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1.
Food Microbiol ; 86: 103335, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31703853

RESUMO

The presence of eight common structural enterocin genes, singly or in varying combinations, in the genome of 15 antagonistic Enterococcus spp. previously isolated from artisan Greek Graviera and Galotyri retail cheeses was tested and associated with the mode of enterocin (Ent+) antilisterial activity of each isolate in three liquid culture media. The isolates were assigned to nine distinct strain genotypes of E. faecium (4 strains), E. durans (2) and E. faecalis (3). All strains were non-hemolytic, except for a cyl-positive E. faecalis genotype isolated from Galotyri cheese, which was strongly listericidal. All other strains varied from being listeriostatic to weakly listericidal in MRS and M17 broth, whereas all failed to inhibit listerial growth in skim milk. Two E. faecium strains retained strong Ent+ activity following neutralization and filter-sterilization of their MRS or M17 co-culture supernatants, whereas, all others required contact or proximity of their viable cells with L. monocytogenes cells in order to display activity. Additional studies to evaluate safety and potential synergistic effects of each strain genotype with starter LAB species in real milk environments will reveal the most active and truly harmless Enterococcus genotypes to be applied as co-starter or bioprotective adjunct cultures in traditional Greek cheese technologies.


Assuntos
Queijo/microbiologia , Enterococcus/química , Listeria monocytogenes/efeitos dos fármacos , Leite/microbiologia , Animais , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Bovinos , Meios de Cultura/química , Meios de Cultura/metabolismo , Enterococcus/genética , Enterococcus/isolamento & purificação , Enterococcus/metabolismo , Grécia , Listeria monocytogenes/crescimento & desenvolvimento
2.
Anticancer Res ; 39(10): 5505-5513, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570444

RESUMO

BACKGROUND/AIM: The potential of the DNA mismatch repair (MMR) system as a prognostic predictor has been evaluated in several cancer types. However, associations between MMR and the prognostic factors of ovarian cancer are poorly understood. PATIENTS AND METHODS: MLH1 expression was evaluated by immunohistochemistry in patients with advanced serous ovarian cancer treated with platinum- and taxane-based chemotherapy. Associations between MLH1 expression and clinicopathological factors as well as claudin-4 expression were examined. RESULTS: Low MLH1 expression was significantly associated with increased progression-free and overall survival, and a normalisation of CA125 levels after chemotherapy. Additionally, low claudin-4 expression was more frequently found among the group with low MLH1 expression. CONCLUSION: Low MLH1 expression was associated with improved prognosis and is a possible predictor of the chemosensitivity of ovarian cancer. Claudin-4 might be involved in the molecular mechanisms underlying how MLH1 influences survival and chemosensitivity in patients with ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteína 1 Homóloga a MutL/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Taxoides/farmacologia , Idoso , Antígeno Ca-125/metabolismo , Claudina-4/metabolismo , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão
3.
Chem Commun (Camb) ; 55(72): 10654-10664, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31418758

RESUMO

Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various nanomaterials such as vesicles, micelles, nanorods, and nanosheets in water. The structures and functions of the nanomaterials can be controlled by supramolecular engineering of the host-guest complexes. In addition, functionalization at the periphery of CB[6] and CB[7] generates CB[n]-based molecular amphiphiles (MAs) that can also self-assemble into vesicles or micelle-like nanoparticles in water. Taking advantage of the molecular cavities of CBs and their strong guest recognition properties, the surface of the self-assembled nanomaterials can be easily decorated with various functional tags in a non-covalent manner. In this feature article, the two types (SAs and MAs) of CB-based amphiphiles, their self-assemblies and their applications for nanotherapeutics and theranostics are presented with future perspectives.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Doxorrubicina/farmacologia , Nanoestruturas/química , Tensoativos/farmacologia , Antibióticos Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Células HeLa , Humanos , Células KB , Tensoativos/química
4.
Poult Sci ; 98(11): 5925-5931, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31298292

RESUMO

Surveillance studies have generally reported an increase in Escherichia coli strains resistant to major classes of antibiotics used for animals' treatment. The aim of this study was to test the susceptibility of 25 strains (isolated from 30 domestic Mallard ducks-Anas platyrhynchos, both sex, aged 8 to 14 wk, taxonomically alloted to the species E. coli using MALDI TOF mass spectrometry system) to antimicrobials (antibiotics, enterocins, and herbal extracts). Testing was performed using the agar disc method and the agar diffusion method. A total of 19 E. coli strains were multiresistant to antibiotics; but 10 of those strains were susceptible to enterocins with an inhibition activity of 100 AU/mL. All strains were susceptible to herbal extracts. These results indicate further benefit application of enterocins and herbal extracts to prevent/reduce problems caused with E. coli. Moreover, additional studies are in process.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Fezes/microbiologia , Extratos Vegetais/farmacologia , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Patos/microbiologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
5.
J Oleo Sci ; 68(8): 765-768, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292340

