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Mangiferin is a glycosylated xanthone widely distributed in nature, which exhibits wide pharmacological activities, highlighting its anti-cancer properties. Mangiferin interferes with inflammation, lipid, and calcium signaling, which selectively inhibits multiple NFkB target genes as interleukin-6, tumor necrosis factor, plasminogen, and matrix metalloproteinase, among others. In this work, the interactions of this polyphenol with MMP-9 and NF-κß are characterized by using computational chemistry methods. The results show MMP-9 inhibition by mangiferina is characterized for the interact with the catalytic Zn atom through a penta-coordinate structure. It is also demonstrated through a strong charge transfer established between mangiferin and Zn in the QM/MM study. Concerning the mangiferin/NF-κß system, the 92.3% of interactions between p50 sub-unity and DNA are maintained with a binding energy of - 8.04 kcal/mol. These findings indicate that mangiferin blocks the p50-p65/DNA interaction resulting in the loss of the functions of this hetero-dimeric member and suggesting inhibition of the cancer progression. Experimental results concerning the anti-cancer properties of mangiferin show that this natural compound can inhibit selectively MMP-9 and NF-Æß. Although the anti-tumor properties of mangiferin are well defined, its molecular mechanisms of actions are not described. In this work, a computational study is carried out to characterize the interactions of mangiferin with these molecular targets. The results obtained corroborate the anti-proliferative and anti-apoptotic activity of mangiferin and provide a depiction of its mechanisms of action.
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Metaloproteinase 9 da Matriz , Xantonas , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Xantonas/química , Xantonas/farmacologiaRESUMO
In spite of the current advances and achievements in cancer treatments, colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. Drug resistance, adverse side effects and high rate of angiogenesis, metastasis and tumor relapse remain one of the greatest challenges in long-term management of CRC and urges need for new leads of anticancer drugs. We demonstrate that CRC treatment with the phytopharmaceutical mangiferin (MGF), a glucosylxanthone present in Mango tree stem bark and leaves (Mangifera Indica L.), induces dose-dependent tumor regression and decreases lung metastasis in a syngeneic immunocompetent allograft mouse model of murine CT26 colon carcinoma, which increases overall survival of mice. Antimetastatic and antiangiogenic MGF effects could be further validated in a wound healing in vitro model in human HT29 cells and in a matrigel plug implant mouse model. Interestingly, transcriptome pathway enrichment analysis demonstrates that MGF inhibits tumor growth, metastasis and angiogenesis by multi-targeting of mitochondrial oxidoreductase and fatty acid ß-oxidation metabolism, PPAR, SIRT, NFκB, Stat3, HIF, Wnt and GP6 signaling pathways. MGF effects on fatty acid ß-oxidation metabolism and carnitine palmitoyltransferase 1 (CPT1) protein expression could be further confirmed in vitro in human HT29 colon cells. In conclusion, antitumor, antiangiogenic and antimetastatic effects of MGF treatment hold promise to reduce adverse toxicity and to mitigate therapeutic outcome of colorectal cancer treatment by targeting mitochondrial energy metabolism in the tumor microenvironment.
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OBJECTIVES: ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. METHODS: The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. RESULTS: The genotype distribution met the Hardy-Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p<0.05) when ethnic background was analyzed. The allelic distribution was similar among Admixed and Black subjects, and they differed from Caucasians. The CC genotype was equally distributed among Admixed and Black subjects, and they differed from Caucasians. The TT genotype frequency differed between Caucasians and Admixed. The CT genotype was distributed differently among the three groups. Similar distribution was obtained in Brazilians, whereas some similarities were observed in African, Spanish and Chinese populations, consistent with the mixed Cuban ethnic origin. CONCLUSIONS: This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.
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Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Frequência do Gene/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , PrevalênciaRESUMO
Advanced metastatic melanoma, one of the most aggressive skin malignancies, is currently without reliable therapy. The process of angiogenesis is crucial for progression and metastasis of the majority of solid tumors including melanomas. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone which exerts many pharmacological activities against cancer-inflammation. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we demonstrate that mangiferin interferes with inflammation, lipid and calcium signaling which selectively inhibits multiple NFkB target genes including interleukin-6, tumor necrosis factor, interferon gamma, vascular endothelial growth factor receptor 2, plasminogen activator urokinase, matrix metalloprotease 19, C-C Motif Chemokine Ligand 2 and placental growth factor. This abrogates angiogenic and invasive processes and capillary tube formation of metastatic melanoma cells as well as human placental blood vessel explants in-vitro and blocks angiogenesis characteristic of the chicken egg chorioallantoic membrane assay and in melanoma syngeneic studies in vivo. The results obtained in this research illustrate promising anti-angiogenic effects of the natural glucosylxanthone mangiferin for further (pre)clinical studies in melanoma cancer patients.
