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Abstract Tetrahydroquinoline derivatives are interesting structures exhibiting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92 on apoptosis, intracellular Ca2+ concentration ([Ca2+]i), and the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity was determined on MCF-7 breast cancer cells. Colorimetric assays were used to assess MCF-7 cells viability and SERCA activity. Fura-2 and rhodamine 123 were used to measure the intracellular Ca2+ concentration and the mitochondrial electrochemical potential, respec tively. TUNEL assay was used to analyze DNA fragmentation, while caspase activity and NF-κB-dependent gene expression were assessed by luminescence. In silico models were used for molecular docking analysis. These compounds increase intracellular Ca2+ concentration; the main contribution is the Ca2+ entry from the extracellular milieu. Both JS-56 and JS-92 inhibit the activity of SERCA and dissipate the mitochondrial electrochemical potential through processes dependent and independent of the Ca2+ uptake by this organelle. Furthermore, JS-56 and JS-92 generate cytotoxicity in MCF-7 cells. The effect of JS-92 is higher than JS-56. Both compounds activate caspases 7 and 9, cause DNA fragmentation, and potentiate the effect of phorbol 12-myristate-13-acetate on NF-κB-dependent gene expression. Molecular docking analysis suggests that both compounds have a high interaction for SERCA, similar to thapsigargin. Both tetrahydroquinoline derivatives induced cell death through a combination of apoptotic events, increase [Ca2+]i, and inhibit SERCA activity by direct interaction.
Resumen Los derivados de tetrahidroquinolina son estructuras interesantes que exhiben una amplia gama de actividades biológicas, incluyendo efectos antitumorales. Se determinó el efecto de las tetrahidroquinolinas sintetizadas JS-56 y JS-92 sobre la apoptosis, concentración intracelular de Ca2+ ([Ca2+]i) y la actividad Ca2+-ATPasa del retículo sarco(endo)plásmico (SERCA) en células de cáncer de mama MCF-7. Se usaron ensayos colorimétricos para evaluar la viabilidad de las células MCF-7 y la actividad SERCA. Se emplearon Fura-2 y rodamina 123 para medir la concentración de Ca2+ intracelular y el potencial electroquímico mitocondrial, respectivamente. El ensayo TUNEL se utilizó para analizar la fragmentación del ADN, mientras que la actividad de caspasas y la expresión génica dependiente de NF-κB se evaluaron mediante luminiscencia. Modelos in silico permitieron el análisis del acoplamiento molecular. Estos compuestos aumentan la concentración de Ca2+ intracelular; la principal contribución es la entrada de Ca2+ desde el medio extracelular. Tanto JS-56 como JS-92 inhiben la actividad de SERCA y disipan el potencial electroquímico mitocondrial a través de procesos dependientes e independientes de la captación de Ca2+ por este orgánulo. Además, JS-56 y JS-92 generan citotoxicidad en células MCF-7. El efecto de JS-92 es mayor que JS-56. Ambos compuestos activan las caspasas 7 y 9, provocan la fragmentación del ADN y potencian el efecto del 12-miristato-13-acetato de forbol en la expresión génica dependiente de NF-κB. El análisis de acoplamiento molecular sugiere que ambos compuestos tienen una alta interacción con SERCA, similar a la tapsigargina. Ambos derivados de tetrahidroquinolina indujeron la muerte celular a través de una combinación de eventos apoptóticos, aumento de [Ca2+]i e inhibición de la actividad SERCA por interacción directa.