RESUMO

γ-Oryzanol is a naturally occurring component of rice bran and consists of various steryl ferulates. The antioxidant activities of γ-oryzanol have mostly been demonstrated in cell-free systems. Therefore, we determined whether steryl ferulate of γ-oryzanol suppress spontaneous intracellular reactive oxygen species (ROS) in cell-based systems. We found that cycloartenyl ferulate and ß-sitosteryl ferulate suppressed spontaneous intracellular ROS in a similar way to N-acetylcysteine and α-tocopherol.


Assuntos
Antioxidantes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Ácidos Cumáricos/farmacologia , Fenilpropionatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sitosteroides/farmacologia , Células HT29 , Humanos
6.
ACS Appl Mater Interfaces ; 11(26): 22925-22931, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31252492

RESUMO

Covalently self-assembled polymer nanocapsules (NCs) based on cucurbit[6]uril have been previously prepared and their applications in payload delivery and bioimaging have been demonstrated, showing significant potentials. However, the preparation of these NCs often requires laborious and tedious multistep reactions, including a low-yield conversion of perhydroxycucurbit[6]uril to perallyloxycucurbit[6]uril, subsequent photopolymerization of perallyloxycucurbit[6]uril with dithiol linkers, and two additional steps of treatment to remove disulfide loops and create cationic sulfoniums. Herein, we report a novel, facile approach leading to cucurbit[6]uril-based polymer NCs via direct alkylation of perhydroxycucurbit[6]uril with a ditopic linker, thereby saving significant time and efforts, which may lead to significant expansion in investigations of these unique materials in various applications, particularly biomedical sciences. As a proof of concept, we have further demonstrated that a photosensitive therapeutic payload, such as chlorin e6, may get encapsulated inside the NCs for improved, targeted photodynamic therapy against cancer cells.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Imidazóis/síntese química , Nanocápsulas/química , Neoplasias/terapia , Fotoquimioterapia , Alquilação/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Nanocápsulas/uso terapêutico , Polímeros/química , Polímeros/farmacologia , Porfirinas/química
7.
Molecules ; 24(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181726

RESUMO

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.


Assuntos
Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/síntese química , Docetaxel/química , Docetaxel/farmacologia , Células HeLa , Humanos , Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Paclitaxel/síntese química , Paclitaxel/química , Paclitaxel/farmacologia , Homologia Estrutural de Proteína , Taxoides/química , Tubulina (Proteína)/química
8.
Biomed Res Int ; 2019: 4094890, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119168

RESUMO

Safety aspects and probiotic properties of Enterococcus faecium FL31 strain producing an enterocin, named BacFL31 were previously demonstrated. Taking into account its originality, the enterocin BacFL31 was added alone at 200 AU/g or in combination with the aqueous peel onion (Allium cepa) extract (APOE) at 1.56 ± 0.3 mg/mL to ground beef meat. Its biopreservative effect was evaluated by microbiological, physicochemical and sensory analyses during 14 days at 4°C. The APOE was characterized for its phytochemical content: total phenolic (TPC), flavonoids (TFC) and tannins contents (TAC), its antioxidant capacity using the in vitro 1,1-diphenyl-2-picrylhydrazyl (DPPH) and its antilisterial activity. APOE had a high TPC, TFC and TAC respectively with 140 ± 2.05 (mg GAE/g), 35 ± 0.5 (mg QE/g) and 20.6 ± 1.4 (mg CE/g). Equally, APOE showed a potential radical scavenging activity compared to the butylated hydroxytoluene (BHT), with an anti-radical power (ARP) of 46 ± 1.5. During 14 days of storage at 4°C, the combination between APOE and BacFL31 limited the microbial deterioration (P < 0.05), led to a decrease in thiobarbituric acid reactive substances (TBARS) values and slowed down the metmyoglobin (MetMb) and carbonyl group accumulation and delayed the disappearance of sulfphydryl proteins (P < 0.05). The combination was also efficient (P < 0.05) against microflora proliferation, decreased primary and secondary lipid oxidation (P < 0.05), reduced protein oxidation and enhanced significantly (P < 0.05) the sensory attributes. Thus, the enterocin BacFL31 use from a safe Enterococcus faecium combined with APOE as a potential natural preservative to biocontrol ground beef was promising as it was effective at low concentration. The data lay bases for new tests to be carried out in other food matrices.