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Inibidores da Angiogênese/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Xantonas/uso terapêutico , Inibidores da Angiogênese/farmacologia , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Xantonas/farmacologiaRESUMO
RESUMEN Introducción: El cáncer de pulmón es uno de los principales problemas de salud en Cuba y el mundo. Las diferencias genéticas a causa de polimorfismos de un solo nucleótido, son factores importantes involucrados en la susceptibilidad genética a esta enfermedad. En Cuba son escasos los datos disponibles sobre los polimorfismos de un solo nucleótido y su posible influencia sobre la aparición y pronóstico del cáncer. Objetivo: Exponer la importancia del estudio de los polimorfismos de un solo nucleótido en genes de la reparación del daño al ADN en el cáncer de pulmón. Desarrollo: El tabaquismo es el principal factor de riesgo para desarrollar cáncer de pulmón, sin embargo, aproximadamente el 15 % de los fumadores desarrollará la enfermedad. Los polimorfismos de un solo nucleótido son factores involucrados en la predisposición genética a las enfermedades. La presencia de variantes polimórficas puede modificar la eficacia de los sistemas de reparación, favoreciendo la aparición de genotoxicidad y/o mutagénesis. También pueden modificar la respuesta a los tratamientos oncológicos y la supervivencia de los pacientes. Por consiguiente, además de ser marcadores de susceptibilidad, los polimorfismos se consideran marcadores de pronóstico individual de respuesta a la terapia. Este trabajo enfatiza la utilidad de su evaluación como biomarcadores clínicos y de susceptibilidad genética a enfermedades en la población cubana. Conclusiones: El estudio de polimorfismos de un solo nucleótido permitirá el abordaje personalizado de enfermedades oncológicas, lo cual podría contribuir a su detección temprana y a definir grupos de individuos con alto riesgo de padecer cáncer de pulmón.
ABSTRACT Introduction: Lung cancer is one of the main health problems in Cuba and worldwide. Genetic differences due to single nucleotide polymorphisms are important factors involved in the genetic susceptibility to this disease. In Cuba, there are scarce data available on single nucleotide polymorphisms and their possible influence on the incidence and prognosis of cancer. Objective: To expose the importance of the study of single nucleotide polymorphisms in DNA damage repair genes in lung cancer. Results: Smoking is the main risk factor for developing lung cancer, however, approximately 15 % of smokers will develop the disease. Single nucleotide polymorphisms are important factors involved in genetic predisposition to diseases. The presence of polymorphic variants can modify the efficacy of repair systems, favoring the occurrence of genotoxicity and/or mutagenesis. They can also modify the response to oncological treatments and patient´s survival. Therefore, in addition to being susceptibility markers, polymorphisms are considered individual prognostic markers of response to therapy. This work emphasizes the usefulness of evaluating single nucleotide polymorphisms as clinical and susceptibility biomarkers in the Cuban population. Conclusions. The study of single nucleotide polymorphisms will allow a personalized approach to oncological diseases, which could contribute to define groups of individuals at high risk of getting lung cancer, therefore, early disease detection.
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Los organismos están constantemente expuestos a una gran variedad de xenobióticos. Las enzimas citocromo P450 participan en la fase I del metabolismo de xenobióticos, incluyendo los fármacos, y en funciones biosintéticas endógenas por reacciones de oxidación, reducción e hidrólisis. En el hombre se estima que pueden metabolizar hasta dos tercios de las drogas y la mayor parte de estas reacciones ocurre en el hígado. Estas enzimas se encuentran en todos los reinos biológicos. Actualmente se conocen más de 18 000 genes citocromo P450 organizados en familias y subfamilias según el porcentaje de identidad de secuencia de sus aminoácidos, y este número aumenta cada año con el hallazgo de nuevas secuencias del genoma. Ellas son una superfamilia de hemoproteínas monooxidasas del sistema oxidasa de función mixta localizadas en las membranas del retículo endoplasmático liso y mitocondrial interna. La diversidad de reacciones que cataliza y su amplia especificidad de sustrato lo destacan como uno de los catalizadores más diversos y versátiles conocidos y juega un papel crítico en la bioquímica, farmacología y toxicología. Se realizó una búsqueda por palabras clave en las bases de datos Pubmed y Medscape en los últimos diez años. También se consultaron sitios de Internet relacionados con investigaciones del citocromo P450 como bases de datos. Esta revisión es una actualización sobre aspectos generales del citocromo P450 y comprende una breve historia de la investigación del citocromo P450, su sistema de nomenclatura estándar; y describe su multiplicidad, la distribución a nivel de órgano y localización subcelular, estructura y función(AU)
