RESUMEN
Peritoneal carcinomatosis is considered as a potentially lethal clinical condition, and the therapeutic options are limited. The antitumor effectiveness of the [Ru(l-Met)(bipy)(dppb)]PF6(1) and the [Ru(l-Trp)(bipy)(dppb)]PF6(2) complexes were evaluated in the peritoneal carcinomatosis model, Ehrlich ascites carcinoma-bearing Swiss mice. This is the first study that evaluated the effect of Ru(II)/amino acid complexes for antitumor activity in vivo. Complexes 1 and 2 (2 and 6 mg kg-1) showed tumor growth inhibition ranging from moderate to high. The mean survival time of animal groups treated with complexes 1 and 2 was higher than in the negative and vehicle control groups. The induction of Ehrlich ascites carcinoma in mice led to alterations in hematological and biochemical parameters, and not the treatment with complexes 1 and 2. The treatment of Ehrlich ascites carcinoma-bearing mice with complexes 1 and 2 increased the number of Annexin V positive cells and cleaved caspase-3 levels and induced changes in the cell morphology and in the cell cycle phases by induction of sub-G1 and G0/G1 cell cycle arrest. In addition, these complexes reduce angiogenesis induced by Ehrlich ascites carcinoma cells in chick embryo chorioallantoic membrane model. The treatment with the LAT1 inhibitor decreased the sensitivity of the Ehrlich ascites carcinoma cells to complexes 1 and 2 in vitro-which suggests that the LAT1 could be related to the mechanism of action of amino acid/ruthenium(II) complexes, consequently decreasing the glucose uptake. Therefore, these complexes could be used to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. Besides, these complexes induce apoptosis by combination of different mechanism of action.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Ehrlich/patología , Neoplasias Peritoneales/patología , Compuestos de Rutenio/farmacología , Aminoácidos/farmacología , Animales , Western Blotting , RatonesRESUMEN
Antifouling biocides, such as irgarol and diuron, are commonly used in antifouling paints. Recently, studies carried out in a Brazilian region of ecological concern have warned for extremely high levels of these biocides. So, this work focused on a 4-year (2015-2018) evaluation considering the occurrence, environmental fate, seasonal variations and ecological risk assessment of irgarol and diuron in water and sediment from São Marcos Bay, Brazil, which is an area of international relevance located in the Amazon region. The results showed the ubiquitous presence of antifouling biocides, as well as their wide distribution along the bay. The concentration range of irgarol was between <0.8 and 89.4 ng L-1 in water and between <0.5 and 9.2 ng g-1dw in sediments, whereas diuron showed a range between <1.4 and 22.0 ng L-1 in water and between <2.0 and 15.0 ng g-1dw in sediments. The distribution of the biocides was mainly related to the intense Bay hydrodynamics. The environmental risk assessment showed that irgarol and diuron posed "high risk" to the aquatic biota of São Marcos Bay, exceeding international Environmental Quality Guidelines. The results represent a robust study on the environmental fate of such biocides and intend to be a useful data source for eventual legislation since regulation concerning antifouling substances is necessary for Brazil.
Asunto(s)
Desinfectantes/análisis , Brasil , Diurona , Monitoreo del Ambiente , Medición de Riesgo , Triazinas , Contaminantes Químicos del AguaRESUMEN
Ruthenium is attracting considerable interest as the basis for new compounds to treat diseases, and studies have shown that complexes with different structures have significant antineoplastic and antimetastatic potential against several types of tumors, including tumors resistant to cisplatin drugs. We examined the cytotoxic, genotoxic, and pro-apoptotic activities of six ruthenium complexes containing amino acid with general formulation [Ru(AA)(bipy)(dppb)]PF6, where AA = amino acid (alanine, glycine, leucine, lysine, methionine, or tryptophan); bipy = 2,2´-bipyridine; and dppb = [1,4-bis(diphenylphosphine)butane], against A549 (lung carcinoma) and K562 (chronic myelogenous leukemia) cancer cells. The results show that the ruthenium complexes tested were able to induce cytotoxicity in A549 and K562 cancer cells. Complex 1 containing alanine inhibited the cell viability of A549 and K562 tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and the induction of DNA damage and cell cycle arrest. Complex 1 was able to induce caspase-mediated apoptosis in K562 cells through the mitochondrial dysfunction, the upregulation of apoptotic genes, and the downregulation of Bcl2 anti-apoptotic gene. Besides being cytotoxic to K562 and A549 cells, ruthenium complex containing alanine shows low cytotoxicity and genotoxicity against non-tumor cells. These results suggest that the ruthenium (II) complex is a potential safe and efficient antineoplastic candidate for leukemia treatment.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Leucemia , Rutenio , Aminoácidos , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Complejos de Coordinación/farmacología , Humanos , Rutenio/farmacologíaRESUMEN