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Introduction: The Vismia genus belongs to the Hypericaceae family and comprises around 57 species of which 17 have been located in Venezuela. Previous investigations have been carried out in extracts as well as pure isolated compounds, revealing antimicrobial, antioxidant and anti-HIV, among other, biological activities. Objective: This investigation aims to determine the cytotoxic activity of essential oils from leaves of Vismia baccifera Triana & Planch (VBJ and VBV) and Vismia macrophylla Kunth (VM) collected in three different locations of the Venezuelan Andean region. Methods: Essential oils obtained by hydrodistillation were analyzed using gas chromatography-mass spectrometry (GC-MS) and their cytotoxic activity was analyzed following the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Human tumor cell lines from SKBr3, MCF-7 and PANC-1, two breast carcinomas and one pancreatic adenocarcinoma of ductal type, were tested with the oil samples and human dermis fibroblasts were used as non-tumor cells. Results: β-caryophyllene and trans-caryophyllene were present as major components in VBJ and VBV, respectively, while γ-bisabolene was the main component in the VM sample. Anticancer activity was observed on V. baccifera essential oil against SKBr3, MCF-7 and PANC-1. The selectivity index showed that VBV is highly selective against the SKBr3 cell line and has no activity against non-tumor cells. Conclusions: These results are considered a contribution to natural products research and may provide supportive data for future studies on cancer.
Introducción: El género Vismia pertenece a la familia Hypericaceae y comprende alrededor de 57 especies de las cuales 17 han sido ubicadas en Venezuela. Se han realizado investigaciones previas tanto en extractos como en compuestos puros aislados revelando actividad antimicrobiana, antioxidante y anti-VIH, entre otras actividades biológicas. Objetivo: El propósito de esta investigación es determinar la actividad citotóxica de los aceites esenciales de las hojas de Vismia baccifera Triana & Planch (VBJ y VBV) y Vismia macrophylla Kunth (VM) recolectadas en tres localidades de la región andina venezolana. Métodos: Aceites esenciales obtenidos por hidrodestilación fueron analizados por cromatografía de gases-espectrometría de masas y su actividad citotóxica fue analizada siguiendo el método MTT (bromuro de 3-[4,5-dimetiltiazol-2-il]-2,5-difeniltetrazolio). Los aceites esenciales fueron ensayados frente a células tumorales humanas SKBr3, MCF-7 y PANC-1, dos carcinomas de mama y un adenocarcinoma pancreático del tipo ductal, usando cultivos primarios de fibroblastos de dermis humana como células no tumorales. Resultados: β-cariofileno y trans-cariofileno estuvieron presentes como compuestos mayoritarios en VBJ y VBV, respectivamente, mientras que γ-bisaboleno fue el componente principal en la muestra VM. El aceite esencial de V. baccifera mostró actividad anticancerígena frente a SKBr3, MCF-7 y PANC-1. El índice de selectividad reveló que VBV es altamente selectivo frente a la línea celular SKBr3 y no presenta actividad contra las células no tumorales. Conclusiones: Estos resultados se consideran una contribución a la investigación de los productos naturales y los datos pueden ser de utilidad en futuras investigaciones sobre el cáncer.
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Cromatografía de Gases , Clusiaceae/toxicidad , Plantas Medicinales , VenezuelaRESUMEN
A series of six 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines were prepared through a facile and efficient one-pot copper-catalyzed procedure from 4-chloro-1-phthalazinyl-arylhydrazones with relatively good yields (62-83%). The one-pot copper-catalytic procedure consists of two simultaneous reactions: (i) a direct intramolecular dehydrogentaive cyclization between ylidenic carbon and adjacent pyrazine nitrogen to form 1,2,4-triazolo ring and, (ii) a direct N-amination on carbon-chlorine bond. Then, an in vitro anticancer evaluation was performed for the synthesized compounds against five selected human cancer cells (A549, MCF-7, SKBr3, PC-3 and HeLa). The nitro-derivatives were significantly more active against cancer strains than against the rest of tested compounds. Specifically, compound 8d was identified as the most promising anticancer agent with significant biological responses and low relative toxicities on human dermis fibroblast. The cytotoxic effect of compound 8d was more significant on PC3, MCF-7 and SKBr3 cancer cells with low-micromolar IC50 value ranging from 0.11 to 0.59 µM, superior to Adriamycin drug. Mechanistic experimental and theoretical studies demonstrated that compounds 8d act as a K+ channel inhibitor in cancer models. Further molecular docking studies suggest that the EGFR Tyrosine Kinase enzyme may be a potential target for the most active 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines.
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Antineoplásicos/uso terapéutico , Cobre/metabolismo , Ftalazinas/uso terapéutico , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Antineoplásicos/farmacología , Catálisis , Células HeLa , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Ftalazinas/farmacología , Relación Estructura-ActividadRESUMEN
We evaluated the antitumoral activity of diverse series of 5-aryl-dihydroisoindolo[2,1-a]quinolin-11-ones, AIIQ (Aryl IsoIndolo-Quinoline, 4a-m), and 5-vinyl dihydroisoindolo[2,1-a]quinolin-11-ones, VIIQ (Vinyl IsoIndolo-Quinoline, 6a-l), obtained using three component imino Diels-Alder (DA) reaction of anilines, o-phthalaldehyde and dienophiles. The first series was obtained in previous work employing isoeugenol and anethole as dienophiles, whereas the vinyl series was synthesized in high yields (75-90%) using isoprene as a dienophile. The cytotoxic activity of both AIIQ and VIIQ series was evaluated against four cancer lines, identifying a new lead compound 4h from the AIIQ series, active against MCF-7 (310 nM), SKBR3 (1434 nM), PC3 (210 nM) and HeLa (79 nM) cells with high selectivity. In addition, in silico ADMET properties for the two series were assessed and discussed.
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Diverse spiro dihydroquinoline-oxindoles (JS series) were prepared using the BF3â¢OEt2-catalyzed imino Diels-Alder reaction between ketimine-isatin derivatives and trans-isoeugenol. Ten spiro-oxiindole derivatives were selected and evaluated at different stages of the life cycle of Leishmania braziliensis parasites, responsible for cutaneous leishmaniasis in South America. Among them, the 8'-ethyl-4'-(4-hydroxy-3-methoxyphenyl)-3'-methyl-3',4'-dihydro-1'H-spiro[indoline-3,2'-quinolin]-2-one called JS87 was able to inhibit the growth of promastigotes without affecting the mammalian cells viability, and to decrease the number of intracellular amastigotes of L. braziliensis. This spiro compound was found to act through the alteration of parasite internal regulation by disrupting the regulatory volume decrease (RVD), and to affect the sterol biosynthetic pathway at level of squalene epoxidase (SE) enzyme. These results revealed that the spiro annulation between quinoline and oxindole scaffolds enhances the anti-leishmanial activity, and could assist in the development of potent quinoline-oxindole hybrids against Leishmania braziliensis, the main etiological agent of cutaneous leishmaniasis in South America.
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Antiprotozoarios/farmacología , Leishmania braziliensis/efectos de los fármacos , Oxindoles/farmacología , Quinolinas/farmacología , Compuestos de Espiro/farmacología , Animales , Antiprotozoarios/química , Concentración 50 Inhibidora , Leishmania braziliensis/crecimiento & desarrollo , Leishmania braziliensis/metabolismo , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Oxindoles/química , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/farmacología , Quinolinas/química , Compuestos de Espiro/químicaRESUMEN
Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against human tumor cells; however, their low relative efficacy has limited their corresponding clinical uses. In order to identify new potent anticancer agents based on 4-aminoquinoline, we evaluated the antiproliferative activity of a series of dehydroxy isoquines and isotebuquines against five human cancer lines. HeLa and SKBr3 were significantly more sensitive to the action of tested quinolines than the A549, MCF-7, and PC-3 cancer lines. Compound 2h was by far the most potent derivative against four of the tested lines (except to PC3 line), exhibiting low micromolar or nanomolar IC50 values superior to adriamycin reference, low toxicities on dermis human fibroblasts (LD50 > 250 µM), and excellent selectivity indexes against the mentioned cancer cells. A structure-activity relationship analysis put in evidence that a pyrrolidine or morpholine moiety as N-alkyl terminal substitution and the incorporation of the extra phenyl attached to aniline ring are pharmacophore essentials for improvement the anticancer activity of the studied dehydroxy isoquines and isotebuquines. From the results, compound 2h emerged as a promising anticancer candidate for further in vitro assays against resistant-strain and in vivo studies as well as pharmacokinetic and genotoxicity studies. Mechanistic assays suggested that the most active quinoline 2h act as calcium-activated potassium channel activator.
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Aminoquinolinas/química , Antineoplásicos/química , Canales de Potasio/química , Potenciales de Acción/efectos de los fármacos , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Canales de Potasio/metabolismo , Relación Estructura-ActividadRESUMEN
The present study evaluates in vitro the effect of two synthetic compounds of the 7-chloro-4-aryloxyquinoline series, QI (C17H12ClNO3) and QII (C18H15ClN4O2S), on Leishmania donovani parasites. The results obtained demonstrate that these compounds are able to inhibit the proliferation of L. donovani promastigotes in a dose-dependent way (QI IC50â¯=â¯13.03⯱â¯3.4 and QII IC50â¯=â¯7.90⯱â¯0.6⯵M). Likewise, these compounds significantly reduced the percentage of macrophage infection by amastigotesand the number of amastigotes within macrophage phagolysosomes, the clinical relevant phase of these parasites. Compound QI showed an IC50 value of 0.66⯱â¯0.2⯵M, while for derivative QII, the corresponding IC50 was 1.02⯱â¯0.17⯵M. Interestingly, the amastigotes were more susceptible to the drug treatment when compared to promastigotes. Furthermore, no cytotoxic effect of these compounds was observed on the macrophage cell line at the concentrations tested. The combination of these compounds with miltefosine and amphotericin B on both parasite morphotypes was evaluated. The isobolograms showed a synergistic effect for both combinations; with a Fractional Inhibitory Concentration (FIC) Index lower than 1 for promastigotes and less than 0.3 for intracellular amastigotes. The effect of QI and QII on mitochondrial membrane potential was also studied. The combination of quinolone derivatives compounds with miltefosine and amphotericin B showed 5-8-fold stronger depolarization of membrane mitochondrial potential when compared to drugs alone. The present work validates the combination of drugs as an effective alternative to potentiate the action of anti-Leishmania agents and points to the quinoline compounds studied here as possible leishmanicidal drugs.
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Anfotericina B/farmacología , Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fosforilcolina/análogos & derivados , Quinolinas/farmacología , Animales , Línea Celular , Quimioterapia Combinada , Macrófagos/efectos de los fármacos , Ratones , Fosforilcolina/farmacologíaRESUMEN
Since the mid-twentieth century, many species, very different from each other and located in all areas and comers of the planet, began presenting various alterations, many of which suggested to be related to endocrine disorders. Research has shown that such alterations were caused by exposure to various chemical contaminants that could affect the health and cause serious illnesses. Among them stands a diverse and large group of compounds, with very different chemical structures, capable of altering the hormonal balance, act at very low doses and with different mechanisms of action, that are called "endocrine disrupting chemicals". When released into the environment or as part of objects, food or medicines, constitute a major risk to animals and humans, which produces not only endocrine dysfunctions but also different cancers, which include the most common types. Despite the importance and significance of the impact of these compounds, they are not sufficiently known or understood, so the aim of this review is to show their origin and impact in the field of human health, highlighting their role as inducers of cancer, which has led to multiple clinical and biological investigations.
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Disruptores Endocrinos/efectos adversos , Contaminación Ambiental/efectos adversos , Neoplasias/inducido químicamente , Humanos , América Latina , VenezuelaRESUMEN
The increase in the intracellular Ca(2+) concentration ([Ca(2+)]i) is the key variable for many different processes, ranging from regulation of cell proliferation to apoptosis. In this work we demonstrated that the sphingolipid sphingosine (Sph) increases the [Ca(2+)]i by inhibiting the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), in a similar manner to thapsigargin (Tg), a specific inhibitor of this Ca(2+) pump. The results showed that addition of sphingosine produced a release of Ca(2+) from the endoplasmic reticulum followed by a Ca(2+) entrance from the outside mileu. The results presented in this work support that this sphingolipid could control the activity of the SERCA, and hence sphingosine may participate in the regulation of [Ca(2+)]I in mammalian cells.
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Calcio/metabolismo , Neoplasias/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Esfingosina/metabolismo , Línea Celular Tumoral , Retículo Endoplásmico/metabolismo , Activación Enzimática , HumanosRESUMEN
Desde mediados del siglo XX numerosas especies, muy diferentes entre sí y ubicadas en todas las áreas y rincones del planeta, comenzaron a presentar diversas alteraciones, muchas de las cuales sugerían estar relacionadas con trastornos del sistema endocrino. Las investigaciones demostraron que tales alteraciones eran producidas por la exposición a diferentes sustancias químicas contaminantes, las cuales podían alterar la salud y producir graves enfermedades. Dentro de ellas destacó un grupo heterogéneo de compuestos con estructuras químicas muy diferentes, capaces de actuar a dosis muy bajas, mostrar distintos mecanismos de acción y ser capaces de alterar el equilibrio hormonal, por lo que se les denominó disruptores endocrinos químicos. Estas sustancias, al ser liberadas al medioambiente o formar parte de objetos, alimentos o medicinas, constituyen un gran riesgo para los seres humanos y toda la vida del planeta, produciendo no solo disfunciones endocrinas sino también diferentes tipos de cáncer, destacando los más frecuentes. A pesar de la trascendencia y significado del impacto de estos compuestos, ellos no son suficientemente conocidos ni entendidos, por lo que el objetivo de esta revisión es mostrar su origen e impacto en la salud humana, resaltando su papel como inductores de cáncer, lo cual ha motivado múltiples investigaciones clínicas y biológicas.
Since the mid-twentieth century, many species, very different from each other and located in all areas and corners of the planet, began presenting various alterations, many of which suggested to be related to endocrine disorders. Research has shown that such alterations were caused by exposure to various chemical contaminants that could affect the health and cause serious illnesses. Among them stands a diverse and large group of compounds, with very different chemical structures, capable of altering the hormonal balance, act at very low doses and with different mechanisms of action, that are called endocrine disrupting chemicals. When released into the environment or as part of objects, food or medicines, constitute a major risk to animals and humans, which produces not only endocrine dysfunctions but also different cancers, which include the most common types. Despite the importance and significance of the impact of these compounds, they are not sufficiently known or understood, so the aim of this review is to show their origin and impact in the field of human health, highlighting their role as inducers of cancer, which has led to multiple clinical and biological investigations.
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Humanos , Contaminación Ambiental/efectos adversos , Disruptores Endocrinos/efectos adversos , Neoplasias/inducido químicamente , Venezuela , América LatinaRESUMEN
The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour's survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible.
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A new indole alkaloid strychnosinol (1) and a new phenolic-glycoside (2) were isolated from the bark and leaves of Strychnos fendleri Sprague & Sandwith, together with six known compounds reported for the first time in this species. The structures of these compounds were determined on the basis of spectroscopic data; mainly those obtained by using (1)H and (13)C NMR (1D and 2D) and mass spectrometry. Strychnosinol (1) and the phenolic glycoside (2) together with compounds 3-8 were evaluated for cytotoxicity against a panel of five tumour cell lines; IC50 values between 0.090 and 0.227 µM for the human tumour cell lines were observed for compound 2.
