we conclude that iron (II) sulphate is actually growth inhibitory and even cytotoxic at high concentrations towards the K562 and T47D cancer cells and the paradoxical proliferative activity of iron (II) sulphate on these two cancer cell lines using the MTS assay was solely due to the oxidation of initial pale green iron (II) to brownish iron (III) during incubation in the aqueous condition.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Compuestos de Hierro/farmacología , Neoplasias/patología , Sulfatos/farmacología , Sales de Tetrazolio/farmacología , Tiazoles/farmacología , Neoplasias de la Mama/patología , Carcinoma/patología , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Tumorales CultivadasRESUMEN
Cantharidin isolated from Mylabris caraganae and other insects has been used as an anti-cancer drug in China for many years. However, its toxicity on the renal system and suppression effect on bone marrow limits its usage clinically. A synthetic analogue of cantharidin (CAN 037) has been shown to have cytotoxic effect on the SK-Hep 1 hepatoma cell line but its underlying working principle remains undefined. Here we further report the action of CAN 037 on an acute myelogenous leukaemia (AML) cell line, KG1a. [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay was used to demonstrate the cytotoxicity of CAN 037 on KG1a cells. Morphological changes of CAN 037-treated leukaemia cells were recorded under an inverted microscope. Possible activation of caspase 3, 8 and 9 from KG1a cells was also investigated. KG1a AML cells were sensitive to CAN 037. Morphological changes including cell shrinkage and loss of colony formation ability were observed. Caspase 3, 8 and 9 activity was elevated, whereas pre-incubating the KG1a cells with the generic caspase inhibitor z-VAD-fmk could only partially reverse the CAN 037-induced cell death. In addition to the SK-Hep-1 hepatoma cell line, CAN 037 is also effective in inducing the death of KG1a AML cells in vitro. Apoptosis is involved in the action of CAN 037 including the activation of the caspase family. Caspase-dependent cell death pathway may be necessary but not essential in CAN 037-induced apoptosis of KG1a cells. Further consideration of the structural activity relationship of CAN 037 may provide opportunities to improve its therapeutic value.
Asunto(s)
Apoptosis/efectos de los fármacos , Cantaridina/toxicidad , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Cantaridina/análogos & derivados , Cantaridina/síntesis química , Cantaridina/química , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Pruebas Inmunológicas de Citotoxicidad , Relación Dosis-Respuesta a Droga , Humanos , Leucemia Mieloide/patología , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-ActividadRESUMEN
Chinese practitioners have employed the use of traditional Chinese medicine as an anti-cancer agent since the ancient period. Different combinations have been formulated for various purposes. Some have been claimed for post-chemotherapy use but their direct actions on cancer cells may not be significantly reported. In the present study, we have tested the possible anti-leukemia potential of a combination regimen including crocodile egg extract, wild radix ginseng and natural Ganoderma lucidum (CGG extract) on acute myelogenous leukemia (AML) in vitro. A water soluble CGG extract was prepared and its antiproliferative activity was tested on the KG1a AML cell line and two freshly prepared bone marrow aspirate samples isolated from patients with de novo AML during presentation by a MTS/PMS assay. Furthermore, the possible activity of the CGG extract on the regeneration potential of KG1a cells was also investigated using a semi-solid methyl-cellulose colony formation assay. Lastly, the acute toxicity of CGG extract was further examined by a single high-dose oral feeding to rats. We found that the CGG extract could possess significant antiproliferative activity on AML cells. A strong colony formation inhibition was further demonstrated on KG1a cells. After feeding the rats with an excessive dose of CGG extract, we observed no development of acute toxicity. We concluded that the CGG extract has growth inhibitory potential on KG1a cells and AML bone marrow samples in vitro. An in vivo toxicity test revealed that no acute toxicity was observed after feeding the rats a high dosage of the CGG extract. Further animal model tests are necessary to investigate the possible chronic toxicity of the CGG extract.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Caimanes y Cocodrilos , Animales , Células de la Médula Ósea/efectos de los fármacos , Extractos Celulares , Línea Celular Tumoral , Huevos , Humanos , Masculino , Panax/química , Fitoterapia , Preparaciones de Plantas/farmacología , Ratas , Reishi/químicaRESUMEN
Cantharidin isolated from Mylabris caraganae and other insects is used traditionally as an anti-cancer drug especially on hepatoma and leukaemia. Previously, we demonstrated that the novel synthetic cantharidin analogue CAN 032 possessed apoptotic activity on two human hepatoma cell lines Hep3B hepatocellular carcinoma and SK-Hep-1 liver adenocarcinoma. However, its underlying mechanistic action on cancer cells remained unclear. Herein, we furthered our work by making use of KG1a acute myelogenous leukaemia (AML) and K562 chronic myelogenous leukaemia (CML) as experimental models. As anticipated, both leukaemia cell lines were sensitive to the cytotoxic action of CAN 032. The activity of CAN 032 was both dose- and time-course-dependent. CAN 032 readily inhibited the colony formation potential of both leukaemia cell lines. KG1a AML treated with CAN032 decreased G1 phase cell population, mitochondrial membrane potential collapse, caspase 3 activation and hence DNA fragmentation. Pre-incubation of leukaemia cells with the general caspase inhibitor Z-VAD-FMK could partially reversed the apoptotic action of CAN 032. This result suggested that the caspase- dependent pathway is necessary for the apoptotic action of CAN 032. CAN 032 provides a new direction for novel drug discovery in experimental cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Cantaridina/análogos & derivados , Línea Celular Tumoral/efectos de los fármacos , Leucemia Mieloide , Tiazoles/farmacología , Adulto , Animales , Antineoplásicos/síntesis química , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Cantaridina/síntesis química , Cantaridina/farmacología , Ciclo Celular , Células Cultivadas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Etiquetado Corte-Fin in Situ , Insectos , Masculino , Mitocondrias/metabolismo , Tiazoles/síntesis químicaRESUMEN
The possible anti-proliferation and cell death induction potential of a novel microbial fermentation extract named as oncogen XP-180 (or simply as XP-180) was tested on three human solid tumour carcinoma cell lines (non-small cell lung cancer A549, breast cancer MDA-MB231, liver adenocarcinoma SK-Hep1) and on the acute myelogenous leukaemia KG1a cell line. Anti-proliferative activity of XP-180 was observed on all of these cancer cell lines with comparable efficiency and in a dose-dependent manner. Morphological investigation further suggested that common features of apoptosis, including cell shrinkage and rounding, are present in XP-180 treated cells. Loss of adhesion properties of these solid tumour cell lines was observed upon XP-180 incubation. Anchorage-dependent clonogenicity assay on solid tumour cell lines and semi-solid methylcellulose colony formation assay on leukaemia cell line further revealed that XP-180 strongly inhibited the regeneration potential of these cancer cells. Using KG1a as an experimental model system, XP-180 was shown to stimulate the activity of caspase 3, 8 and 9 without significant change in caspase 6 activity. Furthermore, XP-180 readily induced collapse of mitochondrial membrane potential after 2 h of incubation. However, the use of the generic caspase specific inhibitor Z-VAD-FMK does not significantly reverse XP-180 mediated cell death. The results obtained suggest that XP-180-mediated cancer cell death could involve mitochondria and both caspase-dependent and -independent pathways. Therefore, XP-180 is an efficient anti-cancer regimen in vitro.
Asunto(s)
Antineoplásicos/farmacología , Bacterias/química , Clorometilcetonas de Aminoácidos/farmacología , Apoptosis/efectos de los fármacos , Bacterias/metabolismo , Productos Biológicos/farmacología , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Caspasa 3 , Caspasa 8 , Caspasa 9 , Inhibidores de Caspasas , Caspasas/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidores de Cisteína Proteinasa/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Fermentación , Humanos , Potenciales de la Membrana/efectos de los fármacos , Membranas Mitocondriales/fisiología , Ensayo de Tumor de Célula MadreRESUMEN
We have recently demonstrated the antiproliferative and apoptotic activities of herbal traditional Chinese medicines, including the analomous fruit extract of Gleditsia sinensis, the fresh juice of Scutellaria barbata and the warmed water extract of Radix Sophorae Tonkinensis on a series of human carcinoma cells. Here, we further report the potential anti-cancer activity of the warmed water extract of Brucea javanica (BJE). Four cancer cell lines, including A549 non-small cell lung cancer, Hep3B hepatocellular carcinoma, MDA-MB231 breast cancer and SLMT-1 oesophageal squamous cell carcinoma, were incubated with BJE and strong apoptotic induction was observed under inverted microscopic investigation for all of the four cell lines tested. Using the MDA-MB231 breast cancer cell line as an experimental model, additional analyses supported the hypothesis that the mitochondrial membrane potential depolarization pathway was induced by BJE. The APO-1/Fas receptor death induction pathway was not activated under the influence of BJE, as studied by staining with Fas ligand and Fas receptor specific antibodies. Accordingly, only weak activation of caspase 8 was observed upon BJE treatment. On the other hand, caspase 3 activity was stimulated up to five-fold in BJE-treated cells compared to untreated controls. Oligonucleosomal DNA fragmentation formation was detected by labelling the nucleic acid ladders with TdT-mediated dUTP nick end labelling. Collectively, BJE-induced cancer cell death proceeds through a mitochondrial dependent pathway associated with caspase 3 activation.
