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1.
Carbohydr Polym ; 255: 117370, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33436203

RESUMEN

Natural polysaccharides have attracted considerable interests due to diverse biological activities. Succinoglycan is an extracellular polysaccharide produced by most Agrobacterium strains. Here, we confirmed riclin was a typical succinoglycan by NMR and methylation analysis, and investigated the antitumor effects of riclin in sarcoma 180 tumor-bearing mice. The results showed that riclin inhibited the tumor growth significantly as well as cyclophosphamide (CTX). While CTX caused serious damage to spleen structure, riclin increased the spleen index and promoted lymphocytes proliferation in peripheral blood, spleen and lymph nodes. Riclin decreased splenocytes apoptosis as evidenced by alterations of B-cell lymphoma-2 family proteins and Cleaved Caspase-3 protein. Moreover, 1H nuclear magnetic resonance (NMR)-based metabolomics analysis revealed that riclin partially altered the metabolic profiles of splenocytes. In conclusion, riclin is a succinoglycan that performed strong immunogenicity and suppressed sarcoma growth in mice. Succinoglycan riclin could be a potential antitumor agent for functional food and pharmaceutical purpose.


Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica , Factores Inmunológicos/farmacología , Linfocitos/efectos de los fármacos , Polisacáridos Bacterianos/farmacología , Sarcoma 180/tratamiento farmacológico , Agrobacterium/química , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Carbohidratos , Caspasa 3/genética , Caspasa 3/inmunología , Proliferación Celular/efectos de los fármacos , Ciclofosfamida/farmacología , Factores Inmunológicos/química , Factores Inmunológicos/aislamiento & purificación , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Linfocitos/inmunología , Linfocitos/patología , Masculino , Metaboloma/inmunología , Metilación , Ratones , Ratones Endogámicos C57BL , Polisacáridos Bacterianos/química , Polisacáridos Bacterianos/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Sarcoma 180/genética , Sarcoma 180/inmunología , Sarcoma 180/patología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Carga Tumoral/efectos de los fármacos
2.
Carbohydr Polym ; 255: 117532, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33436261

RESUMEN

Aldolase A (ALDOA) facilitated aerobic glycolysis in cancer cells is a potential target in the treatment of hepatocellular carcinoma (HCC). However, only few effective inhibitors of ALDOA have been reported until now. In this research, we found a polysaccharide called HDPS-4II from Holotrichia diomphalia Bates, which can specifically bind to ALDOA with a dissociation constant of 2.86 µM. HDPS-4II with a molecular weight of 19 kDa was a linear triple-helix glucan composed of ɑ-d-1,4-Glcp and ɑ-d-1,6-Glcp in a ratio of 1.0:10.0. HDPS-4II significantly inhibited aldolase enzyme activity, glycolysis, and further inhibited the expression of phosphorylated AMPKα in HCC cells. Through analyzing ALDOA-overexpressing and -knockdown cells, it was confirmed that ALDOA mediated the viability and glycolysis inhibition of HDPS-4II. Moreover, HDPS-4II administration markedly inhibited tumor growth in mice xenografted with HCCs. These findings suggest that HDPS-4II, as an ALDOA antagonist, is a promising remedy in the treatment and prevention of HCC.


Asunto(s)
Antineoplásicos/farmacología , Escarabajos/química , Fructosa-Bifosfato Aldolasa/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucanos/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fructosa-Bifosfato Aldolasa/antagonistas & inhibidores , Fructosa-Bifosfato Aldolasa/metabolismo , Glucanos/química , Glucanos/aislamiento & purificación , Glucólisis/efectos de los fármacos , Glucólisis/genética , Células Hep G2 , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Larva/química , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Ethnopharmacol ; 266: 113443, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33022344