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Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Antineoplásicos Fitogénicos/farmacología , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , Indoles/aislamiento & purificación , Indoles/farmacología , Strychnos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Fenoles/aislamiento & purificación , Fenoles/farmacología , Corteza de la Planta/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Sales de Tetrazolio , TiazolesRESUMEN
Seventy percent of cancer patients have detectable metastases when they receive a diagnosis and 90% of cancer deaths result from metastases. These two facts emphasise the urgency for research to study the mechanisms and processes that enable metastasis. We need to develop a greater understanding of the cellular and molecular mechanisms that cause metastasis and also we need to do more. We must also consider the micro- and macro-environmental factors that influence this disease. Studying this environmental context has led us to update the 'seed and soil' hypothesis which dates back to the 19th century. This theory describes cancerous cells as seeds and the substrate as the soil in target organs though this may seem antiquated. Nonetheless, the tissue specificity that researchers have recently observed in metastatic colonisation supports the validity of the seed and soil theory. We now know that the metastatic potential of a tumour cell depends on multiple, reciprocal interactions between the primary tumour and distant sites. These interactions determine tumour progression. Studies of metastasis have allowed us to develop treatments that focus on therapeutic effectiveness. These new treatments account for the frequent metastasis of some tumours to target organs such as bones, lungs, brain, and liver. The purpose of this review is first to describe interactions between the cellular and molecular entities and the target organ tumour environment that enables metastasis. A second aim is to describe the complex mechanisms that mediate these interactions.
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Las úlceras de las extremidades inferiores son afecciones de incidencia y prevalencia elevada, cuya cronicidad y persistencia en hacer recidivas son dos de las características evolutivas más relevantes. A pesar de un tratamiento etiológico correcto, a lo cual se suma una gran variedad de apósitos disponibles, el porcentaje de curación y la velocidad de cicatrización siguen siendo bajos. Por tanto se realizó un estudio con el objetivo de obtener un sustituto de piel para su aplicación en la clínica. Se aislaron y cultivaron queratinocitos, que fueron sembrados a una alta densidad, en un sustrato optimizado de fibrina con fibroblastos. De esta forma se desarrolló un nuevo equivalente cutáneo más práctico y de bajo costo, cuyo transplante es directo y de fácil aplicación. Antes de comenzar los estudios clínicos para evaluar sus ventajas y su alcance, se hizo una prueba preliminar con el fin de ver si los cambios efectuados en la técnica estándar no impedían su viabilidad y su acción. A tal fin fueron seleccionaron seis pacientes con ulceras crónicas, sin curación mediante todo tratamiento, a quienes se les aplicaron los nuevos equivalentes. Los pacientes tratados mostraron que los equivalentes eran viables, efectivos, de fácil manipulación y de rápida acción sobre los tejidos afectados. Todos los pacientes que completaron el procedimiento se recuperaron, fue excelente ejemplo un paciente con una lesión crónica de seis meses de evolución que había sido refractaria a los múltiples tratamientos convencionales empleados.
Ulcers of the lower extremities have high prevalence and incidence. Their chronicity and frequent recurrences are two of their most important characteristics. Despite proper etiologic treatment and the great variety of dressings available, the healing rate and recovery speed remain low. Therefore, we conducted a study to obtain skin substitutes for clinical application by isolating and cultivating keratinocytes, which were seeded on a fibroblast-containing fibrin gel at high density. Hence, a new practical and inexpensive skin equivalent of straightforward and easy-to-perform transplantation was developed. Before starting the clinical trials to evaluate its advantages and applicability, we conducted a preliminary test to determine if the changes to the standard technique affected its feasibility and action. For this purpose, we implanted the new equivalents into six patients with chronic ulcers unresponsive to treatment. Outcomes in these patients showed that skin equivalents were feasible, effective, easy to handle and had rapid action on target tissues. All patients who completed the procedure recovered. An excellent example was a patient with a chronic lesion refractory to multiple conventional treatments that had been present for six months.
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New synthetic compounds based on tetrahydroindenoquinoline structure were evaluated for their in vitro antileishmanial activities. The seven compounds assayed have antiproliferative activities against promastigotes of Leishmania mexicana. Compound 1 and 3 were the most active (IC50 1.0 µg/ml) and showed high selectivity towards the parasite. These compounds were selected to evaluate their effect on promastigote morphology and mitochondrial transmembrane potential as well as on the amastigote capability to survive into macrophages J774 cell line. Whereas compound 1 affected the promastigote cell cycle, compound 3 induced morphological changes and the total collapse of the mitochondrial transmembrane potential, a hallmark of apoptosis. Both compounds also affected the amastigote form of the parasite, decreasing their survival rate in J774 macrophages. Due to the greatest selectivity index, the apparent effect as apoptotic inducer and its sustained inhibition on intracellular amastigote replication, compound 3 is the best candidate to be tested in vivo. This compound is worth considering for the development of new antileishmanial drugs.