Assuntos
Microbiologia de Alimentos , Conservação de Alimentos , Cebolas/química , Animais , Produtos Biológicos/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Bovinos , Enterococcus faecium/química , Armazenamento de Alimentos , Humanos , Carne/microbiologia , Carne Vermelha/microbiologia
9.
BMC Cancer ; 19(1): 236, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30935371

RESUMO

BACKGROUND: Triple Negative breast cancer (TNBC) is a poor outcome subgroup of breast cancer defined based on the absence of expression of ERα and PR and HER2 amplification. These hard to treat cancers lack targeted treatment options and are therefore treated with a standard of care (SoC) generic cocktail of DNA damaging chemotherapy, with a wide range of clinical responses. While a subset of TNBC patients respond very well to this treatment, others receive no clinical benefit and die from their disease within a short time period. We currently lack biomarkers to prospectively identify patients likely to relapse and we lack alternate treatment options. METHODS: NUP98 protein expression was investigated in patient samples using two independent tissue microarrays (TMAs), as well as a normal breast TMA. Correlation with pathological response to various chemotherapy regimens was investigated. RESULTS: We have shown that high NUP98 is significantly associated with poor outcome in TNBC patient samples both by gene expression and IHC-based protein analysis. While trends linking NUP98 expression with poorer outcomes were observed in breast cancer overall (and more specifically in the LuminalB Her2- subgroup), significant correlations were observed in TNBC. This appeared to be specific to anthracycline based regimens as the association between NUP98 and response was not observed in patients treated with taxane-based chemotherapy. CONCLUSIONS: We have identified a novel biomarker, NUP98, that can predict response to anthracycline based chemotherapy in TNBC. The ability to prospectively identify patients who are less likely to respond to SoC chemotherapy is a vital step in improving the overall survival of these patients.


Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Antraciclinas/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Taxoides/farmacologia , Taxoides/uso terapêutico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
10.
Nat Biomed Eng ; 3(4): 264-280, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30952988

RESUMO

Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/uso terapêutico , Receptor EphA2/metabolismo , Animais , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Docetaxel/sangue , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Humanos , Lipossomos , Camundongos Endogâmicos NOD , Camundongos SCID , Taxoides/farmacologia , Taxoides/uso terapêutico , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Molecules ; 24(6)2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30889936

RESUMO

As part of our efforts to exploit the antitrypanosomal potential of sesquiterpene lactones (STL) from Helianthus tuberosus L. (Asteraceae), besides the known 4,15-iso-atriplicolide tiglate, -methacrylate and -isobutyrate, a hitherto unknown STL was isolated. Its structure was solved by extensive NMR measurements and confirmed by single crystal X-ray crystallography. This novel compound is a structural analog 4,15-iso-atriplicolide tiglate that possesses the same basic furanoheliangolide skeleton but differs in the position of the oxo function which is at C-2 instead of C-1, as well as in the fact that the oxygen atom of the furanoid ring is part of a hemiketal structure at C-3 and a double bond between C-5 and C-6. For this new STL we propose the name heliantuberolide-8-O-tiglate. Its activity against Trypanosoma brucei rhodesiense (causative agent of East African Human Typanosomiasis, Trypanosoma cruzi (Chagas Disease), Leishmania donovani (Visceral Leishmaniasis) and Plasmodium falciparum (Tropical Malaria) as well as cytotoxicity against rat skeletal myoblasts (L6 cell line) was determined along with those of the hitherto untested 4,15-iso-atriplicolide methacrylate and isobutyrate. In comparison with the iso-atriplicolide esters, the new compound showed a much lower level of bioactivity.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Furanos/química , Furanos/farmacologia , Helianthus/química , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Cristalografia por Raios X , Furanos/isolamento & purificação , Lactonas/química , Lactonas/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Sesterterpenos
12.
Bioorg Chem ; 85: 585-599, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30878891

