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1.
Exp Oncol ; 43(3): 209-216, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34591419

RESUMEN

BACKGROUND: Uterine leiomyosarcoma is a rare malignant smooth muscle tumor originating in the uterine wall that generally responds poorly to chemotherapy and radiation. AIM: We investigated the in vitro effects of a novel nutrient mixture containing lysine, proline, ascorbic acid, and green tea extract on the human leiomyosarcoma cell line SK-UT-1 by measuring cell proliferation, invasiveness, apoptosis, and expression of matrix metalloproteinases (MMP). We also tested the effects of nutrient mixture in vivo using nude mice. MATERIALS AND METHODS: Human leiomyosarcoma SK-UT-1 cells were treated with different concentrations of nutrient mixture. Cell proliferation was determined by MTT assay; MMP expression by gelatinase zymography; invasion by Matrigel assay; migration by scratch test; apoptosis using Live Green caspase kit. In vivo studies were conducted on 5-6 weeks old female nude mice inoculated subcutaneously with 3 â€¢ 106 SK-UT-1 cells. The mice were fed a regular diet or a diet supplemented with 0.5% nutrient mixture. After four weeks, the mice were sacrificed and the tumors were weighed and processed for histology. RESULTS: In vitro, nutrient mixture treatment was not toxic to SK-UT-1 cells at 250 µg/ml but exhibited 20% and 40% cytotoxicity at 500 and 1000 µg/ml respectively. Zymography did not show bands for either MMP-2 or MMP-9 in SK-UT-1 cells. However, treatment with phorbol myristate acetate stimulated the expression of MMP-9, both active and inactive forms in equal proportion. Nutrient mixture inhibited the secretion of both active and inactive forms in a dose dependent manner. Invasion through Matrigel and migration by scratch test were inhibited in a dose dependent fashion, with both invasion and migration inhibited at 250 µg/ml. Live Green Caspase apoptosis assay demonstrated slight apoptosis at 100 µg/ml and significant apoptosis at 250 to 1000 µg/ml. The results of in vitro studies were further confirmed in vivo by showing 50% decrease in tumor weight, 40% reduction in tumor burden compared to the tumors from mice fed regular diet. CONCLUSION: The results suggest a therapeutic potential for nutrient mixture in uterine leiomyosarcoma treatment.


Asunto(s)
Leiomiosarcoma/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 9 de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Nutrientes/farmacología , Extractos Vegetales/farmacología , Neoplasias Uterinas/tratamiento farmacológico , Animales , Antioxidantes , Apoptosis , Proliferación Celular , Suplementos Dietéticos , Femenino , Humanos , Leiomiosarcoma/metabolismo , Leiomiosarcoma/patología , Ratones , Ratones Desnudos , Té/química , Células Tumorales Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Mol Cell Biochem ; 476(9): 3341-3351, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33929675

RESUMEN

Metastatic breast cancer remains a serious health concern and numerous investigations recommended medicinal plants as a complementary therapy. Crocin is one of the known anticancer bio-component. Recently, the inhibitory effect of metformin has been studied on the various aspects of cancer. However, no study reported their combination effects on metastatic breast cancer. In the present study, we have assessed their anti-metastatic effects on in vitro and in vivo breast cancer models. Using MTT assay, scratch, and adhesion tests, we have evaluated the cytotoxic, anti-invasive and anti-adhesion effects of crocin and metformin on 4T1 cell line, respectively. Their protective effects and MMP9 as well as VEGF protein expression levels (Western blotting) investigated in the 4T1 murine breast cancer model. Our results showed that both crocin and metformin reduced cell viability, delayed scratch healing and inhibited the cell adhesion, in vitro. While crocin alone restored the mice's weight reduction, crocin, metformin, and their combination significantly reduced the tumor volume size and enhanced animal survival rate in murine breast cancer model, responses that were associated with VEGF and MMP9 down-regulation. These findings suggest that a combination of crocin and metformin could serve as a novel therapeutic approach to enhance the effectiveness of metastatic breast cancer therapy.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Carotenoides/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz/química , Metformina/farmacología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Humanos , Hipoglucemiantes/farmacología , Técnicas In Vitro , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Molecules ; 25(20)2020 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-33066411