Asunto(s)
Apoptosis/efectos de los fármacos , Brucea/química , Neoplasias/patología , Fitoterapia , Extractos Vegetales/farmacología , Médula Ósea/efectos de los fármacos , Caspasa 3 , Caspasa 8 , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Humanos , Potenciales de la Membrana/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Receptor fas/metabolismoRESUMEN
The anomalous fruit extract of Gleditsia sinensis (GSE) was shown to possess anticancer potential on various solid tumour and leukaemia cell lines in vitro. We have recently demonstrated that the mitochondrial-dependent apoptotic pathway including mitochondrial membrane potential depolarization, changes in the level of reactive oxygen species and activation of caspase 3 were recruited in GSE-induced apoptosis. Whether receptor-dependent APO-1/Fas apoptotic pathway is also involved remains uncertain. Using two solid tumour cell lines, the HepG2 hepatoblastoma carcinoma cells and MDA-MB231 breast cancer cells, we demonstrated that the Fas ligand and Fas receptor protein levels did not have significant variation after GSE incubation. Caspase 8 activity increased only weakly when compared with that of caspase 3. The chrymotrypsin-like activity of proteasome was partially inhibited up to 30-40% when compared with the untreated control. Taken together, we believe that GSE- mediated apoptosis on HepG2 and MDA-MB231 carcinoma cells is mainly dictated by the mitochondrial-dependent pathway while inhibition of proteasome activity may also be involved in GSE-induced apoptosis.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis , Carcinoma/enzimología , Medicamentos Herbarios Chinos/farmacología , Gleditsia/química , Inhibidores de Proteasoma , Caspasa 3 , Caspasa 8 , Caspasas/metabolismo , Línea Celular Tumoral , Proteína Ligando Fas , Frutas/química , Humanos , Glicoproteínas de Membrana/metabolismo , Factores de Necrosis Tumoral/metabolismo , Receptor fas/metabolismoRESUMEN
Astaxanthin has been shown to have antiproliferative activity on breast cancer and skin cancer cells. However, the high cost of production, isolation and purification of purified astaxanthin from natural sources or chemically synthetic methods limit its usage on cancer therapy. We show that astaxanthin could be produced by fermentating the Phaffia rhodozyma (Xanthophyllomyces dendrorhous) yeast cells with brewer malt waste using a 20 L B. Braun fermentor. The percentage composition of astaxanthin from the P. rhodozyma was >70% of total pigment as estimated by the high performance liquid chromatographic analysis. Furthermore, the antiproliferative activity of this P. rhodozyma cell extract (PRE) was demonstrated on breast cancer cell lines including the MCF-7 (estrogen receptor positive) and MDA-MB231 (estrogen receptor negative) by using the [3-(4,5-dimethylthiazol-2-yl)-5-(3-arboxymethoxyphenyl)-2- (4-sulfophenyl)-2H-tetrazolium] (MTS) assay. No apoptotic cell death, but growth inhibitory effect was induced after 48 h of PRE incubation as suggested by morphological investigation. Anchorage-dependent clonogenicity assay showed that PRE could reduce the colony formation potential of both breast cancer cell lines. Cell death was observed from both breast cancer cell lines after incubation with PRE for 6 days. Taken together, our results showed that by using an economic method of brewer malt waste fermentation, we obtained P. rhodozyma with a high yield of astaxanthin and the corresponding PRE could have short-term growth inhibition and long-term cell death activity on breast cancer cells.
Asunto(s)
Antibióticos Antineoplásicos/biosíntesis , Antibióticos Antineoplásicos/uso terapéutico , Basidiomycota/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , beta Caroteno/análogos & derivados , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fragmentación del ADN , Grano Comestible/metabolismo , Femenino , Fermentación , Humanos , Residuos , Xantófilas , beta Caroteno/biosíntesis , beta Caroteno/uso terapéuticoRESUMEN
Recently, we have shown that the anomalous fruit extract of Gleditsia sinensis (GSE) processes apoptotic activity on numerous solid tumour and leukaemia cell lines as well as primary cultured leukaemia cells obtained from bone marrow aspirate of patients. GSE treated cancer cells exhibited apoptotic features as readily illustrated by morphological investigation, DNA fragmentation analysis and TUNEL labelling methods. Elevation of intracellular superoxide dismutase activity was observed. However, the detailed mechanism still remains undefined. Here we further demonstrated that cell cycle arrest, increment of hydrogen peroxide production, changes of intracellular acid-base equilibrium and mitochondrial membrane potential depolarization (DeltaPsi(m)) were induced from cancer cells after GSE incubation. Caspase 3 protease activity was significantly enhanced upon GSE treatment. Taken together, a defined signaling pathway for the mechanistic action of GSE on cancer cells was worked out.