The organisms are constantly exposed to a wide array of xenobiotics. Cytochrome P450 enzymes are involved in the phase I of xenobiotic metabolism, including pharmaceuticals, and in endogenous biosynthetic functions through oxidation, reduction reactions and hydrolysis. It is estimated that cytochrome P450 can metabolize up to two-thirds of drugs present in humans and that the bulk of these reactions occur in the liver. These enzymes are found in all biological domains. More than 18 000 cytochrome P450 genes are currently known and arranged into families and subfamilies on the basis of amino acid sequence identity percentage, and this number increases each year as new genome sequences are reported. They are a superfamily of monooxidase hemoproteins in the oxidase system with mixed functions and found on the membranes of the smooth endoplasmic reticulum and in the inner mitochondrial membrane. The diversity of reactions that catalyzes and its extensive substrate specificity turn it into one of the most diverse and versatile catalysts ever known and plays a critical role in biochemistry, pharmacology and toxicology. A keyword search was performed in Pubmed and Medscape databases in the last ten years. Websites related to cytochrome P450 research as databases were also consulted. This updated review covered general aspects of cytochrome P450, a brief history of the research on this enzyme and its standard nomenclature system, and also described its multiplicity, its distribution in body organs and its sub-cellular location, structure and function(AU)
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Humanos , Xenobióticos/farmacologia , Efeitos Colaterais Metabólicos de Drogas e SubstânciasRESUMO
INTRODUCCIÓN: la mangiferina posee diferentes propiedades farmacológicas, y otras están por ser investigadas, tal como su actividad antitumoral como agente adyuvante a la quimioterapia antineoplásica convencional en la terapia combinada. OBJETIVO: evaluar el efecto antiproliferativo de la mangiferina sola y combinada con concentraciones bajas de agentes quimioterapéuticos. MÉTODOS: las líneas celulares de carcinoma de colon de ratón CT26.WT y normal de ovario de hámster chino CHO-K1, se trataron con mangiferina en combinación con cisplatino y 5-fluorouracilo bajo diferentes esquemas de tratamiento (secuencial y simultáneo), a diferentes concentraciones y tiempos de incubación. La viabilidad celular se determinó por el ensayo de MTT. RESULTADOS: la mangiferina (1-200 µg/mL) no fue citotóxica para ambas líneas celulares. El cotratamiento secuencial con mangiferina (1-200 µg/mL) por 3 h y cisplatino a concentraciones no citotóxicas (1 µM y 5 µM) durante 72 h, mostró un incremento significativo de la muerte celular en CT26.WT, sin inducir incremento significativo de la muerte en células CHO-K1, a concentraciones bajas de ambos compuestos. En el caso de los cotratamientos con mangiferina y 5-fluorouracilo (0,1 µM y 0,5 µM), se incrementó significativamente la muerte celular en los cotratamientos simultáneo por 72 h y secuencial 5-fluorouracilo 72 h y mangiferina 24 h en células CT26.WT; pero solo en este último, no se incrementó significativamente la muerte celular en CHO-K1. CONCLUSIONES: la mangiferina en combinación con concentraciones bajas no citotóxicas de cisplatino y 5-fluorouracilo, promueve la muerte celular e incrementa la citotoxicidad de estos agentes quimioterapéuticos en las condiciones de experimentación realizadas(AU)
INTRODUCTION: mangiferin has several pharmacological properties, but others remain to be deeply explored, such as antitumor activity since it may serve as adjuvant agent in conventional antitumoral chemotherapy in a combined treatment. OBJECTIVE: to evaluate the antiproliferative effect of the use of mangiferin alone and in combination with low concentrations of chemotherapeutic agents. METHODS: the CT26.WT mouse colon carcinoma and the CHO-K1 hamster ovary normal cell lines were treated with mangiferin in combination with cisplatin and 5-fluorouracil in several treatment schedules (sequential and simultaneous), at different concentrations and incubation times. The cell viability was evaluated by MTT assay. RESULTS: mangiferin (1-200 µg/mL) was not cytotoxic in both cell lines. Mangiferin (1-200 µg/mL) for 3h plus cisplatin at not citotoxic concentrations (1 µM and 5 µM) for 72 h in sequential combined treatment showed a significant increase of cell death in CT26.WT, without inducing significant increase of cell death in CHO-K1 cells at low concentrations of both compounds. In the case of combined mangiferina and 5-fluorouracil (0,1 µM and 0,5 µM) treatments, cell death rose in a significant way in simultaneous combined treatments for 72 h whereas sequential combined therapy with 5-fluorouracil for 72 h plus mangiferin for 24 h in CT26.WT cells, a significant rise was not induced in the cell line death of CHO-K1 hamster CONCLUSIONS: mangiferin in combination with low non cytotoxic concentrations of cisplatin and 5-fluorouracil promotes cell death and increases the cytotoxicity of these chemotherapeutic agents in experimental conditions of this study(AU)