RESUMO

A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The aim of this study was to design and synthesize propellane derivatives that can act as DNA intercalators and/or groove binders. The unique structure of the propellane derivatives and their ability to display planar ligands with numerous possible geometries, renders them potential starting points to design new drugs targeting DNA in cancer cells. New substituted furo-imidazo[3.3.3]propellanes were synthesized via the reaction of substituted alkenylidene-hydrazinecarbothioamides with 2-(1,3-dioxo-2,3-dihydro-1H-2-ylidene)propanedinitrile in tetrahydrofuran at room temperature. The structures of the products were confirmed by a combination of elemental analysis, NMR, ESI-MS, IR and single crystal X-ray analysis. Interestingly, 5c, 5d and 5f showed an ability to interact with Calf Thymus DNA (CT-DNA). Their DNA-binding mode was investigated using a combination of absorption spectroscopy, DNA melting, viscosity, CD spectroscopy measurements, as well as competitive binding studies with several dyes. Their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. 5c, 5d and 5f exhibited similar anti-proliferative activity against the A549 non-small cell lung cancer (NSCLC) cell line. Further mechanistic studies revealed their ability to induce DNA damage in the A549 cell line, as well as apoptosis, evidenced by elevated Annexin V expression, enhanced caspase 3/7 activation and PARP cleavage. In this study, we present the potential for designing novel propellanes to provoke cytotoxic activity, likely through DNA binding-induced DNA damage and apoptosis.


Assuntos
Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , DNA/metabolismo , Furanos/farmacologia , Imidazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Linhagem Celular Tumoral , DNA/química , Dano ao DNA/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/metabolismo , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Conformação de Ácido Nucleico/efeitos dos fármacos , Temperatura de Transição , Viscosidade
13.
Nat Commun ; 10(1): 1033, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833575

RESUMO

Taxanes are a family of natural products with a broad spectrum of anticancer activity. This activity is mediated by interaction with the taxane site of beta-tubulin, leading to microtubule stabilization and cell death. Although widely used in the treatment of breast cancer and other malignancies, existing taxane-based therapies including paclitaxel and the second-generation docetaxel are currently limited by severe adverse effects and dose-limiting toxicity. To discover taxane site modulators, we employ a computational binding site similarity screen of > 14,000 drug-like pockets from PDB, revealing an unexpected similarity between the estrogen receptor and the beta-tubulin taxane binding pocket. Evaluation of nine selective estrogen receptor modulators (SERMs) via cellular and biochemical assays confirms taxane site interaction, microtubule stabilization, and cell proliferation inhibition. Our study demonstrates that SERMs can modulate microtubule assembly and raises the possibility of an estrogen receptor-independent mechanism for inhibiting cell proliferation.


Assuntos
Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Taxoides/química , Taxoides/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Tubulina (Proteína)/química , Antineoplásicos/farmacologia , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Ligantes , Proteínas dos Microtúbulos/efeitos dos fármacos , Modelos Moleculares , Paclitaxel/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Microambiente Tumoral
14.
Oncogene ; 38(21): 4125-4141, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30700828

RESUMO

The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Palbociclib in combination with anti-hormonal therapy brings significant benefit to breast cancer patients. In this study, novel combination approaches and underlying molecular/cellular mechanisms for palbociclib were explored in squamous cell lung cancer (SqCLC), the second most common subtype of non-small cell lung cancer. While approximate 20% lung patients benefit from immunotherapy, most SqCLC patients who receive platinum-doublet chemotherapy as first-line treatment, which often includes a taxane, are still in need of more effective combination therapies. Our results demonstrated enhanced cytotoxicity and anti-tumor effect with palbociclib plus taxanes at clinically achievable doses in multiple SqCLC models with diverse cancer genetic backgrounds. Comprehensive gene expression analysis revealed a sustained disruption of pRB-E2F signaling by combination that was accompanied with enhanced regulation of pleiotropic biological effects. These included several novel mechanisms such as abrogation of G2/M and mitotic spindle assembly checkpoints, as well as impaired induction of hypoxia-inducible factor 1 alpha (HIF-1α). The decrease in HIF-1α modulated a couple key angiogenic and anti-angiogenic factors, resulting in an enhanced anti-angiogenic effect. This preclinical work suggests a new therapeutic opportunity for palbociclib in lung and other cancers currently treated with taxane based chemotherapy as standard of care.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fatores de Transcrição E2F/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteína do Retinoblastoma/metabolismo , Taxoides/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos
15.
Theranostics ; 9(3): 633-645, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809298

