Antibacterial properties of phosphine gold(i) complexes with 5-fluorouracil

New gold(I) complexes with coordination to 5-fluorouracil (5-FU), an anticancer drug with antibacterial properties, have been synthesised and characterised, and are the first reported examples of 5-FU–Au compounds. These new complexes show high solution stability, even in the presence of a cysteine derivative, and so were evaluated as antibacterial compounds against model Gram-positive and Gram-negative bacteria. All the complexes show excellent antibacterial activity against Gram-positive B. subtilis, most of them improving the activity of 5-FU alone. Furthermore, these new complexes are also active against Gram-negative E. coli, where [Au(5-FU)(PTA)], the complex with the smallest phosphane, is the most bactericidal, 32 times more active than 5-FU on its own

Gold as a possible alternative to platinum-based chemotherapy for colon cancer treatment

Due to the increasing incidence and high mortality associated with colorectal cancer (CRC), novel therapeutic strategies are urgently needed. Classic chemotherapy against CRC is based on oxaliplatin and other cisplatin analogues; however, platinum-based therapy lacks selectivity to cancer cells and leads to deleterious side effects. In addition, tumor resistance to oxaliplatin is related to chemotherapy failure. Gold(I) derivatives are a promising alternative to platinum complexes, since instead of interacting with DNA, they target proteins overexpressed on tumor cells, thus leading to less side effects than, but a comparable antitumor effect to, platinum derivatives. Moreover, given the huge potential of gold nanoparticles, the role of gold in CRC chemotherapy is not limited to gold(I) complexes. Gold nanoparticles have been found to be able to overcome multidrug resistance along with reduced side effects due to a more efficient uptake of classic drugs. Moreover, the use of gold nanoparticles has enhanced the effect of traditional therapies such as radiotherapy, photothermal therapy, or photodynamic therapy, and has displayed a potential role in diagnosis as a consequence of their optic properties. Herein, we have reviewed the most recent advances in the use of gold(I) derivatives and gold nanoparticles in CRC therapy

Diseño de potenciales agentes anticancerigenos

El desarrollo de nuevas investigaciones contra el cáncer es primordial en la actualidad. Tras el descubrimiento de la actividad anticancerígena del cisplatino, ha sido de gran interés la síntesis de nuevos complejos de coordinación y organometálicos como agentes anticancerígenos. Este trabajo tiene por objetivo el diseño de agentes anticancerígenos basados en oro(I) empleando como ligandos, moléculas derivadas de chalconas. Las chalconas son precursores de los flavonoides que presentan una variedad de propiedades biológicas, entre las que destaca la actividad anticancerígena. Para completar la esfera de coordinación del centro metálico se han empleado ligandos del tipo fosfina y carbeno, tales como PTA (1,3,5-triaza-7-fosfaadamantano), trifenilfosfina y 1,3-bis(2,6-di-i-propilfenil)imidazol-2-ilideno), con el objetivo de modificar el carácter lipófilo del complejo resultante y conseguir establecer un balance entre lipofilicidad e hidrofilicidad para favorecer su distribución y su entrada a las células. La elección, tanto del metal de transición como de los ligandos, es fundamental para diseñar un fármaco eficaz respecto a su difusión a través del organismo y su actividad antitumoral. Se llevó a cabo una serie ensayos físico–químicos y biológicos sobre los nuevos complejos, basados en el estudio del coeficiente de reparto octanol-agua, así como medidas de estabilidad tras su incubación a 37°C durante 24 horas en condiciones fisiológicas, permitiendo conocer si el carácter lipofílico se encontraba en el rango permitido para su administración y si conservaba su estructura tras 24 horas sin descomposición aparente. Los ensayos biológicos se basaron en el ensayo MTT, test de Ames, además del marcaje y visualización de los núcleos de las células. De esta forma se estudió la capacidad anticancerígena de los complejos coordinados con PTA, así como su ausencia de capacidad mutagénica. Tras resultados obtenidos, se concluye que los complejos sintetizados muestran tener un potencial adecuado para su estudio en profundidad como fármacos contra el cáncer

Desarrollo de nuevos agentes antibacterianos basados en complejos metálicos de 5-Fluoroacilo

En este trabajo fin de grado se han sintetizado complejos de oro(I) del tipo [Au(5-FU)(PR3)] y [Au2(5-FU)(PR3)2]. Para ello se emplearon como ligandos: 5-FU (5-fluoroacilo) y PR3 las fosfinas PTA (1,3,5-triaza-7-fosfaadamantano), DAPTA (3,7-diacetil-1,3,7-triaza-5-fosfabicyclo[3.3.1]nonano), TPPTS (m- trifenilfosfinatrisulfonada), HMPT (trisdimetilamino fosfano) y PPh3 (trifenilfosfina).Los complejos [Au(5-FU)(PTA)], [Au2(5-FU)(PTA)2], [Au(5-FU)(PPh3)], [Au(5-FU)(TPPTS)] y [Au(5-FU)(DAPTA)] se formaron satisfactoriamente.Además, se evaluó la farmacocinética de estos compuestos y aparentemente resultaron ser estables en las condiciones de los experimentos. También se estudió la actividad antibacteriana de los complejos sintetizados frente a las bacterias Escherichia coli y Bacillus subtilis. Para ello se midieron las MIC (minimal inhibitory concentration) las MBC (minimal bactericidal concentration). Los complejos resultaron tener una gran actividad antibacteriana generalmente con MIC desde 256 a 1 μg/mL. Estos complejos tienen una mayor actividad antibacteriana contra B. subtilis (Gram+) que contra E. coli (Gram-) posiblemente debido a su diferente conformación y composición de la pared celular. Finalmente se visualizó mediante microscopía electrónica de barrido (SEM) los daños externos de las bacterias. Se observaron deformaciones, desprendimientos, roturas y agregados debido a la actividad antibacteriana de estos compuestos. También se observó que el oro podría estar acumulándose en la pared celular de las bacterias provocando su muerte.<br /