RESUMEN

Matrix metalloproteinase9 (MMP9) is known to be highly expressed during metastatic cancer where most known potential inhibitors failed in the clinical trials. This study aims to select local plants in our state, as anti-breast cancer agent with hemopexin-like domain of MMP9 (PEX9) as the selective protein target. In silico screening for PEX9 inhibitors was performed from our in house-natural compound database to identify the plants. The selected plants were extracted using methanol and then a step-by-step in vitro screening against MMP9 was performed from its crude extract, partitions until fractions using FRET-based assay. The partitions were obtained by performing liquid-liquid extraction on the methanol extract using n-hexane, ethylacetate, n-butanol, and water representing nonpolar to polar solvents. The fractions were made from the selected partition, which demonstrated the best inhibition percentage toward MMP9, using column chromatography. Of the 200 compounds screened, 20 compounds that scored the binding affinity -11.2 to -8.1 kcal/mol toward PEX9 were selected as top hits. The binding of these hits were thoroughly investigated and linked to the plants which they were reported to be isolated from. Six of the eight crude extracts demonstrated inhibition toward MMP9 with the IC50 24 to 823 µg/mL. The partitions (1 mg/mL) of Ageratum conyzoides aerial parts and Ixora coccinea leaves showed inhibition 94% and 96%, whereas their fractions showed IC50 43 and 116 µg/mL, respectively toward MMP9. Using MTT assay, the crude extract of Ageratum exhibited IC50 22 and 229 µg/mL against 4T1 and T47D cell proliferations, respectively with a high safety index concluding its potential anti-breast cancer from herbal.


Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz/química , Extractos Vegetales/química , Animales , Neoplasias de la Mama/patología , Chlorocebus aethiops , Cromatografía en Capa Delgada , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Cromatografía de Gases y Espectrometría de Masas , Indonesia , Extracción Líquido-Líquido , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Ratones , Simulación del Acoplamiento Molecular , Plantas/química , Dominios Proteicos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Células Vero
4.
J Mater Chem B ; 8(12): 2454-2465, 2020 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-32108210

RESUMEN

Tissue response to intestinal injury or disease releases pro-inflammatory host stress signals triggering microbial shift to pathogenic phenotypes. One such phenotype is increased protease production resulting in collagen degradation and activation of host matrix metalloproteinases contributing to tissue breakdown. We have shown that surgical injury depletes local intestinal phosphate concentration triggering bacterial virulence and that polyphosphate replenishment attenuates virulence and collagenolytic activity. Mechanistic studies of bacterial and host protease expression contributing to tissue breakdown are difficult to achieve in vivo necessitating the development of novel in vitro tissue models. Common techniques for screening in vitro protease activity, including gelatin zymography or fluorogenic protease-sensitive substrate kits, do not readily translate to 3D matrix degradation. Here, we report the application of an in vitro assay in which collagenolytic pathogens are cultured in the presence of a proteolytically degradable poly(ethylene) glycol scaffold and a non-degradable phosphate and/or polyphosphate nanocomposite hydrogel matrix. This in vitro platform enables quantification of pathogen-induced matrix degradation and screening of sustained release of phosphate-based therapeutic efficacy in attenuating protease expression. To evaluate matrix degradation as a function of bacterial enzyme levels secreted, we also present a novel method to quantify hydrogel degradation. This method involves staining protease-sensitive hydrogels with Sirius red dye to correlate absorbance of the degraded gel solution with hydrogel weight. This assay enables continuous monitoring and greater accuracy of hydrogel degradation kinetics compared to gravimetric measurements. Combined, the proposed in vitro platform and the presented degradation assay provide a novel strategy for screening efficacy of therapeutics in attenuating bacterial protease-induced matrix degradation.


Asunto(s)
Matriz Extracelular/metabolismo , Hidrogeles/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Péptido Hidrolasas/metabolismo , Fosfatos/metabolismo , Polietilenglicoles/metabolismo , Evaluación Preclínica de Medicamentos , Enterococcus faecalis/enzimología , Enterococcus faecalis/crecimiento & desarrollo , Humanos , Hidrogeles/química , Metaloproteinasa 9 de la Matriz/química , Metaloproteinasa 9 de la Matriz/aislamiento & purificación , Tamaño de la Partícula , Péptido Hidrolasas/química , Péptido Hidrolasas/aislamiento & purificación , Fosfatos/química , Polietilenglicoles/química , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/crecimiento & desarrollo , Serratia marcescens/enzimología , Serratia marcescens/crecimiento & desarrollo , Propiedades de Superficie , Ingeniería de Tejidos
5.
Nat Prod Res ; 33(12): 1765-1768, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29394875

RESUMEN

Dysregulation of matrix metalloproteinases (MMPs) activity is known in many pathological conditions with which most of the conditions are related to elevate MMPs activities. Ficus deltoidea (FD) is a plant known for its therapeutic properties. In order to evaluate the therapeutic potential of FD leaf extract, we study the enzymatic inhibition properties of FD leaf extract and its major bioactive compounds (vitexin and isovitexin) on a panel of MMPs (MMP-2, MMP-8 and MMP-9) using experimental and computational approaches. FD leaf extract and its major bioactive compounds showed pronounced inhibition activity towards the MMPs tested. Computational docking analysis revealed that vitexin and isovitexin bind to the active site of the three tested MMPs. We also evaluated the cytotoxicity and cell migration inhibition activity of FD leaf extract in the endothelial EA.hy 926 cell line. Conclusively, this study provided additional information on the potential of FD leaf extract for therapeutical application.


Asunto(s)
Apigenina/farmacología , Ficus/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Extractos Vegetales/farmacología , Apigenina/química , Apigenina/metabolismo , Dominio Catalítico , Línea Celular , Movimiento Celular , Evaluación Preclínica de Medicamentos/métodos , Humanos , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 8 de la Matriz/química , Metaloproteinasa 8 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/química , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Extractos Vegetales/química , Hojas de la Planta/química
6.
Interdiscip Sci ; 10(4): 722-733, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28488219

RESUMEN

A stroke or cerebrovascular accident is a serious, life-threatening medical condition that occurs when the blood supply to part of the brain is severely reduced or cut off, depriving brain tissue of oxygen and nutrients. Studies suggested that level of gelatinases (MMP-2 and MMP-9) usually increases in the brain after stroke. The elevated activity of gelatinases plays the deleterious role in ischemic stroke, hemorrhagic stroke and perinatal hypoxic-ischemic brain injury. Therefore, matrix metalloproteinase (MMP)-2 and MMP-9 inhibition have therapeutic importance in stroke condition. Present in silico study investigates whether Withania somnifera (WS) phytochemicals inhibit the MMP-2 and MMP-9 by binding to the catalytic domain, as similar to their inhibitor or not. For that, we performed molecular docking study to evaluate the gelatinases-inhibitory potential of 36 WS phytochemicals, which compared with gelatinases inhibitors viz. hydroxamic acid, quercetin, doxycycline, minocycline and reverse hydroxamate. The results suggest that 28 out of 36 WS phytochemicals show higher affinity for MMP-2 owing to bind with active site residues of S1'-pocket with lower binding energy and smaller inhibition constant (Ki) than considered inhibitors. As well as, withanolide G and withafastuosin E show higher affinity for MMP-9 than reverse hydroxamate inhibitor. These phytochemicals have neuroprotective potential as an inherently useful oral drug to combat ischemic and hemorrhagic stroke mediated by gelatinases.


Asunto(s)
Simulación por Computador , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Neuroprotección/efectos de los fármacos , Fitoquímicos/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Withania/química , Dominio Catalítico , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 9 de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Simulación del Acoplamiento Molecular , Fitoquímicos/uso terapéutico , Accidente Cerebrovascular/enzimología
7.
J Nat Prod ; 80(5): 1347-1353, 2017 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-28493718

RESUMEN

Neem (Azadirachta indica) is a well-known medicinal and insecticidal plant. Although previous studies have reported the antiulcer activity of neem leaf extract, the lead compound is still unidentified. The present study reports tamarixetin 3-O-ß-d-glucopyranoside (1) from a methanol extract of neem leaves and its gastroprotective activity in an animal model. Compound 1 showed significant protection against indomethacin-induced gastric ulceration in mice in a dose-dependent manner. Moreover, ex vivo and circular dichroism studies confirmed that 1 inhibited the enzyme matrix metalloproteinase-9 (MMP-9) activity with an IC50 value of ca. 50 µM. Molecular docking and dynamics showed the binding of 1 into the pocket of the active site of MMP-9, forming a coordination complex with the catalytic zinc, thus leading to inhibition of MMP-9 activity.


Asunto(s)
Antiulcerosos/farmacología , Azadirachta/química , Disacáridos/aislamiento & purificación , Disacáridos/farmacología , Indometacina/farmacología , Metaloproteinasa 9 de la Matriz/química , Quercetina/análogos & derivados , Animales , Antiulcerosos/química , Disacáridos/química , Indometacina/química , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Fitoterapia , Hojas de la Planta , Quercetina/química , Quercetina/aislamiento & purificación , Quercetina/farmacología
8.
J Biol Chem ; 292(16): 6810-6820, 2017 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-28235803

RESUMEN

Matrix metalloproteinase 9 (MMP9) is a member of a large family of proteases that are secreted as inactive zymogens. It is a key regulator of the extracellular matrix, involved in the degradation of various extracellular matrix proteins. MMP9 plays a pathological role in a variety of inflammatory and oncology disorders and has long been considered an attractive therapeutic target. GS-5745, a potent, highly selective humanized monoclonal antibody inhibitor of MMP9, has shown promise in treating ulcerative colitis and gastric cancer. Here we describe the crystal structure of GS-5745·MMP9 complex and biochemical studies to elucidate the mechanism of inhibition of MMP9 by GS-5745. GS-5745 binds MMP9 distal to the active site, near the junction between the prodomain and catalytic domain, and inhibits MMP9 by two mechanisms. Binding to pro-MMP9 prevents MMP9 activation, whereas binding to active MMP9 allosterically inhibits activity.