RESUMO

Accidental or suicidal ingestion of the world's most widely used herbicide, paraquat (PQ), may result in rapid multi-organ failure with a 60% fatality rate due to the absence of an effective detoxification solution. Effective, specific antidotes to PQ poisoning have been highly desired. Methods: The binding constant of PQ and a synthetic receptor, cucurbit[7]uril (CB[7]), was first determined in various pH environments. The antidotal effects of CB[7] on PQ toxicity were firstly evaluated with in-vitro cell lines. With in-vivo mice models, the pharmacokinetics and the biodistribution of PQ in major organs were determined to evaluate the influence of CB[7] on the oral bioavailability of PQ. Major organs' injuries and overall survival rates of the mice were systemically examined to evaluate the therapeutic efficacy of CB[7] on PQ poisoning. Results: We demonstrate that CB[7] may complex PQ strongly under various conditions and significantly reduce its toxicity in vitro and in vivo. Oral administration of PQ in the presence of CB[7] in a mouse model significantly decreased PQ levels in the plasma and major organs and alleviated major organs' injuries, when compared to those of mice administered with PQ alone. Further studies indicated that oral administration of CB[7] within 2 h post PQ ingestion significantly increased the survival rates and extended the survival time of the mice, in contrast to the ineffective treatment by activated charcoal, which is commonly recommended for PQ decontamination. Conclusion: CB[7] may be used as a specific oral antidote for PQ poisoning by strongly binding with PQ and inhibiting its absorption in the gastrointestinal tracts.


Assuntos
Antídotos/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Herbicidas/antagonistas & inibidores , Imidazóis/administração & dosagem , Paraquat/antagonistas & inibidores , Envenenamento/terapia , Receptores Artificiais/administração & dosagem , Administração Oral , Estruturas Animais/patologia , Animais , Antídotos/farmacocinética , Antídotos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular , Herbicidas/toxicidade , Imidazóis/farmacocinética , Imidazóis/farmacologia , Camundongos , Paraquat/toxicidade , Análise de Sobrevida
16.
Bioorg Med Chem Lett ; 29(6): 832-835, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30711393

RESUMO

Bisorbicillinol, which is isolated from Trichoderma sp. USF2690, is an inhibitor of ß-hexosaminidase release and tumor necrosis factor (TNF)-α, and Interleukin (IL)-4 secretion from rat basophilic leukemia (RBL-2H3) cells, with IC50 values of 2.8 µM, 2.9 µM and 2.8 µM respectively. We showed that the inhibitory mechanism of ß-hexosaminidase release and TNF-α secretion involved inhibition of Lyn, a tyrosine kinase. The inhibitory activities of bisorbicillinol indicate that this compound is a new candidate anti-allergic agent.


Assuntos
Antialérgicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases da Família src/antagonistas & inibidores , Animais , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Mastócitos/efeitos dos fármacos , Ratos , Receptores de IgE/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
17.
Phys Biol ; 16(3): 036003, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30763921

RESUMO

Androgen receptor (AR) signaling drives prostate cancer (PC) progression and remains active upon transition to castration resistant prostate cancer (CRPC). Active AR signaling is achieved through the nuclear accumulation of AR following ligand binding and through expression of ligand-independent, constitutively active AR splice variants, such as AR-V7, which is the most commonly expressed variant in metastatic CRPC (mCRPC) patients. Most currently approved PC therapies aim to abrogate AR signaling and activity by inhibiting this ligand-mediated nuclear translocation. In a prospective multi-institutional clinical study, we recently showed that taxane based chemotherapy is also capable of impairing AR nuclear localization (ARNL) in circulating tumor cells (CTCs) from CRPC patients, whereas taxane induced decreases in ARNL were associated with response. Thus, quantitative assessment of ARNL in CTCs can be used to monitor therapeutic response in patients and help guide clinical decisions. Here, we describe the development and implementation of quantitative high throughput (QHT) image analysis algorithms to aid in CTC identification and quantitative assessment of percent ARNL (%ARNL). We applied this algorithm to fifteen CRPC patients at the start of taxane chemotherapy, quantified %ARNL in CTCs, and correlated with expression of AR-V7 mRNA (from CTCs enriched via negative, CD45+ depletion of peripheral blood) and with biochemical (prostate specific antigen; PSA) response to taxane chemotherapy. We found that CTCs from AR-V7 positive patients had higher baseline %ARNL compared to CTCs from AR-V7 negative patients, consistent with the constitutive nuclear localization of AR-V7. In addition, lower %ARNL in CTCs at baseline was associated with biochemical response to taxane chemotherapy. High inter- and intra-patient heterogeneity was also observed. As ARNL is required for active AR signaling, the QHT algorithms described herein can provide prognostic and/or predictive value in future clinical studies.


Assuntos
Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Neoplásicas Circulantes/efeitos dos fármacos , Sinais de Localização Nuclear/análise , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Algoritmos , Núcleo Celular/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Células Neoplásicas Circulantes/metabolismo , Sinais de Localização Nuclear/efeitos dos fármacos , Neoplasias da Próstata/secundário , RNA Mensageiro/genética , Células Tumorais Cultivadas
18.
J Appl Microbiol ; 126(4): 1059-1069, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30637906

RESUMO

AIMS: To understand the bactericidal action of enterocin LD3 against Gram-negative bacteria. METHODS AND RESULTS: Minimum inhibitory concentration (MIC) of enterocin LD3 against Micrococcus luteus MTCC 106 and Escherichia coli NCDC 135 was 80 and 112 µg ml-1 , and minimum bactericidal concentration (MBC) was 128 and 180 µg ml-1 , respectively. The efflux of potassium ion (K+ ) was 14 and 13 ppm and electrical conductivity 10·5 and 8·3 mS cm-1 in cell-free supernatant of MIC-treated cells of M. luteus and E. coli respectively. The increased absorbance (OD260/280 ) 0·422/0·260 and 0·110/0·075 in the bacteriocin-treated cells of M. luteus MTCC 106 and E. coli, NCDC 135, respectively, suggested the release of nucleic acids and proteins. The higher infrared absorbance at 1451·82 and ~1094·30 cm-1 further suggested its interaction with cell membrane and nucleic acids of the target bacteria. The interaction of bacteriocin with nucleic acids was also confirmed using gel retardation assay. Transmission electron microscopy of the bacteriocin-treated cells revealed disruption of cell membrane and leakage of cytoplasmic contents. CONCLUSIONS: Enterocin LD3 demonstrates bactericidal activity against Gram-negative bacteria interacting with cell membrane and nucleic acids. SIGNIFICANCE AND IMPACT OF THE STUDY: The study discloses the possible mechanism of action of enterocin LD3 against Gram-negative bacteria which is a rare phenomenon.


Assuntos
Antibacterianos/farmacologia , Streptococcus faecium ATCC 9790/química , Bactérias Gram-Negativas/efeitos dos fármacos , Íons/metabolismo , Transporte Biológico/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Membrana Celular/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Testes de Sensibilidade Microbiana , Ácidos Nucleicos/metabolismo
19.
Proc Natl Acad Sci U S A ; 116(5): 1698-1703, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30647111

RESUMO

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived "surge" of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias Ovarianas/metabolismo , Platina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia
20.
PLoS One ; 14(1): e0210879, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30668583

RESUMO

In a previously published study, higher levels of spleen tyrosine kinase (Syk) were observed in recurrent post-chemotherapy ovarian cancers compared to primary tumors. Syk inhibition was found to stabilize microtubules and potentiate paclitaxel activity in cellular models of taxane-resistant ovarian cancers. We further studied the effects of Syk inhibition on paclitaxel activity in Syk(+) ovarian cancer cell models and in variants selected for taxane resistance. Syk inhibition was accomplished using RNAi and by exposure to the small molecule competitive inhibitor R406, the active metabolite of fostamatinib. Exposure to R406 or to a SYK-specific pool of siRNAs did not alter taxane activity in the OVCAR-3 cell line, which has the most Syk content in our panel of nine human ovarian cancer cell lines. However, treatment with R406 sensitised the multidrug resistant (MDR) variants MES-SA/Dx5 and SK-OV-3/TR to paclitaxel in a dose-dependent manner resulting from the inhibition of the ABCB1/P-glycoprotein (P-gp) drug transporter. These observations are Syk-independent since both MDR cell models are Syk negative. R406 modulated resistance to other known P-gp substrates, and we observed orthovanadate-sensitive ATPase stimulation resulting from treatment with R406. These data indicate that the chemo-sensitizing effect of R406 in taxane-resistant cells previously reported was not associated with Syk but resulted from the modulation of P-gp-mediated MDR.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Oxazinas/farmacologia , Piridinas/farmacologia , Quinase Syk/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/metabolismo , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , RNA Interferente Pequeno/genética , Quinase Syk/genética , Taxoides/farmacologia
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