RESUMEN
The World Health Organization (WHO) has reported that cancer is one of the most prevalent diseases and a leading cause of death worldwide. Many anticancer drug development studies have been pursued over the last few decades and several viable drugs have been discovered, such as paclitaxel, topotecan and irinotecan. Previously, our research group uncovered the cytocidal and cytostatic effects of the plant Stephania delavayi Diels. In this study, we determined the active chemical to be 6,7-di-O-acetylsinococuline (FK-3000). The FK-3000 half maximal inhibitory concentration (IC50) in MDA-MB-231 breast carcinoma cells at 48 h was 0.52 µg/ml and it induced apoptosis in a dose- and time-dependent manner. FK-3000 suppressed NF-κB nuclear translocation, decreased NF-κB phosphorylation, and decreased COX-2 protein expression. MDA-MB-231 xenografted mice were treated with FK-3000, Taxol, or their combination for 21 days. The tumor size was smallest in the co-treatment group, indicating that FK-3000 may have a synergistic effect with Taxol. FK-3000 treatment showed no adverse effects on blood cell counts, serum protein levels, or pathology. These studies demonstrate that FK-3000, isolated from S. delavayi Diels., is a promising, pathway-specific anticancer agent that exhibits low toxicity.
Asunto(s)
Alcaloides/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Ciclooxigenasa 2/metabolismo , Neoplasias Mamarias Experimentales/tratamiento farmacológico , FN-kappa B/metabolismo , Alcaloides/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Células HT29 , Humanos , Células MCF-7 , Masculino , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Fosforilación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We evaluated the cytostatic effect of 6,7-di-O-acetyl-sinococuline (FK-3000) isolated from Stephania delavayi Diels. against breast carcinoma cell lines MDA-MB231 and MCF-7. FK-3000 suppressed CDC25B phosphorylation directly and indirectly via p38 MAPK phosphorylation. CDC25B dephosphorylation decreased levels of cyclin B and phospho-CDC-2, and ultimately induced cell cycle arrest at the G2/M phase. The p38 MAPK inhibitor, SB 239063 blocked FK-3000-induced p38 MAPK phosphorylation and nuclear accumulation, but did not completely rescue cell death. Conclusively FK-3000 exerts its antiproliferative effect through two pathways: i) G2/M cell cycle arrest via downregulation of cyclin B and phospho-CDC2 by p38 MAPK phosphorylation and CDC25B dephosphorylation, and ii) p38 MAPK-independent induction of apoptosis.
Asunto(s)
Alcaloides/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Fosfatasas cdc25/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/biosíntesis , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma/genética , Carcinoma/patología , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Fosforilación , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
The World Health Organization reports that 235 million people are currently affected by asthma. This disease is associated with an imbalance of Th1 and Th2 cells, which results in the upregulation of cytokines that promote chronic inflammation of the respiratory system. The inflammatory response causes airway obstruction and can ultimately result in death. In this study we evaluated the effect of 1'-acetoxychavicol acetate (ACA) isolated from Alpinia galanga rhizomes in a mouse model of ovalbumin (OVA)-induced asthma. To generate the mouse model, BALB/c mice were sensitized by intraperitoneal injection of OVA and then challenged with OVA inhalation for 5 days. Mice in the vehicle control group were sensitized with OVA but not challenged with OVA. Treatment groups received dexamethasone, 25 mg/kg/day ACA, or 50 mg/kg/day ACA for 5 days. Asthma-related inflammation was assessed by bronchoalveolar lavage fluid cell counts and histopathological and immunohistochemical analysis of lung tissues. Our results showed that ACA reduced the infiltration of white blood cells (especially eosinophils) and the level of IgE in the lungs of mice challenged with OVA and suppressed histopathological changes such as airway remodeling, goblet-cell hyperplasia, eosinophil infiltration, and glycoprotein secretion. In addition, ACA inhibited expression of the Th2 cytokines interleukin (IL)-4 and IL-13, and Th1 cytokines IL-12α and interferon-γ. Because asthmatic reactions are mediated by diverse immune and inflammatory pathways, ACA shows promise as an antiasthmatic drug candidate.
Asunto(s)
Alpinia/química , Antiasmáticos/uso terapéutico , Asma/inducido químicamente , Asma/tratamiento farmacológico , Alcoholes Bencílicos/uso terapéutico , Ovalbúmina/farmacología , Animales , Antiasmáticos/química , Asma/metabolismo , Alcoholes Bencílicos/química , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Ratones , Ratones Endogámicos BALB CRESUMEN
FK-3000 can inhibit proliferation of carcinomas and arrest the growth of carcinoma cells through cytotoxic (apoptosis induction) and cytostatic (cell cycle arrest) effects. A rapid and sensitive assay was developed and validated using liquid chromatography-mass spectrometry (LC-MS) for FK-3000 in rat plasma. FK-3000 was extracted with ethyl acetate from rat plasma samples, and the residue containing the FK-3000 was dried in a gentle stream of nitrogen and reconstituted with acetonitrile. The FK-3000 was quantified using high-performance liquid chromatography (HPLC; Waters Alliance 2695) with a reversed phase Gemini column (3 mm × 150 mm, 5 µm; Phenomenex, USA) and a Waters Micromass ZQ detector. FK-3000 and phenazine, an internal standard (IS), were analyzed by selected ion monitoring (SIM) at m/z transitions of 418.45 and 256, respectively. A lower limit of quantification (LLOQ) of 10 ng/mL was observed, with a linear dynamic range from 10 to 10,000 ng/mL (R>0.999). The accuracy, precision, recovery, matrix effects, and stability of the assay were deemed acceptable according to the FDA guidance for industry (bioanalytical method validation). The FK-3000 concentration was measured in plasma samples up to 6 h following FK-3000 administration at an oral dose of 20 mg/kg. The findings indicate that the assay method is suitable for routine pharmacokinetic (PK) studies of FK-3000 in rats.