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Ratos , Protocolos de Quimioterapia Combinada Antineoplásica , /uso terapêutico , Cisplatino/uso terapêutico , Fluoruracila/uso terapêuticoRESUMO
Introducción: las plantas medicinales son todas aquellas que contienen un principio activo o más, los cuales, administrados con la dosis adecuada, producen un efecto curativo a las enfermedades del hombre y los animales. El hecho de contener más de un principio activo hace que una planta medicinal pueda servir para tratar diferentes afecciones o trastornos. Objetivo: analizar los beneficios y las potencialidades terapéuticas de la planta marina Thalassia testudinum a partir de una revisión de la información existente y los principales resultados de las investigaciones realizadas sobre este organismo marino. Desarrollo: los productos naturales con propiedades terapéuticas han sido muy utilizados en la medicina tradicional. Indudablemente, los extractos de plantas de origen terrestre han representado hasta el presente una de las fuentes de mayor interés para la obtención de fitofármacos. Sin embargo, una fuente útil aún no explorada lo suficiente son los organismos marinos, que al evolucionar y vivir en condiciones ecológicas únicas y como resultado de su gran diversidad taxonómica en relación con la de los organismos terrestres, pueden sintetizar moléculas que no tienen equivalencia con las encontradas hasta el presente en estos últimos. Eso puede derivar en la obtención de estructuras químicas novedosas con efectos farmacológicos sui generis, tal es el caso de la fenograma marina Thalassia testudinum...
Introduction: medicinal plants are those which contain one or more active principles that have a curative effect upon some illnesses which affect men and animals, whenever it is adequately administered. When one plant contains more than one active principle, it can be used to treat different ailments or body disorders. Objective: to analyze the benefits and therapeutic potentialities of the sea plant Thalassia testudinum based on the existent information and in the main results of research works about this sea organism. Development: natural products with therapeutic properties have been widely used in traditional medicine. Undoubtedly, the extracts from ground origin trees have so far represented one of the most interesting sources for phytodrugs. Nevertheless, sea organisms are a useful source which has not been fully explored. As they live and evolve in unique ecologic conditions, and as a result of their great taxonomic diversity in relation to that of ground organisms, they can synthesize molecules that are not equivalent to those of ground organisms found until now. This can derive in obtaining new chemical structures with sui generis pharmacological effects as in the case of the marine phenogram Thalassia testudinum. From this plant, poliphelonic structure-rich extract has been obtained, which show therapeutic potentialities associated to the great variety of beneficial effects that have been described in the studies such as anti-inflammatory, cytoprotective, antioxidative and neuroprotective properties. All the aforementioned turns this new developing product into a possible phytodrug. Conclusions: the sea organisms represent a new source to obtain new phytodrugs and nutritional supplements of great use in human health and nutrition
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Hydrocharitaceae , Medicamento FitoterápicoRESUMO
Las enzimas de biotransformación y eliminación de los fármacos en pacientes con leucemia linfoide aguda tienen una acción determinante en el efecto terapéutico de los medicamentos antineoplßsicos. La presencia y actividad de estos complejos enzimáticos está codificada genéticamente y sujeta a variaciones alélicas, cuyas frecuencias son variables en las diferentes poblaciones humanas. Este polimorfismo genético influye sobre la efectividad terapéutica de los medicamentos y condiciona la carencia de toxicidad o presencia de esta, que en ocasiones puede ser fatal. Las enzimas tiopurin-metil-transferasa, metilén-tetrahidrofolato-reductasa y glutatión-tranferasa son sistemas destoxificadores de algunos de los quimioterápicos empleados en el tratamiento de la leucemia linfoide aguda. En este trabajo se revisan las características genéticas de estas enzimas, la frecuencia de sus polimorfismos y las implicaciones clínicas de su expresión. De igual modo se discute la importancia y los beneficios del genotipaje previo al inicio del tratamiento, con el fin de modificar las dosis de los medicamentos para optimizar su efecto terapéutico y disminuir su toxicidad. La farmacogenética constituye un área de creciente interés que ha tenido un desarrollo considerable en los últimos años, su conocimiento e implementación nos colocará en el camino de la medicina personalizada