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Chansu, dried secretions from Bufonidae, has long been used for cancer treatment as a traditional Chinese medicine. In searching for effective anti-hepatoma agents from Chansu, our preliminary drug screening found that a bufadienolide, namely 1ß-hydroxyl-arenobufagin (1ß-OH-ABF), displays anti-hepatoma activities. However, the anti-hepatoma effects and molecular mechanisms of 1ß-OH-ABF have not been defined. AIM OF THE STUDY: To evaluate the anti-hepatoma activity of 1ß-OH-ABF against liver cancer Hep3B and HepG2 cells in vitro and in vivo, as well as explore the underlying mechanisms. MATERIALS AND METHODS: The anti-proliferative effects of 1ß-OH-ABF on liver cancer Hep3B, HepG2, HuH7, SK-HEP-1 and normal hepatocyte LO2 cells were examined by MTT assay and colony formation assay. Hoechst 33258 staining and Annexin V-FITC/PI staining assay were used to analyze apoptosis induced by 1ß-OH-ABF. The collapse of the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining assay. Western blotting was used to examine the expression levels of targeted proteins. The role of mTOR in 1ß-OH-ABF-induced apoptosis was investigated using small interfering RNA (siRNA) transfection. Zebrafish xenograft model was established to evaluate the anti-hepatoma effects of 1ß-OH-ABF in vivo. RESULTS: We found that 1ß-OH-ABF inhibits the proliferation of Hep3B, HepG2, HuH7, SK-HEP-1 cells but has little cytotoxicity towards LO2 cells. 1ß-OH-ABF induces mitochondria dysfunction and triggers mitochondria apoptotic pathway, which is accompanied by the loss of ΔΨm, upregulation and translocation of Bax, as well as cleavages of caspase-9, caspase-3 and PARP. Mechanistically, 1ß-OH-ABF markedly decreases the expression level of p-AKT/AKT and p-mTOR (Ser2248 and Ser2481)/mTOR in a time-dependent manner. Inhibition of mTOR by siRNA strengthens 1ß-OH-ABF-mediated apoptosis. Critically, 1ß-OH-ABF shows a marked in vivo anti-hepatoma effect on human Hep3B cell xenografts in zebrafish model. CONCLUSION: 1ß-OH-ABF induces mitochondrial apoptosis through the suppression of mTOR signaling in vitro and in vivo, indicating that 1ß-OH-ABF may serve as a potential agent for the treatment of liver cancer.


Asunto(s)
Antineoplásicos/farmacología , Bufanólidos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Bufanólidos/química , Bufanólidos/aislamiento & purificación , Carcinoma Hepatocelular/patología , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/patología , Mitocondrias/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra
4.
J Ethnopharmacol ; 266: 113456, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33039631

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Poria cocos Wolf has been used in traditional East-Asian medicine for centuries to effectively treat various gastrointestinal disorders such as diarrhea for its tonic, anti-fungal and anti-bacterial activities. Previous studies have revealed that the tumor development would induce intestinal microbiota dysbiosis and intestinal barrier dysfunction to the patients with breast cancer. AIM OF STUDY: To investigate the effect and the mechanism of ethanol extract of Poria cocos (PC) on intestinal barrier function and intestinal microbiota in the mice with breast cancer. MATERIALS AND METHODS: Thirty-six female BALB/c mice were randomly divided into four groups (the normal control, model, PC and positive control group). Intestinal histopathological was evaluated by H&E staining. The difference of the intestinal microbiota in each group was studied by 16S rDNA high-throughput sequencing. The level of plasma endotoxin, D -lactic acid (D-LA) and diamine oxidase (DAO) were measured by ELISA. The putrescine content in serum and urine were detected by HPLC. Expression of the tight junction (TJ) proteins, phosphorylated p38 MAPK and ERK1/2 were determined by western blotting. RESULTS: Our results showed that tumor development prominently induced the intestinal damage and microbiome dysbiosis in mice. PC prominently remit such histologic damage through enhancing the expression of TJ proteins and decreasing the levels of DAO, D-LA and endotoxin via upregulating the expression of phosphorylated ERK1/2 and p38 MAPK. Furthermore, PC increased the diversity of the intestinal microbiota and strikingly changed the structure and composition of the gut microbiota in the mice by increasing the beneficial bacteria Lactobacillus, Bifidobacterium, and decreasing the sulfate-reducing bacteria Desulfovibrio and inflammatory associated bacteria Mucispirillum, S24-7 and Staphylococcus. Moreover, PICRUSt analysis and the putrescine detection might indicate that PC might be involved in the putrescine metabolism in the mice. Correlation analysis indicated that Prevotella, Rikenellaceae and Bacteroidetes were significantly correlated with Claudin-8 and p38-MAPK expression (p < 0.05). CONCLUSION: PC could improve the dysbacteriosis and repair the intestinal barrier function in the mice with breast cancer. This study provide more data to support the application of PC in breast cancer treatment.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Wolfiporia/química , Animales , Antineoplásicos/aislamiento & purificación , Disbiosis/tratamiento farmacológico , Etanol/química , Femenino , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Uniones Estrechas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Ethnopharmacol ; 265: 113321, 2021 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-32877719