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Antiprotozoarios/farmacología , Indenos/farmacología , Leishmania mexicana/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Macrófagos/parasitología , Quinolinas/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular , Humanos , Macrófagos/inmunología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Pruebas de Sensibilidad ParasitariaRESUMEN
Colorectal cancer is a serious health problem, a challenge for research, and a model for studying the molecular mechanisms involved in its development. According to its incidence, this pathology manifests itself in three forms: family, hereditary, and most commonly sporadic, apparently not associated with any hereditary or familial factor. For the types having inheritance patterns and a family predisposition, the tumours develop through defined stages ranging from adenomatous lesions to the manifestation of a malignant tumour. It has been established that environmental and hereditary factors contribute to the development of colorectal cancer, as indicated by the accumulation of mutations in oncogenes, genes which suppress and repair DNA, signaling the existence of various pathways through which the appearance of tumours may occur. In the case of the suppressive and mutating tracks, these are characterised by genetic disorders related to the phenotypical changes of the morphological progression sequence in the adenoma/carcinoma. Moreover, alternate pathways through mutation in BRAF and KRAS genes are associated with the progression of polyps to cancer. This review surveys the research done at the cellular and molecular level aimed at finding specific alternative therapeutic targets for fighting colorectal cancer.
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La cirugía, la radioterapia y la quimioterapia siguen siendo los tratamientos reconocidos universalmente como los más efectivos en la lucha contra el cáncer, a pesar de los avances logrados para elucidar sus mecanismos moleculares y haber desarrollado nuevas y sofisticadas técnicas para su tratamiento. Al ser esta enfermedad un importante problema de salud pública, el descubrimiento y estudio de las células madres tumorales ha creado nuevas líneas de investigación dirigidas a comprender y controlar la recurrencia de un tumor, la resistencia a los medicamentos y los mecanismos que hacen posible las metástasis. De esta forma, con una mejor comprensión de las células tumorales, surgen nuevas alternativas terapéuticas que hacen más factible el control y la posible solución que permita la cura definitiva del cáncer. Por la importancia fundamental del tema, el presente artículo tiene como objetivo resumir las características y propiedades de las células madres tumorales, las investigaciones en curso y las nuevas estrategias para la prevención y control de los mecanismos que llevan a la recurrencia de los tumores en los pacientes de cáncer que han sido tratados.
Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Cancer stem cells are a subpopulation of the cells that form the tumor. The discovery of these human cancer cells opens a perspective for understanding tumor recurrence, drug resistance and metastasis; and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Therapeutic alternatives emerge from a better understanding of the biology and the environment of tumor stem cells. The present paper aims to summarize the characteristics and properties of cancer stem cells, the ongoing research, as well as the best strategies for prevention and control of the mechanisms of tumor recurrence.
RESUMEN
Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Cancer stem cells are a subpopulation of the cells that form the tumor. The discovery of these human cancer cells opens a perspective for understanding tumor recurrence, drug resistance and metastasis; and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Therapeutic alternatives emerge from a better understanding of the biology and the environment of tumor stem cells. The present paper aims to summarize the characteristics and properties of cancer stem cells, the ongoing research, as well as the best strategies for prevention and control of the mechanisms of tumor recurrence.