The biotransformation and elimination enzymes of drugs in patients suffering from acute lymphoid leukemia play a decisive role on the therapeutical effect of anti-neoplastic drugs. The presence and activity of these enzymatic complexes are genetically coded and subjected to allele variations, the frequency of which is variable in the different human populations. This genetic polymorphism has an impact on the therapeutic effectiveness of drugs and determines the lack or the existence of toxicity that may sometimes become lethal. The enzymes called thiopurine-methyltransferase, methylen-tetrahydropholate-reductase and glutathione-transferase are detoxifying systems of some of the chemotherapeutic drugs that are used for the treatment of acute lymphoid leukemia. This paper reviewed the genetic characteristics of the enzymes, the frequency of polymorphisms and the clinical implications of their expression. Similarly, the importance and the benefits of genotyping before the treatment were discussed in order to change the drug doses to maximize the therapeutic effect and reduce toxicity. Pharmacogenetics has experienced great development in the last few years and draws growing interest; the knowledge about and the implementation of this discipline will take us to the customized medicine
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Farmacogenética/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Técnicas de Genotipagem/métodosRESUMO
Vimang® es un producto de origen natural que se obtiene del árbol del mango (Manguifera indica L. familia Anacardiaceae). Este compuesto ha sido clasificado como antioxidante, inmunomodulador, etc. Por ello, resulta importante conocer su potencial citotóxico. OBJETIVOS: evaluar la citotoxicidad de un extracto acuoso del Vimang®. MÉTODOS: se emplearon los modelos procariótico (Escherichia coli, cepa PQ37) y eucariótico (eritrocitos humanos), se realizaron curvas de supervivencia celular con la cepa PQ37 (con activación metabólica y sin esta); así como se cuantificaron los niveles de la actividad fosfatasa alcalina (mediante la realización del SOS Chromotest). Posteriormente, se desarrolló el ensayo de inhibición de la actividad mitocondrial en eritrocitos. Las concentraciones de Vimang® estudiadas fueron: 50, 250, 500 y 1 000 mg de extracto liofilizado/mL. RESULTADOS: el ensayo procariótico indicó que, en ausencia de fracción S9, el Vimang® diminuye significativamente la viabilidad celular cuando se aplica a concentración igual o superior que 500 mg/mL. Sin embargo, la presencia de activación metabólica podría ocasionar una biotransformación de los componentes del Vimang® que conduce a la no citotoxicidad del producto en el rango de concentraciones analizado. El análisis de los niveles de fosfatasa alcalina cuantificados en presencia del Vimang®; sugirió que la citotoxicidad detectada en E. coli PQ37 no parece estar relacionada con la inhibición de la síntesis proteica. En el caso del ensayo eucariótico empleado y las concentraciones ensayadas, la supervivencia celular de los eritrocitos (en presencia de Vimang®)no disminuyó de forma significativa en relación con los controles correspondientes. CONCLUSIONES: el Vimang® es citotóxico para la cepa PQ37 de Escherichia coli...
Vimang® is a product of natural origin obtained from the mango tree (Manguifera indica L. Anacardiaceae family. This compound has been classified as antioxidant, immunomodulation agent, etc. Thus, it is important to know its cytotoxic potential. OBJECTIVES: to assess the cytotoxicity of a aqueous extract of Vimang®. METHODS: the prokaryotic (PQ37 strain-Escherichia coli and eukaryotic (human erutjrocytes) models and cellular survival curves with PQ37 strain (with and without metabolic activation) were made and the levels of alkaline phosphatase were quantified (by Chromotest SOS test). Later, a trial of mitochondria activity was developed in erythrocytes. The concentrations of study Vimang® were: 50, 250, 500 and 1 000 µg of lyophilized/mL extract. RESULTS: the prokaryotic trial indicated that, in absence of S9, Vimang® decrease significantly the cell viability when it is applied at a concentration similar o higher than 500 µg/mL. However, the presence of a metabolic activation could to cause a biotransformation of the Vimang's® components leading to the no-cytotoxicity of product within the study concentration rank. Analysis of alkaline phosphatase levels quantified in presence of Vimang® suggested that the cytotoxicity detected in PQ37 Escherichia coli apparently isn't related to protein synthesis inhibition. In the case of the eukaryotic trial used and the assayed concentrations, the cell survival of erythrocytes (in presence of Vimang® not decreased significantly in relation to the corresponding controls. CONCLUSIONS: Vimang® is cytotoxic for the PQ37 strain of E.coli when it is applied at a concentration similar or higher than 500 µg/mL. This effect is not observed in these cells neither when a metabolic activation is applied nor in the human erythrocytes for the conditions reported in present paper