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The crude extracts of the medicinal mushroom Inonotus obliquus have been used as an effective traditional medicine to treat malicious tumors, gastritis, gastric ulcers, and other inflammatory conditions in Russia and most Baltic countries. AIM OF THIS REVIEW: Deciphering the antitumoral potential of the bioactive metabolites from I. obliquus and addressing its possibility to be used as effective agents for tumor treatment, restoration of compromised immunity and protection of gastrointestinal damage caused by chemotherapy. MATERIALS AND METHODS: We analysed the current achievements and dilemma in tumor chemo- or immunotherapy. In this context, we searched the published literatures on I. obliquus covering from 1990 to 2020, and summarized the activities of antitumor, antioxidation, and immunomodulation by the polysaccharides, triterpenoids, small phenolic compounds, and hispidin polyphenols. By comparing the merits and shortcomings of current and traditional methodology for tumor treatment, we further addressed feasibility for the use of I. obliquus as an effective natural drug for tumor treatment and prevention. RESULTS: The diverse bioactive metabolites confer I. obliquus great potential to inhibit tumor growth and metastasis. Its antitumor activities are achieved either through suppressing multiple oncogenic signals including but not limited to the activation of NF-κB and FAK, and the expression of RhoA/MMP-9 via ERK1/2 and PI3K/Akt signaling pathway. The antitumor activities can also be achieved by inhibiting tyrosinase activity via PAK1-dependent signaling pathway or altering lysosomal membrane permeabilization through blocking tubulin polymerization and/or disturbing energy metabolism through LKB1/AMPK pathway. In addition, the metabolites from I. obliquus also harbour the potentials to reverse MDR either through selective inhibition on P-gp/ABCB1 or MRP1/ABCC1 proteins or the induction of G2/M checkpoint arrest in tumor cells of chemoresistant phenotypes mediated by Nox/ROS/NF-kB/STAT3 signaling pathway. In addition to the eminent effects in tumor inhibition, the metabolites in I. obliquus also exhibit immunomodulatory potential to restore the compromised immunity and protect against ulcerative damage of GI tract caused by chemotherapy. CONCLUSIONS: I. obliquus possesses the potential to reduce incidence of tumorigenesis in healthy people. For those whose complete remission has been achieved by chemotherapy, administration of the fungus will inhibit the activation of upstream oncogenic signals and thereby prevent metastasis; for those who are in the process of chemotherapy administration of the fungus will not only chemosensitize the tumor cells and thereby increasing the chemotherapeutic effects, but also help to restore the compromised immunity and protect against ulcerative GI tract damage and other side-effects induced by chemotherapy.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/aislamiento & purificación , Mezclas Complejas/farmacología , Humanos , Medicina Tradicional , Neoplasias/patología , Federación de Rusia
6.
Biomed Pharmacother ; 133: 111090, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378984

RESUMEN

Cancer incidence rates are on the increase worldwide. The most common brain cancer in adults is glioblastoma. Currently available treatment modalities are limited and natural products such as mushrooms could enhance them. Apart from nutritional value, mushrooms are an excellent source of bioactive compounds and therefore could be used to treat various disorders. The aim of the study was to assess the anti-glioma potential of selected mushrooms on U87MG, LN-18 glioblastoma and SVGp12 normal human astroglial cell lines. The materials were Cantharellus cibarius, Coprinus comatus, Lycoperdon perlatum and Lactarius delicious. Aqueous, 70 % ethanol or 95 % ethanol extracts from mushrooms were used for analysis including assessment of antioxidant activity by DPPH assay, cell viability by MTT assay, DNA biosynthesis by thymidine incorporation assay, activity of metalloproteinase by gelatin zymography and cell cycle assay by flow cytometry. Mushroom extracts influenced the viability and DNA biosynthesis of cancer cells. Activity of ethanol mushroom extracts was stronger than that of aqueous extracts. Anti-glioma mechanism consisted in inhibition of cancer cell proliferation and induction of apoptosis associated with arrest of cells in subG1 or G2/M phase of cell cycle, and inhibition of metalloproteinases activity. Among investigated mushrooms, L. deliciosus and C. comatus showed the greatest anti-glioma potential.