Asunto(s)
Anticuerpos Monoclonales Humanizados/química , Colitis Ulcerosa/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/química , Neoplasias Gástricas/tratamiento farmacológico , Sitio Alostérico , Anticuerpos/química , Dominio Catalítico , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Gelatina/química , Eliminación de Gen , Células HEK293 , Humanos , Concentración 50 Inhibidora , Unión Proteica , Proteínas Recombinantes/química , Resonancia por Plasmón de Superficie
9.
J Nutr Biochem ; 41: 56-64, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28040581

RESUMEN

Epigallocatechin-3-gallate (EGCG), the bioactive polyphenol in green tea, has been demonstrated to have various biological activities. Our study aims to investigate the antiproliferation and antimigration effects of EGCG against bladder cancer SW780 cells both in vitro and in vivo. Our results showed that treatment of EGCG resulted in significant inhibition of cell proliferation by induction of apoptosis, without obvious toxicity to normal bladder epithelium SV-HUC-1 cells. EGCG also inhibited SW780 cell migration and invasion at 25-100 µM. Western blot confirmed that EGCG induced apoptosis in SW780 cells by activation of caspases-8, -9 and -3, Bax, Bcl-2 and PARP. Besides, animal study demonstrated that EGCG [100 mg/kg, intraperitoneal (i.p.) injection daily for 3 weeks] decreased the tumor volume significantly in mice bearing SW780 tumors, as well as the tumor weight (decreased by 68.4%). In addition, EGCG down-regulated the expression of nuclear factor-kappa B (NF-κB) and matrix metalloproteinase (MMP)-9 in both protein and mRNA level in tumor and SW780 cells. When NF-κB was inhibited, EGCG showed no obvious effect in cell proliferation and migration. In conclusion, our study demonstrated that EGCG was effective in inhibition SW780 cell proliferation and migration, and presented first evidence that EGCG inhibited SW780 tumor growth by down-regulation of NF-κB and MMP-9.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Catequina/análogos & derivados , Regulación hacia Abajo/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/metabolismo , Apoptosis/efectos de los fármacos , Catequina/administración & dosificación , Catequina/efectos adversos , Catequina/metabolismo , Catequina/uso terapéutico , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Intraperitoneales , Metaloproteinasa 9 de la Matriz/química , Metaloproteinasa 9 de la Matriz/genética , Ratones Endogámicos BALB C , Ratones Desnudos , FN-kappa B/metabolismo , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Distribución Aleatoria , Organismos Libres de Patógenos Específicos , Carga Tumoral/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Exp Hematol ; 44(5): 358-362.e5, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26845021

RESUMEN

With its ability to degrade extracellular matrix proteins and activate growth factors and cytokines, matrix metalloproteinase (MMP)-9 is an important regulator of cell function. Previously, we reported that myeloid leukemic cells express a unique 82kDa-proMMP-9 variant on their cell surface that is not affected by its natural inhibitor. In this study, we generated monoclonal antibodies that specifically recognize 82kDa-proMMP-9. Flow cytometry analysis using these antibodies revealed significant surface expression of 82kDa-proMMP-9 in monocytes, but minimal amounts in T and B cells isolated from peripheral blood of nine healthy donors and 22 patients with acute myeloid leukemia (AML). In all AML patients, blasts expressed 82kDa-proMMP-9 at levels of 4%-46%, with significantly higher levels in patients with a better risk defined according to National Comprehensive Cancer Network (NCCN) guidelines (ρ = -0.748, p < 0.001) and favorable phenotype according to the French-American-British classification (p = 0.02) compared with patients with adverse prognoses. Receiver operating characteristic curve analysis confirmed the diagnostic accuracy of 82kDa-proMMP-9 measurement in AML blasts (area under the curve: 0.893 [0.739-1.000], p = 0.019). It led us to define a cutoff value of 11.5% for identifying patients with lower NCCN risk (p = 0.005) and with a tendency toward a higher probability of response to anthracycline-based therapy (p = 0.109) and increased event-free survival (p = 0.24). Thus, 82kDa-proMMP-9 expression on blasts may represent a novel independent marker of prognosis in patients with AML.


Asunto(s)
Células de la Médula Ósea/metabolismo , Precursores Enzimáticos/metabolismo , Leucemia Mieloide/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Células Madre Neoplásicas/metabolismo , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/uso terapéutico , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Células Cultivadas , Precursores Enzimáticos/química , Femenino , Humanos , Quimioterapia de Inducción/métodos , Estimación de Kaplan-Meier , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/genética , Masculino , Metaloproteinasa 9 de la Matriz/química , Persona de Mediana Edad , Peso Molecular , Pronóstico , Factores de Riesgo , Células U937 , Adulto Joven
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