Asunto(s)
Neoplasias/patología , Células Madre Neoplásicas/patología , Animales , Diferenciación Celular , Transformación Celular Neoplásica , Humanos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Ratones , Modelos Biológicos , Metástasis de la Neoplasia , Proteínas de Neoplasias/fisiología , Recurrencia Local de Neoplasia , Neoplasias/terapia , Células Neoplásicas Circulantes , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/efectos de la radiación , Transducción de Señal/fisiología , Células Madre/clasificación , Células Madre/citologíaRESUMEN
A series of diverse simple C2-aryl quinolines was synthesized de novo via a straightforward synthesis based on the acid-catalyzed multicomponent imino Diels-Alder reactions. Seven selected quinolines were evaluated at different stages of Leishmania braziliensis parasite. Among them, the 6-ethyl-2-phenylquinoline 5f was able to inhibit the growth of promastigotes of this parasite without affecting the mammalian cells viability and decreasing the number of intracellular L. braziliensis amastigotes on BMDM macrophages. The mechanism of action studied for the selected compound consisted in: (1) alteration of parasite bioenergetics, by disrupting mitochondrial electrochemical potential and alkalinization of acidocalcisomes, and (2) inhibition of ergosterol biosynthetic pathway in promastigote forms. These results validate the efficiency of quinoline molecules as leishmanicide compounds.
Asunto(s)
Antiparasitarios/farmacología , Leishmania braziliensis/efectos de los fármacos , Quinolinas/farmacología , Animales , Antiparasitarios/química , Metabolismo Energético/efectos de los fármacos , Estadios del Ciclo de Vida/efectos de los fármacos , Macrófagos/parasitología , Estructura Molecular , Quinolinas/químicaRESUMEN
El cáncer es una enfermedad multifactorial caracterizada por anormalidad en el crecimiento celular provocado por factores ambientales y múltiples cambios en la expresión de los genes. El cáncer de mama representa una de las enfermedades que más afecta a la población femenina mundial. Actualmente, se ha mostrado un auge en las investigaciones sobre compuestos extraídos de diversas plantas y origen sintético con posibles agentes antitumorales, entre los que se pueden nombrar los derivados sintéticos de quinolinas. Realizado estudio del grupo sintético indeno (2,1-c) quinolinas y sus efectos citotóxicos sobre líneas de cáncer de mama SKBr3 yMCF-7. La evaluación de la actividad citotóxica de estos compuestos fue determinada a través del método del MTT, se calcularon los valores de concentración inhibitoria, los índices de selectividad y combinaciones con taxanos. Los resultados obtenidos muestran una alta selectividad de los compuestos sintéticos y natural evaluados hacia las líneas celulares MCF-7 y SKBr3 con respecto a las células control (fibroblastos dérmicos humanos); además de una interacción de tipo potenciación en la combinación de un derivado quinolínico y la drogataxano. Con todo esto se puede inferir que solo ciertos compuestos que tuvieron modificaciones químicas realizadas sobre el compuesto patrón del grupo sintético indeno (2,1-c) quinolinas mostraron una inhibición sobre la viabilidad celular sobre las líneas tumorales SKBr3 y MCF-7, conforme aumenta la dosis de los compuestos, además de evidenciar la efectividad de compuestos derivados de quinolinas como moléculas con características antineoplásicas
The cancer is a multifactorial disease characterized by abnormal cell growth caused by environmental factors and for multiple changes in the gene expression. The breast cancer is a disease that affects the female population in worldwide. Currently, there is shown an increment in the research on compounds that we extracted from various plants and synthetic origin with potential antitumor agents, among which can be namedthe synthetic derivatives of the quinolines. A study was performed on an group of synthetic indeno (2,1-c) quinolines and their cytotoxic effects on breast cancer cell lines SKBR3 and MCF-7 was performed. The evaluation of the cytotoxic activity of these compounds was determined through the MTT method; we were calculated inhibitory concentration values, the rates of selectivity and the drug combinations with taxanes. The results show a high selectivity of the natural and the synthetic compounds evaluated towards the cell lines MCF-7 and SKBR3 cells with respect to control (dermal fibroblasts human), besides an enhancement type interaction in the combination of a drug derivative and the quinolinic taxanes. With all this we can infer that only certain compounds had chemical modifications performed on the composite pattern of synthetic group indeno (2, 1-c) quinolines showed an inhibition on cell viability on tumor cell lines SKBR3 and MCF-7, with increasing dose of the compounds, also showing the effectiveness of compounds derived from the quinolines as molecules with the antineoplastic properties and his characteristics