Asunto(s)
Agaricales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Agaricales/química , Antineoplásicos/aislamiento & purificación , Basidiomycota/química , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Coprinus/química , Replicación del ADN/efectos de los fármacos , Glioblastoma/enzimología , Glioblastoma/patología , Humanos , Metaloproteinasas de la Matriz/metabolismo , Estrés Oxidativo/efectos de los fármacos
7.
PLoS One ; 15(12): e0244385, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33347500

RESUMEN

Resorting to a One Strain Many Compounds (OSMAC) approach, the marine Streptomyces sp. BRB081 strain was grown in six different media settings over 1, 2, 3 or 7 days. Extractions of mycelium and broth were conducted separately for each media and cultivation period by sonication using methanol/acetone 1:1 and agitation with ethyl acetate, respectively. All methanol/acetone and ethyl acetate crude extracts were analysed by HPLC-MS/MS and data treatment was performed through GNPS platform using MZmine 2 software. In parallel, the genome was sequenced, assembled and mined to search for biosynthetic gene clusters (BGC) of secondary metabolites using the AntiSMASH 5.0 software. Spectral library search tool allowed the annotation of desferrioxamines, fatty acid amides, diketopiperazines, xanthurenic acid and, remarkably, the cyclic octapeptides surugamides. Molecular network analysis allowed the observation of the surugamides cluster, where surugamide A and the protonated molecule corresponding to the B-E isomers, as well as two potentially new analogues, were detected. Data treatment through MZmine 2 software allowed to distinguish that the largest amount of surugamides was obtained by cultivating BRB081 in SCB medium during 7 days and extraction of culture broth. Using the same data treatment, a chemical barcode was created for easy visualization and comparison of the metabolites produced overtime in all media. By genome mining of BRB081 four regions of biosynthetic gene clusters of secondary metabolites were detected supporting the metabolic data. Cytotoxic evaluation of all crude extracts using MTT assay revealed the highest bioactivity was also observed for extracts obtained in the optimal conditions as those for surugamides production, suggesting these to be the main active compounds herein. This method allowed the identification of compounds in the crude extracts and guided the selection of best conditions for production of bioactive compounds.


Asunto(s)
Antineoplásicos/aislamiento & purificación , Metabolómica/métodos , Metabolismo Secundario , Streptomyces/crecimiento & desarrollo , Proteínas Bacterianas/genética , Técnicas Bacteriológicas , Vías Biosintéticas , Biología Marina , Familia de Multigenes , Filogenia , Streptomyces/química , Streptomyces/clasificación , Secuenciación Completa del Genoma
8.
PLoS One ; 15(6): e0235131, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32569333

RESUMEN

BACKGROUND: Residual contamination by intravenous conventional antineoplastic drugs (ICAD) is still a daily issue in hospital facilities. This study aimed to compare the efficiency (EffQ) of 4 different solutions to remove 23 widely used ICADs from surfaces. METHOD AND FINDINGS: A solution containing 23 ICADs (4 alkylating agents, 8 antimetabolites, 2 topo-I inhibitors, 6 topo-II inhibitors and 3 spindle poisons) was spread over 100 cm2 stainless steel. After drying, decontamination was carried out using 10×10 cm wipes moistened with 300 µL of one of the following solutions: 70% isopropanol (S1); ethanol-hydrogen peroxide 91.6-50.0 mg/g (S2); 10-2 M sodium dodecyl sulphate/isopropanol 80/20 (S3) or 0.5% sodium hypochlorite (S4). Six tests were performed for each decontamination solution. Two modalities were tested: a single wipe motion from top to bottom or vigorous wiping (n = 6 for each modality). Residual contamination was measured with a validated liquid chromatography with tandem mass spectrometry detection method. Solution efficiency (in %) was computed as follows: EffQ = 1-(quantity after decontamination/quantity before decontamination), as median (min-max) for the 23 ICADs. The overall decontamination efficiency (EffQ) of the 4 solutions was compared by a Kruskall-Wallis test. Decontamination modalities were compared for each solution and per ICAD with a Mann-Whitney test (p<0.05). EffQ were significantly different from one solution to the next for single wipe motion decontamination: 79.9% (69.3-100), 86.5% (13.0-100), 85.4% (56.5-100) and 100% (52.9-100) for S1, S2, S3 and S4 (p<0.0001), respectively. Differences were also significant for vigorous decontamination: EffQ of 84.3% (66.0-100), 92.3% (68.7-100), 99.6% (84.8-100) and 100% (82.9-100) for S1, S2, S3 and S4, respectively (p<0.0001). Generally, vigorous decontamination increased EffQ for all tested solutions and more significantly for the surfactant. CONCLUSION: Decontamination efficiency depended on the solution used but also on the application modality. An SDS admixture seems to be a good alternative to sodium hypochlorite, notably after vigorous chemical decontamination with no hazard either to materials or workers.


Asunto(s)
Antineoplásicos/aislamiento & purificación , Descontaminación , Contaminación de Medicamentos , Soluciones , Acero Inoxidable , Propiedades de Superficie
9.
Anticancer Res ; 40(5): 2549-2557, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366399

RESUMEN

BACKGROUND/AIM: Sonodynamic cancer therapy is based on the preferential uptake and/or retention of a sonosensitizing drug (sonosensitizer) in tumor tissues and the subsequent activation of the drug by ultrasound irradiation. In the present study, we investigated the sonodynamically-induced antitumoral effect with functionalized carbon nanotubes, such as poly-ethylene glycol-modified carbon nanotubes (PEG-modified CNTs). MATERIALS AND METHODS: Antitumor effects were evaluated using histological observation and assessing tumor growth following sonodynamic exposure to PEG-modified CNTs. RESULTS: The combined treatment of 100 µM PEG-modified CNT and ultrasound induced a 2-fold cytotoxicity. Sodium azide, which quenches singlet oxygen, significantly inhibited ultrasonication induced cell damage in the presence of PEG-modified CNTs. This suggests that singlet oxygen produced by the combined use of PEG-modified CNTs and ultrasound is involved in the induction of antitumoral effects. The destruction of tumor tissue was observed with the ultrasonic treatment in combination with PEG-modified CNTs, while neither the treatment with PEG-modified CNTs alone nor ultrasound alone caused any necrosis. CONCLUSION: These results indicate that PEG-modified CNT functions as a sonosensitizer and is effective for sonochemical treatment of solid tumors.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Nanotubos de Carbono , Polietilenglicoles , Ondas Ultrasónicas , Animales , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Estructura Molecular , Nanotubos de Carbono/química , Polietilenglicoles/química , Especies Reactivas de Oxígeno/metabolismo , Sarcoma 180 , Terapia por Ultrasonido , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Sci Rep ; 10(1): 7942, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32409719

RESUMEN

In the near future, the demand for L-asparaginase is expected to rise several times due to an increase in its clinical and industrial applications in various industrial sectors, such as food processing. Streptomyces sp. strain NEAE-K is potent L-asparaginase producer, isolated and identified as new subsp. Streptomyces rochei subsp. chromatogenes NEAE-K and the sequence data has been deposited under accession number KJ200343 at the GenBank database. Sixteen different independent factors were examined for their effects on L-asparaginase production by Streptomyces rochei subsp. chromatogenes NEAE-K under solid state fermentation conditions using Plackett-Burman design. pH, dextrose and yeast extract were the most significant factors affecting L-asparaginase production. Thus, using central composite design, the optimum levels of these variables were determined. L-asparaginase purification was carried out by ammonium sulfate followed by DEAE-Sepharose CL-6B ion exchange column with a final purification fold of 16.18. The monomeric molecular weight of the purified L-asparaginase was 64 kD as determined by SDS-PAGE method. The in vitro effects of L-asparaginase were evaluated on five human tumor cell lines and found to have a strong anti-proliferative effects. The results showed that the strongest cytotoxic effect of L-asparaginase was exerted on the HeLa and HepG-2 cell lines (IC50 = 2.16 ± 0.2 and 2.54 ± 0.3 U/mL; respectively). In addition, the selectivity index of L-asparaginase against HeLa and HepG-2 cell lines was 3.94 and 3.35; respectively.


Asunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Asparaginasa/biosíntesis , Asparaginasa/farmacología , Streptomyces/metabolismo , Antineoplásicos/aislamiento & purificación , Asparaginasa/aislamiento & purificación , Línea Celular Tumoral , Humanos , Filogenia , Streptomyces/enzimología
11.
Sci Rep ; 10(1): 8096, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32415084

RESUMEN

Abnormal regulation of ß-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, ß-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel ß-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of ß-catenin. C2 selectively inhibits ß-catenin, lowers its cellular load and significantly reduces viability of ß-catenin-driven cancer cells. Through direct binding to ß-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of ß-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of ß-catenin.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/antagonistas & inhibidores , Regulación Alostérica , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Apoptosis , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/aislamiento & purificación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
12.
J Chromatogr A ; 1621: 461053, 2020 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-32276857