Ruthenium complexes are being considered as novel chemotherapeutic alternatives for cancer treatment. In our study, we assessed the antitumoral activities of novel ruthenium complexes coupled to the amino acids proline (RuPro) and threonine (RuThr) in prostate tumor cell lines (DU145) and breast (MCF7), and normal cell lines of the lung fibroblast (GM07492A). Our results revealed that the EC50 of the complexes for DU145 and MCF7 was two times lower than that GM07492A. Moreover, RuPro and RuThr were not able to induce significant genomic instability, cell cycle arrest or cell death in GM07492A, but could induce DNA damage, arrest in G2/M and apoptosis in DU145 and MCF7. Furthermore, BAX, TP53 and ATM were found to be upregulated in DU145 and MCF7 treated with RuPro and RuThr, in which, a higher ASCT2 gene expression was also observed. Using molecular docking, RuPro and RuThr interact with ASCT2, suggesting that this transporter might have a pivotal role in the execution of their activities. Hence, our results with RuPro and RuThr are capable of selectively inducing genetic damage, cell cycle arrest and apoptosis in DU145 and MCF7. We suggest that the selective action of the RuPro and RuThr complexes is related to the higher expression of ASCT2 in the tumor cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Quelantes/farmacología , Inestabilidad Genómica/efectos de los fármacos , Prolina/química , Neoplasias de la Próstata/tratamiento farmacológico , Compuestos de Rutenio/farmacología , Treonina/química , Sistema de Transporte de Aminoácidos ASC/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Femenino , Humanos , Ligandos , Masculino , Antígenos de Histocompatibilidad Menor/efectos de los fármacos , Simulación del Acoplamiento Molecular , Neoplasias de la Próstata/patologíaRESUMEN
Fouling organisms attach and grow on submerged surfaces causing several economic losses. Thus, biocides have been introduced in antifouling paints in order to avoid this phenomenon, but their widespread use became a global problem, mainly in ports, leisure and fishing boat harbors, since these substances can be highly toxic to non-target organisms. The occurrence and environmental behavior of antifouling biocides are especially unknown in some peculiar regions, such as Amazon areas. Thus, the aim of this work was to evaluate, for the first time, levels and the partitioning behavior of the antifouling organic biocides irgarol, diuron and also stable degradation products of dichlofluanid and diuron (DMSA and DCPMU, respectively) in sediments and porewaters from a high boat traffic area located in the Northeast of Brazil, a pre-Amazon region. Our results showed high concentrations of irgarol (<1.0-89.7⯵gâ¯kg-1) and diuron (<5.0-55.2⯵gâ¯kg-1) in sediments. In porewater, DCPMU (<0.03-0.67⯵gâ¯L-1) and DMSA (<0.008-0.263⯵gâ¯L-1) were the mainly substances detected. High Kd and Koc obtained for both irgarol and diuron showed a partitioning preference in the solid phase. This work represents one of the few registers of contamination by antifouling substances in Amazonian areas, despite their environmental relevance.
Asunto(s)
Desinfectantes/análisis , Monitoreo del Ambiente/métodos , Sedimentos Geológicos/química , Agua de Mar/química , Contaminantes Químicos del Agua/análisis , Compuestos de Anilina/análisis , Brasil , Diurona/análisis , Pintura/análisis , Navíos , Triazinas/análisisRESUMEN
Anticancer potential of ruthenium complexes has been widely investigated, but safety evaluation studies are still scarce. Despite of ruthenium-based anticancer agents are known to cause fewer side effects compared to other metal-based drugs, these compounds are not fully free of toxicity, causing mainly nephrotoxicity. Based on the promising results from antitumor activity of the complexes [Ru(L-Met)(bipy)(dppb)]PF6 (RuMet) and [Ru(L-Trp)(bipy)(dppb)]PF6 (RuTrp), for the first time we investigated the toxicity profile of these complexes in rodent and zebrafish models. The acute oral toxicity was evaluated in Swiss mice. The mutagenic and genotoxic potential was determined by a combination of Micronucleus (MN) and Comet assay protocols, after exposure of Swiss mice to RuMet and RuTrp in therapeutic doses. Zebrafish embryos were exposed to these complexes, and their development observed up to 96 h post-fertilization. RuMet and RuTrp complexes showed low acute oral toxicity. Recorded behavioral changes were not recorded, nor were macroscopic morphological changes or structural modifications in the liver and kidneys. These complexes did not cause genetic toxicity, presenting a lack of micronuclei formation and low DNA damage induction in the cells from Swiss mice. In contradiction, cisplatin treatment exhibited high mutagenicity and genotoxicity. RuMet and RuTrp showed low toxicity in the embryo development of zebrafish. The RuMet and RuTrp complexes demonstrated low toxicity in the two study models, an interesting property in preclinical studies for novel anticancer agents.
Asunto(s)
Antineoplásicos/toxicidad , Daño del ADN/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Compuestos de Rutenio/toxicidad , Administración Oral , Aminoácidos/química , Animales , Antineoplásicos/química , Cisplatino/toxicidad , Ensayo Cometa , Femenino , Masculino , Ratones , Pruebas de Micronúcleos , Compuestos de Rutenio/química , Pruebas de Toxicidad Aguda , Pez CebraRESUMEN
Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas.