RESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.
Assuntos
Adenocarcinoma/genética , Carcinogênese/genética , Células-Tronco Neoplásicas , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Movimento Celular/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
Anti- and prooxidant properties of quercetin under different conditions were investigated using glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme containing essential cysteine residues. Quercetin was shown to produce hydrogen peroxide in aqueous solutions at pH 7.5, this resulting in the oxidation of the cysteine residues of the enzyme. Quercetin significantly increased oxidation of GAPDH observed in the presence of ferrous ions, particularly when FeSO(4) was added to the solution containing GAPDH and quercetin. The results suggest the formation of hydroxyl radical in the case of the addition of FeSO(4) to a quercetin solution. At the same time, quercetin protects GAPDH from oxidation in the presence of ascorbate and Fe(3+). In the absence of metals, quercetin protects SH-groups of GAPDH from oxidation by the superoxide anion generated by the system containing xanthine/xanthine oxidase.
Assuntos
Antioxidantes , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Oxidantes , Quercetina/farmacologia , Hidrolases Anidrido Ácido/metabolismo , Ácido Edético/farmacologia , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Oxirredução , Compostos de Sulfidrila/metabolismo , AcilfosfataseRESUMO
Magnetic nanoparticles (MNPs) are the major class of nanoparticles (NPs) with specific functional properties that make them good candidates for biomedical applications. Due to their response to the magnetic field, they can be used in targeted drug delivery systems. In current research, the MNPs were synthesized with the general formula of Fe1-xMnxFe2O4 by the co-precipitation technique. First, the effect of the Fe2+ ions in the system was investigated. Succinic anhydride was used as the first stabilizer to prepare surface for binding two types of polymer, including Polyethylene glycol (PEG) and palmitoylated Polyethylene glycol-grafted Chitosan (Cs-PEG-PA) were introduced as a polymeric shell. The composition, size, structure and magnetic properties of NPs were determined by the particle size analysis (PSA), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and vibrating sample magnetometer (VSM). Determining the well-defined properties of MNPs, methotrexate (MTX), as a common anticancer drug, was encapsulated into the coated MNPs. The drug encapsulation efficiency was as high as 92.8% with the magnetization value of 19.7emu/g. The in-vitro release pattern was studied, showing only 6% of the drug release in pH=7.4 (as a model of the physiological environment) and 25% in pH=5.4 (as a model of the tumor tissue environment) after 72h. Based on these results, we may be able to introduce this specific system as a novel pH sensitive MNP system for MTX targeting to tumor tissues in cancer chemotherapy.
Assuntos
Quitosana , Materiais Revestidos Biocompatíveis , Compostos Férricos , Compostos de Manganês , Metotrexato , Nanopartículas/química , Polietilenoglicóis , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacocinética , Materiais Revestidos Biocompatíveis/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Compostos Férricos/química , Compostos Férricos/farmacocinética , Compostos Férricos/farmacologia , Humanos , Células MCF-7 , Compostos de Manganês/química , Compostos de Manganês/farmacocinética , Compostos de Manganês/farmacologia , Metotrexato/química , Metotrexato/farmacocinética , Metotrexato/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologiaRESUMO
P-glycoprotein (P-gp) is a transmembrane efflux pump that has been associated with ineffective cancer chemotherapy and multidrug resistance (MDR). Chemical inhibitors of P-gp could have potential cancer therapeutic applications by preventing or reversing MDR. To exploit this, we designed twenty-five tetrahydroquinolinone analogs bearing pyridyl methyl carboxylate at C3 and different substituents at C4 as MDR reversal agents. The inhibitory effects of the synthesized compounds against P-gp were assessed by flow cytometric determination of rhodamine 123 accumulation in P-gp over-expressing MES-SA/DX5 cells. Fluorescence imaging of intracellular rhodamine 123 accumulation in MES-SA/DX5 cells was also performed. Furthermore, the effect of active derivatives on the reduction of doxorubicin's IC50 in MES-SA/DX5 cells was evaluated using MTT assay. Molecular docking was used to confirm the binding mode of some of the synthesized compounds. Five compounds in group A, bearing a 2-pyridyl methyl ester substituent at the C3 position, significantly increased rhodamine accumulation at 25 µM comparable to verapamil, a well-established P-gp inhibitor, while only 2 compounds in group B bearing 3-pyridyl methyl ester at the same position had this effect. This study shows that tetrahydroquinolinones containing methyl pyridine esters could represent an attractive scaffold for the discovery of P-gp inhibitors as MDR reversal agents in cancer cells.
RESUMO
Atractylis gummifera L. (Asteraceae) is a thistle located in the Mediterranean regions. Despite the plant's well-known toxicity, its ingestion continues to be a common cause of poisoning. The toxicity of Atractylis gummifera resides in atractyloside and carboxyatractyloside, two diterpenoid glucosides capable of inhibiting mitochondrial oxidative phosphorylation. Both constituents interact with a mitochondrial protein, the adenine nucleotide translocator, responsible for the ATP/ADP antiport and involved in mitochondrial membrane permeabilization. Poisoned patients manifest characteristic symptoms such as nausea, vomiting, epigastric and abdominal pain, diarrhoea, anxiety, headache and convulsions, often followed by coma. No specific pharmacological treatment for Atractylis gummifera intoxication is yet available and all the current therapeutic approaches are only symptomatic. In vitro experiments showed that some compounds such as verapamil, or dithiothreitol could protect against the toxic effects of atractyloside, but only if administered before atractyloside exposure. New therapeutic approaches could come from immunotherapy research: some studies have already tried to produce polyclonal Fab fragments against the toxic components of Atractylis gummifera.
Assuntos
Atractylis , Atractilosídeo , Atractilosídeo/análogos & derivados , Inibidores Enzimáticos , Intoxicação , Atractylis/química , Atractylis/intoxicação , Atractilosídeo/química , Atractilosídeo/isolamento & purificação , Atractilosídeo/toxicidade , Criança , Pré-Escolar , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/toxicidade , Etnofarmacologia , Humanos , Região do Mediterrâneo , Intoxicação/mortalidade , Intoxicação/fisiopatologia , Intoxicação/terapiaRESUMO
Hydroxycinnamic acids (HCAs) are important phytochemicals possessing significant biological properties. Several investigators have studied in vitro antioxidant activity of HCAs in detail. In this review, we have gathered the studies focused on the structure-activity relationships (SARs) of these compounds that have used medicinal chemistry to generate more potent antioxidant molecules. Most of the reports indicated that the presence of an unsaturated bond on the side chain of HCAs is vital to their activity. The structural features that were reported to be of importance to the antioxidant activity were categorized as follows: modifications of the aromatic ring, which include alterations in the number and position of hydroxy groups and insertion of electron donating or withdrawing moieties as well as modifications of the carboxylic function that include esterification and amidation process. Furthermore, reports that have addressed the influence of physicochemical properties including redox potential, lipid solubility and dissociation constant on the antioxidant activity were also summarized. Finally, the pro-oxidant effect of HCAs in some test systems was addressed. Most of the investigations concluded that the presence of ortho-dihydroxy phenyl group (catechol moiety) is of significant importance to the antioxidant activity, while, the presence of three hydroxy groups does not necessarily improve the activity. Optimization of the structure of molecular leads is an important task of modern medicinal chemistry and its accomplishment relies on the careful assessment of SARs. SAR studies on HCAs can identify the most successful antioxidants that could be useful for management of oxidative stress-related diseases.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Antioxidants could be promising agents for management of oxidative stress-related diseases. New biologically active compounds, belonging to a rare class of natural lignans with antiangiogenic, antitumoral and DNA intercalating properties, have been recently synthesized. These compounds are benzo[kl]xanthene lignans (1,2) and dihydrobenzofuran neolignans (3,4). The radical scavenging and chain-breaking antioxidant activities of compounds 1-4 were studied by applying different methods: radical scavenging activity by DPPH rapid test, chain-breaking antioxidant activity and quantum chemical calculations. All studied compounds were found to be active as DPPH scavengers but reaction time with DPPH and compounds' concentrations influenced deeply the evaluation. The highest values of radical scavenging activity (%RSAmax) and largest rate constants for reaction with DPPH were obtained for compounds 2 and 3. Comparison of %RSAmax with that of standard antioxidants DL-α-tocopherol (TOH), caffeic acid (CA) and butylated hydroxyl toluene (BHT) give the following new order of %RSA max: TOH (61.1%) > CA (58.6%) > 3 (36.3%) > 2 (28.1%) > 4 (6.7%) > 1 (3.6%) = BHT (3.6%). Chain-breaking antioxidant activities of individual compounds (0.1-1.0 mM) and of their equimolar binary mixtures (0.1 mM) with TOH were determined from the kinetic curves of lipid autoxidation at 80 °C. On the basis of a comparable kinetic analysis with standard antioxidants a new order of the antioxidant efficiency (i.e., protection factor, PF) of compounds 1-4 were obtained: 2 (7.2) ≥ TOH (7.0) ≥ CA (6.7) > 1 (3.1) > 3 (2.2) > ferulic acid FA (1.5) > 4 (0.6); and of the antioxidant reactivity (i.e. inhibition degree, ID): 2 (44.0) >> TOH (18.7) >> CA (9.3) >> 1 (8.4) > 3 (2.8) > FA (1.0) > 4 (0.9). The important role of the catecholic structure in these compounds, which is responsible for the high chain-breaking antioxidant activity, is discussed and a reaction mechanism is proposed. Higher oxidation stability of the lipid substrate was found in the presence of equimolar binary mixtures 2 + TOH, 3 + TOH and 4 + TOH. However, an actual synergism was only obtained for the binary mixtures with compounds 3 and 4. The geometries of compounds and all possible phenoxyl radicals were optimized using density functional theory. For description of the scavenging activity bond dissociation enthalpies (BDE), HOMO energies and spin densities were employed. The best correlation between theoretical and experimental data was obtained for compound 2, with the highest activity, and for compound 4 with the lowest activity. The BDE is the most important theoretical descriptor, which correlates with the experimentally obtained antioxidant activity of the studied benzo[kl]xanthene lignans and dihydrobenzofuran neolignans.
Assuntos
Antioxidantes/química , Benzofuranos/química , Lignanas/química , Xantenos/síntese química , Antioxidantes/síntese química , Benzofuranos/síntese química , Compostos de Bifenilo/química , Hidroxitolueno Butilado/química , Ácidos Cafeicos/química , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Temperatura Alta , Cinética , Lignanas/síntese química , Lipídeos/química , Oxirredução , Fenóis/química , Picratos/química , Teoria Quântica , Soluções , Relação Estrutura-Atividade , Termodinâmica , alfa-Tocoferol/químicaRESUMO
Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.
Assuntos
Antioxidantes/uso terapêutico , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Antioxidantes/farmacologia , Antipirina/análogos & derivados , Antipirina/farmacologia , Antipirina/uso terapêutico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Edaravone , Humanos , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêutico , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Vitamina A/farmacologia , Vitamina A/uso terapêutico , Vitamina E/farmacologia , Vitamina E/uso terapêuticoRESUMO
In patients with rheumatoid arthritis (RA) a decrease in the terminal galactose content of N-linked glycans of the Fc region of agalactosyl immunoglobulin G (IgG) (G0) occurs. The aim of this study was to evaluate, for the first time, the effect of infliximab, a new monoclonal antibody for the treatment of RA, on this phenomenon. A total of 19 patients with active RA were treated with intravenous infliximab (3 mg/kg) in combination with methotrexate (MTX) (10-20 mg). IgG was purified from their serum by caprylic acid. Analysis of IgG glycosylation was performed by lectin blotting/immunoblotting and enzyme linked lectin assay (ELLA)/enzyme linked immunosorbent assay (ELISA) using the Griffonia (bandeiraea) simplicifolia lectin II and protein-A/alkaline phosphatase. The purity of IgG samples obtained was higher than 90%. The sensitivity of the lectin/immunoblotting method was of about 0.25 microg of IgG. The inter- and intraassay coefficients of variation (CV) were 1.3% and 9.0% for lectin blotting, and 4.6% and 8.3% for immunoblotting, respectively. The sensitivity of the ELLA/ELISA approach was 0.025 microg/microL and the inter- and intraassay CV were 6.2% and 7.7% for ELLA, and 5.1% and 14.1% for ELISA, respectively. A good linear correlation (r2=0.18, P<0.05) was obtained between the two different experimental approaches. A decrease of G0 was observed in patients who clinically improved (according to the American College of Rheumatology criteria) following the pharmacological treatment. Our data indicate that infliximab can reduce the concentration of G0 in patients with active RA.