RESUMEN

The chromatographic properties of a new coated amylose tris(3-chloro-5-methylphenylcarbamate) were evaluated in supercritical fluid chromatography for the separation of enantiomers of chiral 1-aryl-5-aryl-pyrrolidin-2-one derivatives, potential anticancer agents, and some commercial drugs. The mobile phase consisted of CO2-modifier mixtures with 30% of either methanol or ethanol, the flow rate was 3 mL/min. The column oven temperature was 40 °C and the outlet pressure was 15 MPa, in order to limit the compressibility of the CO2, thus limiting density variation along the column. The obtained results were then compared to those observed toward 3 other stationary phases: the coated amylose tris(3,5-dimethylphenylcarbamate), the immobilized amylose tris(3,5-dimethylphenylcarbamate) and the coated amylose tris(5-chloro-2-methylphenylcarbamate). It was shown that the new coated amylose tris(3-chloro-5-methylphenylcarbamate) was the most retentive column whatever the studied compounds, particularly for thalidomide and omeprazole with retention factors up to 73.3 and 29.5for the second enantiomer, respectively. Concerning the enantioselectivity, even most of the compounds are separated on all the four columns, the coated amylose tris(3-chloro-5-methylphenylcarbamate) allows the best resolution for most of the ten studied analytes (except omeprazole for which the resolution values are equal to 7.8 and 9.7 on the coated amylose tris(3-chloro-5-methylphenylcarbamate) and amylose tris(3,5-dimethylphenylcarbamate), respectively). Acting in complementary ways, the two chlorinated stationary phases permitted the complete separation of enantiomers of nine compounds out of the ten.


Asunto(s)
Amilosa/análogos & derivados , Cromatografía con Fluido Supercrítico/métodos , Amilosa/química , Antineoplásicos/análisis , Antineoplásicos/aislamiento & purificación , Carbamatos/química , Preparaciones Farmacéuticas/análisis , Preparaciones Farmacéuticas/aislamiento & purificación , Fenilcarbamatos/química , Pirrolidinonas/análisis , Pirrolidinonas/aislamiento & purificación , Dióxido de Silicio/química , Estereoisomerismo
13.
Carbohydr Polym ; 237: 116143, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32241440

RESUMEN

A sulfated glucurono-xylo-rhamnan (EP-3-H) was purified from a green alga, Enteromorpha prolifera. EP-3-H and its oligomers were characterized by high performance liquid chromatography, mass spectrometry and one and two-dimensional nuclear magnetic resource spectroscopy. The structural analysis showed EP-3-H has a backbone of glucurono-xylo-rhamnan, branches with glucuronic acid and sulfated at C3 of rhamnose and/or C2 of xylose. The inhibition of EP-3-H on human lung cancer A549 cell proliferation in vitro and its therapeutic effects in BALB/c-nu mice in vivo were determined to evaluate the anti-lung cancer activity of EP-3-H. The tumor inhibition level was 59 %, suggesting that EP-3-H might be a good candidate for the treatment of lung cancer. Surface plasmon resonance (SPR) studies revealed the IC50 on the binding of fibroblast growth factors, (FGF1 and FGF2), to heparin were 0.85 and 1.47 mg/mL, respectively. These results suggest that EP-3-H inhibits cancer proliferation by interacting with these growth factors.


Asunto(s)
Antineoplásicos , Desoxiazúcares , Neoplasias Pulmonares/tratamiento farmacológico , Mananos , Células A549 , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Desoxiazúcares/aislamiento & purificación , Desoxiazúcares/farmacología , Desoxiazúcares/uso terapéutico , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Heparina/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Mananos/aislamiento & purificación , Mananos/farmacología , Mananos/uso terapéutico , Ratones Endogámicos BALB C , Ratones Desnudos , Sulfatos , Ulva/química
14.
Sci Rep ; 10(1): 4929, 2020 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-32188923

RESUMEN

Mesopelagic organisms form huge biomass aggregations, supporting important pelagic trophic webs and several top predators. Although some studies on the occurrence, biology and ecology of these organisms are available, to date there are no investigations on their potential use for anticancer and antimicrobial biotechnological applications. The aim of this study was to screen extracts of seven mesopelagic species for possible anticancer (Lung cell line A549, skin cell line A2058, liver cell line HepG2, breast cell line MCF7 and pancreas cell line MiaPaca-2) and antibacterial (Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae, the Gram-positive bacteria methicillin resistant/sensitive Staphylococcus aureus, and Mycobacterium tuberculosis) activities. Results showed that only two species were active, the lanternfish Myctophum punctatum and the Mediterranean krill Meganyctiphanes norvegica. In particular, M. punctatum showed strong activity against the A549 and MCF7 cells, while M. norvegica was more active against HepG2 cells. Regarding antibacterial assays, both species were active against methicillin resistant S. aureus. Fractionation and LC/MS dereplication of the fractions showed that the main compounds found in extracts of both species were EPA, DHA and ETA. For some of the detected compounds anticancer and/or antibacterial activity are already known, but this is the first time that such activities have been found for mesopelagic species.


Asunto(s)
Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Organismos Acuáticos/química , Productos Biológicos/farmacología , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Fraccionamiento Químico , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Humanos , Espectrometría de Masas , Mar Mediterráneo , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos
15.
J Appl Microbiol ; 129(2): 356-366, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32119169

RESUMEN

AIMS: Utilization of l-asparaginase has been one of the effective strategies for the treatment of lymphoblastic leukaemia. Since the currently used bacterial l-asparaginase causes side effects, searching for new enzyme sources has been an active field of research. This study focuses on the characterization of an l-asparaginase-producing fungal strain. METHODS AND RESULTS: Sarocladium strictum was identified as a potent enzyme-producing strain. For the enhancement of enzyme production, we used two-level factorial design and response surface methodology. The optimization of significant factors showed a 1·84-fold increase in enzyme production. The Km and Vmax values of the enzyme were 9·74 mmol l-1 and 8·19 µmol min-1 . The toxicity of the produced l-asparaginase was measured on K562 and HL60 cancer cell lines and L6 as normal cells. The IC50 values were calculated as 0·4 and 0·5 IU ml-1 for K562 and HL60 respectively and no significant effect was observed in L6. BrdU proliferation and caspase-3 activity assay in l-asparaginase treated HL60 and K562 cells indicated that cell proliferation rates and apoptotic cell death were reduced. CONCLUSIONS: The cytotoxic properties of the produced fungal enzyme indicated significant growth inhibition in cancer cells while having a little toxic effect on normal cells. The possibility of mass production alongside having suitable cytotoxic and kinetic properties suggest the probable use of the produced l-asparaginase for further researches as a potential chemotherapeutic agent. SIGNIFICANCE AND IMPACT OF THE STUDY: The lack of significant l-glutaminase activity and promising toxicity properties in S. strictum and the closer evolutionary relativeness of fungi enzymes to human enzymes compared to bacterial enzymes suggest a new source with lower toxicity and anti-cancerous properties, causing less side effect problems.


Asunto(s)
Antineoplásicos/farmacología , Asparaginasa/farmacología , Hypocreales/metabolismo , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Asparaginasa/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Células HL-60 , Humanos , Hypocreales/enzimología , Células K562 , Cinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología
16.
J Nat Med ; 74(3): 584-590, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32207026

RESUMEN

Three new 5,6-dihydro-α-pyrones derivatives, named (S)-rugulactone (1) pulchrinervialactone A (2), and pulchrinervialactone B (4), along with one known pyrone, cryptobrachytone C (3), and three known amide derivatives (5-7) have been isolated from the leaves of Cryptocarya pulchrinervia. The structures of 1-7 were elucidated based on extensive spectroscopic data and comparison with literatures. The configurations of compounds 3 and 4 were established by single crystal X-ray diffraction analysis. This is also the first report in finding (S)-rugulactone (1) as a natural product. In addition, the preliminary cytotoxic activity of the isolated compounds was evaluated against P-388 cells using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. All the pyrones, except compound 4, were active significantly inhibiting the growth of P-388 cells, while the amides derivatives (5-7) showed moderate to weak activities. Therefore, compounds 1-3 could be potentially examined further for anticancer agents.


Asunto(s)
Antineoplásicos/farmacocinética , Proliferación Celular/efectos de los fármacos , Cryptocarya/química , Lactonas/farmacología , Pironas/farmacología , Animales , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Lactonas/aislamiento & purificación , Ratones , Estructura Molecular , Neoplasias/tratamiento farmacológico , Hojas de la Planta/química , Pironas/aislamiento & purificación
17.
Carbohydr Polym ; 236: 116065, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32172880

RESUMEN

The present study aimed at investigating the structural features and antitumor properties of a novel heteropolysaccharide (CSP-W-2) obtained from the fruit of Chaenomeles Speciosa (Sweet) Nakai. CSP-W-2 demonstrate that they mainly contain glucose, galactose, arabinose, mannose, xylose in a ratio of 3.7: 3.2: 1.7: 0.9: 0.4, with the molecular weight of 8.7 kDa. Its backbone is predominantly composed of 1,4 linked ß-D-Galp, 1,4 linked α-D-Glcp, 1,4 linked ß-D-Glcp, and 1,4,6-ß-D-Glcp, additionally some branches contained 1,5 linked α-L-Araf, 1,4 linked ß-D-Glcp, 1,3 linked α-L-Araf, and T linked ß-D-Manp according to the results of partial acid hydrolysis analysis, methylation analysis, IR and NMR spectra. The antitumor properties study results demonstrated that CSP-W-2 had an inhibitory effect on HepG2 growth by enhancing the nucleus shrinkage and apoptosis. These findings indicate that CSP-W-2 had antitumor potential in the treatment of human liver tumor.


Asunto(s)
Antineoplásicos/farmacología , Polisacáridos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Secuencia de Carbohidratos , Núcleo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Frutas/química , Células Hep G2 , Humanos , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Rosaceae/química
18.
Alkaloids Chem Biol ; 83: 1-112, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32098648

RESUMEN

Lamellarins are marine alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. To date, more than 50 lamellarins have been isolated from a variety of marine organisms, such as mollusks, tunicates, and sponges. Many of them, especially fused type I lamellarins, exhibit impressive biological activity, such as potent cytotoxicity, topoisomerase I inhibition, protein kinases inhibition, and anti-HIV-1 activity. Due to their useful biological activity and limited availability from natural sources, a number of synthetic methods have been developed. In this chapter, we present an updated and comprehensive review on lamellarin alkaloids summarizing their isolation, synthesis, and biological activity.


Asunto(s)
Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Fármacos Anti-VIH/farmacología , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/aislamiento & purificación , Pirroles/farmacología , Inhibidores de Topoisomerasa I/farmacología , Alcaloides/síntesis química , Alcaloides/química , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Humanos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/aislamiento & purificación , Pirroles/síntesis química , Pirroles/química , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/aislamiento & purificación
19.
Biochem Biophys Res Commun ; 525(2): 303-307, 2020 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-32089263

RESUMEN

Microtubules are involved in celluar processes of movement, intracellular trafficking and mitosis, thus microtubule-targeting agents have been widely used in cancer therapy. Herein, we report isopenicin A, a novel meroterpenoid isolated from the plant endophytic fungus of Penicillium sp. sh18, as a novel microtubule binding molecule that efficiently depolymerizes microtubule polymerization to evoke G2/M cell cycle arrest and subsequent cell apoptosis, contributing to proliferation inhibition of human tumor cell lines. The discovery of isopenicin A provides a new chemotype for discovery and development of promising microtubule inhibitors.


Asunto(s)
Antineoplásicos/aislamiento & purificación , Penicillium/química , Moduladores de Tubulina/aislamiento & purificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Microtúbulos/metabolismo , Polimerizacion/efectos de los fármacos , Terpenos/aislamiento & purificación , Terpenos/farmacología , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacología
20.
Carbohydr Polym ; 234: 115895, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32070515

RESUMEN

Fucosylated chondroitin sulfate (FCS) HeSp was isolated from the Patagonian sea cucumber Hemioedema spectabilis. Ion-exchange chromatography was applied for purification of the FCS from the crude extract of sulfated polysaccharides. Analysis of monosaccharide and sulfate content of HeSp revealed the molar ratio of GlcA:GalNAc:Fuc:SO3Na as 1.15:1:1.1:3.9. Molecular weight of HeSp (44.1 kDa) was determined by GPC. According to the NMR spectral data, the main fragment of HeSp was the trisaccharide →3)-ß-d-GalNAc-(1→4)-ß-d-GlcA(3-O-α-l-Fuc)-(1→, where GalNAc units were sulfated either at O-4, at O-6 or both at O-4 and O-6. The fucosyl branches attached to O-3 of GlcA showed also different patterns of sulfation: Fucp2S4S, Fucp4S and Fucp3S4S were found in a ratio of 3.8:1.5:1. Besides, small amounts of the disaccharide fragment →3)-ß-d-GalNAc-(1→4)-ß-d-GlcA3S-(1→ were observed in a structure of HeSp. The polysaccharide was found to block cancer cells adhesion to platelet-coated surface and to inhibit tubulogenesis, thus demonstrating the potential antitumor activity.


Asunto(s)
Antineoplásicos/farmacología , Sulfatos de Condroitina/farmacología , Polisacáridos/farmacología , Pepinos de Mar/química , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sulfatos de Condroitina/química , Sulfatos de Condroitina/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Especificidad de la Especie , Células Tumorales Cultivadas
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