Biological Activity of NHC-Gold-Alkynyl Complexes Derived from 3-Hydroxyflavones

In this paper we describe the synthesis of new N-heterocyclic carbene (NHC) gold(I) derivatives with flavone-derived ligands with a propargyl ether group. The compounds were screened for their antimicrobial and anticancer activities, showing greater activity against bacteria than against colon cancer cells (Caco-2). Complexes [Au(L2b)(IMe)] (1b) and [Au(L2b)(IPr)] (2b) were found to be active against both Gram-positive and Gram-negative strains. The mechanism of action of 1b was evaluated by measurement of thioredoxin reductase (TrxR) and dihydrofolate reductase (DHFR) activity, besides scanning electron microscopy (SEM). Inhibition of the enzyme thioredoxin reductase is not observed in either Escherichia Coli or Caco-2 cells; however, DHFR activity is compromised after incubation of E. coli cells with complex 1b. Moreover, loss of structural integrity and change in bacterial shape is observed in the images obtained from scanning electron microscopy (SEM) after treatment E. coli cells with complex 1b

A combination of Rosa canina extracts and gold complex favors apoptosis of caco-2 cells by increasing oxidative stress and mitochondrial dysfunction

Given the alarming increase in colorectal cancer (CRC) worldwide, novel therapies are urgently needed. Plant-derived extracts have gained considerable interest in the last years due to their strong anticancer effect mediated by their unique bioactive compounds. Specifically, rosehips from Rosa canina have been successfully tested against several cancer models, including colon cancer. Moreover, gold derivatives are a promising alternative to the current platinum-based drugs commonly used in CRC chemotherapy due to their lack of affinity for DNA. Herein we have investigated the antitumor potential of a drug combination made of acidic polyphenols extracted from R. canina and the gold complex (Au(C=C-2-NC5H4) (PTA)) in Caco-2 cell line as a model of CRC. The combination triggered strong apoptosis mediated by a blockage of the autophagic flux, which might be a consequence of a reactive oxygen species (ROS) increase and mitochondrial dysfunctionality. Our results suggest that the clinical application of plant polyphenols might enhance the anticancer effect of metallodrugs and reduce drug exposure time and therefore its side effects

Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-ß, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects

Sulfonamide-derived Dithiocarbamate Gold(i) complexes induce the apoptosis of colon cancer cells by the activation of Caspase 3 and redox imbalance

Two new families of dithiocarbamate gold(I) complexes derived from benzenesulfonamide with phosphine or carbene as ancillary ligands have been synthesized and characterized. In the screening of their in vitro activity on human colon carcinoma cells (Caco-2), we found that the more lipophilic complexes—those with the phosphine PPh3—exhibited the highest anticancer activity whilst also displaying significant cancer cell selectivity. Au(S2CNHSO2C6H5)(PPh3)] (1) and Au(S2CNHSO2-p-Me-C6H4)(IMePropargyl)] (8) produce cell death, probably by intrinsic apoptosis (mitochondrial membrane potential modification) and caspase 3 activation, causing cell cycle arrest in the G1 phase with p53 activation. Besides this, both complexes might act as multi-target anticancer drugs, as they inhibit the activity of the enzymes thioredoxin reductase (TrxR) and carbonic anhydrase (CA IX) with the alteration of the redox balance, and show a pro-oxidant effect

Estudio de la actividad antitumoral de complejos metálicos por hipertermia

Se ha llevado a cabo el estudio de las propiedades biológicas de seis complejos de oro (I) y de los ligandos libres sobre una línea celular de cáncer de colon humano (Caco-2/TC7). Se han realizado diversos ensayos para evaluar tanto su actividad anticancerígena como su selectividad. Además, en el trabajo se han analizado los efectos de un leve aumento de temperatura sobre el tratamiento (hipertermia), así como los efectos del flúor sobre la actividad antitumoral. De los seis complejos estudiados, cinco de ellos han demostrado tener una alta capacidad para producir la muerte de las células cancerosas, siendo además totalmente inocuos para las células normales. Se ha confirmado la presencia de flúor como un factor decisivo, aumentando la actividad anticancerígena de los complejos

Estudio de las propiedades anticancerígenas de complejos metálicos de oro

El cáncer de colon es uno de los cuatro tipos de cáncer más mortales y el tercero de mayor incidencia. Los efectos secundarios y la falta de efectividad de la radioterapia y la quimioterapia hacen que sea necesario continuar con la investigación para encontrar nuevos fármacos. Un ejemplo de ellos son los compuestos basados en metales, como los complejos organometálicos de oro estudiados en este trabajo. Se ha probado la citotoxicidad sobre células de cáncer de colon humano (Caco-2/TC7) de complejos de oro(I) con PTA (1,3,5-triaza-7-fosfaadamantano) y alquino derivados de flavonas, así como de las correspondientes flavonas precursoras de los mismos. Se buscaba comprobar si la efectividad de los compuestos flavona-complejo es mayor que la de cada componente por separado. También se ha estudiado la posible interacción de algunos de los compuestos con uno de los componentes mayoritarios de la sangre, la albúmina sérica. Los resultados parecen indicar que pueden ser transportados por esta proteína. Además interesa saber el mecanismo que conduce a la muerte celular, para lo que se han llevado a cabo diversos experimentos con el complejo que mejores resultados ha dado en las pruebas de citotoxicidad y de unión a albúmina. Este complejo produce apoptosis por vía intrínseca en las células tumorales