Asunto(s)
Alcaloides/sangre , Alcaloides/farmacocinética , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacocinética , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Espectrometría de Masa por Ionización de Electrospray , Acetatos/química , Acetonitrilos/química , Administración Oral , Alcaloides/administración & dosificación , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Calibración , Cromatografía Líquida de Alta Presión/normas , Cromatografía de Fase Inversa/normas , Estabilidad de Medicamentos , Límite de Detección , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de Electrospray/normasRESUMEN
The nuclear factor κB (NF-κB)/inhibitor of κ kinase-ß (IKKß) signaling pathway is important in tumor promotion and progression. MDA-MB-231 human breast carcinoma cells express COX-2 and show a constitutive phosphorylation of NF-κB. Many non-specific inhibitors of IKKß and NF-κB are used to inhibit tumor promotion and progression. The Stephania delavayi Diels. (S. delavayi Diels.) extract has been reported to safely activate B cell immunity and there is evidence suggesting that it may be a promising new anticancer therapeutic agent. S. delavayi Diels. extract suppressed proliferation of the breast cancer cell lines MDA-MB-231 and MCF-7 by inducing cell death. To aid in the development of the S. delavayi Diels. extract as a therapeutic agent, its mechanisms of action were investigated, in particular its effects on p38 MAPK, NF-κB and COX-2, which play important roles in inflammation and cancer. S. delavayi Diels. stimulated p38 MAPK phosphorylation but reduced NF-κB phosphorylation and COX-2 expression in a dose- and time-dependent manner. Thus, S. delavayi Diels., which appears to act primarily through p38 MAPK/NF-κB/COX-2 signaling in breast carcinomas, may be a potent anticancer agent with target specificity and low toxicity.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Helechos/química , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclooxigenasa 2/biosíntesis , Femenino , Humanos , Ratones , Ratones Desnudos , Fosforilación , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/farmacologíaRESUMEN
Quinone type compound, pulsaquinone 1, isolated from the aqueous ethanol extract of the roots of Pulsatilla koreana exhibited antimicrobial activities against an anaerobic non-spore-forming gram-positive bacillus, Propionibacterium acnes, which is related with the pathogenesis of the inflamed lesions in a common skin disease, acne vulgaris. Compound 1 was unstable on standing and thus converted to more stable compound 2, namely hydropulsaquinone by hydrogenation, whose activity was comparable to mother compound 1 (MIC for 1 and 2 against P. acnes: 2.0 and 4.0 microg/mL, respectively). Other structurally-related quinone derivatives (3-13) were also tested for structure-activity relationship against anaerobic and aerobic bacteria, and fungi. The antimicrobial activity was fairly good when the quinone moiety was fused with a nonpolar 6- or 7-membered ring on the right side whether or not conjugated (1,4-naphtoquinone derivatives 3-5), while simple quinone compounds 6-9 showed poor activity. It seems that the methoxy groups at the left side of the quinone function deliver no considerable antimicrobial effect.
Asunto(s)
Acné Vulgar/tratamiento farmacológico , Antibacterianos/farmacología , Propionibacterium acnes/efectos de los fármacos , Quinonas/farmacología , Ranunculaceae , Acné Vulgar/microbiología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antifúngicos/farmacología , Bacterias Aerobias/efectos de los fármacos , Estabilidad de Medicamentos , Hongos/efectos de los fármacos , Hongos/crecimiento & desarrollo , Hidrogenación , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Extractos Vegetales/farmacología , Raíces de Plantas , Propionibacterium acnes/crecimiento & desarrollo , Quinonas/química , Quinonas/aislamiento & purificación , Ranunculaceae/química , Relación Estructura-ActividadRESUMEN
Two new C(14) polyacetylenes dendrazawayne A(7) and dendrazawayne B (9) together with known C(13) polyacetylenes (2, 3), C(14) polyacetylenes (1, 4, and 8) and polyacetylene amides (5 and 6) were isolated from the roots of Dendranthema zawadskii. The structures of 7 and 9 were elucidated based on spectroscopic methods including 2D-NMR, HR-TOF-MS, IR, and UV. Compounds 1, 2, 3, 5, and 6 showed moderate activity against tumor cell lines (human small lung cancer cell line A549, melanoma SK-Mel-2, and mouse melanoma B16F1) with IC(50) values in the range of 7.4 - 30 microg/mL. Compounds 7 and 9, including other polyacetylenes, showed strong activity against the fungus Trichophyton (MIC: 5 - 10 microg/mL).
Asunto(s)
Antifúngicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Asteraceae , Fitoterapia , Extractos Vegetales/farmacología , Poliinos/farmacología , Trichophyton/efectos de los fármacos , Animales , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Raíces de Plantas , Poliinos/administración & dosificación , Poliinos/uso terapéuticoRESUMEN
Bioassay-guided purification of a methanol extract from Amomum tsao-ko led to the isolation of the bicyclic nonane isotsaokoin (1) as the major active principle, an isomer of the previously reported tsaokoin (2). The stereochemical relationship of 1 and 2 was investigated by NOE experiments and Mosher ester derivatization. Compound 1 showed antifungal activity against Trycophyton mentagrophytes.