Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.039
Filtrar
2.
Lancet Haematol ; 7(9): e649-e659, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32758434

RESUMO

BACKGROUND: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma. METHODS: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing. FINDINGS: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation. INTERPRETATION: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting. FUNDING: Celgene Corporation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Piperidonas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Meia-Vida , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/patologia , Piperidonas/efeitos adversos , Piperidonas/farmacocinética , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Recidiva , Índice de Gravidade de Doença , Trombocitopenia/etiologia , Trombocitopenia/patologia , Resultado do Tratamento
3.
Parasitol Res ; 119(7): 2159-2176, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32424554

RESUMO

The proteasome is the key player in the cellular protein degradation machinery and is pivotal for protein homeostasis and Schistosoma mansoni (S. mansoni) survival. Our group study provides insights into proteasome inhibitors and reveals that selective schistosomiasis agents represent an interesting branch of proteasome research linked to the development of new drugs for this neglected disease. Here, we explored the phenotypic response of S. mansoni to b-AP15, a bis-benzylidine piperidone that inhibits 26S proteasome deubiquitinases (DUBs), ubiquitin-specific protease 14 (USP14), and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5). b-AP15 induces a modest decrease in egg production in vitro and reduces viability, leading to the death of parasite couples. This inhibitor also induces a twofold increase in the accumulation of polyubiquitinated proteins in S. mansoni adult worms and causes tegument changes such as disintegration, wrinkling, and bubble formation, both throughout the length of the parasite and in the oral sucker. b-AP15 alters the cell organelles of adult S. mansoni worms, and we specifically observed mitochondrial alterations, which are suggestive of proteotoxic stress leading to autophagy. Taken together, these results indicate that the deubiquitinase function of the proteasome is essential for the parasite and support the hypothesis that the proteasome constitutes an interesting drug target for the treatment of schistosomiasis.


Assuntos
Enzimas Desubiquitinantes/antagonistas & inibidores , Oviposição/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Feminino , Proteínas de Helminto/metabolismo , Piperidonas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Schistosoma mansoni/metabolismo , Schistosoma mansoni/fisiologia , Ubiquitinação/efeitos dos fármacos
4.
Chem Pharm Bull (Tokyo) ; 68(2): 150-154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009082

RESUMO

Singlet oxygen (1O2) is highly oxidative and exerts strong cytotoxic effects. We tried to establish the best combination of a singlet oxygen generation system and a detection method with ESR, for measurement of the quenching activities of various substances. The photosensitizing reaction of rose bengal or thermal decomposition of 4-methyl-1,4-etheno-2,3-benzodioxin-1(4H)-propanoic acid (endoperoxide, EP) was used for the generation of 1O2, and a sterically hindered secondary amine, 2,2,6,6-tetramethyl-4-piperidone (TEMPD) or 2,2,6,6-tetramethyl-4-piperidinol (TEMP-OH), was used as the 1O2 detection probe. These secondary amines were oxidized by 1O2 to form stable nitroxide radicals, which were detectable by ESR. TEMPD was found to be readily oxidized by air, causing large background signals in comparison with TEMP-OH. The ESR signal obtained by the irradiation of rose bengal with visible light in the presence of TEMP-OH consisted of two kinds of nitroxide radical overlapping. In contrast, only a single nitroxide signal was observed when TEMP-OH was reacted with 1O2 generated from EP. Therefore, the best combination should be EP as the 1O2 generator and TEMP-OH as the detection probe. When using this combination, we found that the concentrations of some organic solvents such as dimethyl sulfoxide and acetonitrile should be kept constant for reliable quantification, because the concentrations of organic solvents affect the ESR signal intensity.


Assuntos
Espectroscopia de Ressonância de Spin Eletrônica/métodos , Oxigênio Singlete/análise , Oxirredução , Fármacos Fotossensibilizantes/química , Piperidonas/química , Propionatos/química , Rosa Bengala/química
5.
Acta Trop ; 205: 105350, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31962096

RESUMO

Schistosomiasis is one of the most important parasitic infections in terms of its negative effects on public health and economics. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new anthelmintic agents. Piplartine, also known as piperlongumine, is a biologically active alkaloid/amide from peppers that can be detected in high amounts in the roots of Piper tuberculatum. Previously, it has been shown to have in vitro schistosomicidal effects. However, its anthelmintic activity in an animal host has not been reported. In the present work, in vivo antischistosomal properties of isolated piplartine were evaluated in a mouse model of schistosomiasis infected with either adult (patent infection) or juvenile (pre-patent infection) stages of Schistosoma mansoni. A single dose of piplartine (100, 200 or 400 mg/kg) or daily doses for five consecutive days (100 mg/kg/day) administered orally to mice infected with schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest piplartine dose (400 mg/kg) caused a significant reduction in a total worm burden of 60.4% (P < 0.001) in mice harbouring adult parasites. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also significantly inhibited by piplartine. Studies using scanning electron microscopy revealed substantial tegumental alterations in parasites recovered from mice. Since piplartine has well-characterized mechanisms of toxicity, is easily available, and is cost-effective, our results indicate that this bioactive molecule derived from medicinal plants could be a potential lead compound for novel antischistosomal agents.


Assuntos
Piperidonas/uso terapêutico , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Piper/química
6.
J Antibiot (Tokyo) ; 73(3): 184-188, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31853030

RESUMO

A LC-MS-guided screening led to the isolation of two new streptimidone derivatives (2 and 3) containing a glutarimide ring and two glutarimide ring-opened compounds (4 and 5) along with a known glutarimide-containing polyketide, streptimidone (1) from Streptomyces sp. W3002 strain. Their structures were elucidated by MS and NMR spectroscopic analyses and by comparison with data from the literature. Compound 2 is a non-hydroxylated analog at the C-5 position of streptimidone. The structure of 3 was determined as a streptimidone derivative possessing the α, ß-unsaturated ketone moiety at positions C-5 and C-6. Compound 4 had similar chemical shifts and splitting patterns with 3, but the glutarimide ring is opened. Compound 5 closely resembles that of 4 with the only difference being the existence of an additional methoxy group instead of an amide group. Streptimidone (1) and 3 showed weak cytotoxic activity against three human cancer cell lines, respectively.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Piperidonas/química , Piperidonas/farmacologia , Streptomyces/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Cromatografia Líquida , Espectrometria de Massas , Estrutura Molecular
7.
Pak J Pharm Sci ; 32(5): 2033-2039, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31813868

RESUMO

In this present study seven novel thiazole derivatives (PM3-PM9) were synthesized by cyclization of key intermediate thiosemicarbazone (PM2), derived from 4-piperidone (PM1). The parent 4-piperidone was synthesized by Mannich condensation reaction with good yield (89%). All the derivatives were characterized by UV, IR, 1HNMR and mass spectral analysis. All the synthesized products were screened for their in vivo analgesic activities. Most of the tested compounds exhibited potential to reduce pain and some of them showed good analgesic properties. Thiosemicarbazone derivative showed most significant activity (p-value 0.01). All the thiazole derivatives exhibited dose dependent mild to good analgesic activities. Among thiazole derivatives, chloro and nitro substituted compounds (PM3, PM4, and PM5) showed highest analgesic activities.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Piperidonas/química , Piperidonas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Feminino , Masculino , Camundongos , Dor/tratamento farmacológico , Relação Estrutura-Atividade
8.
Molecules ; 24(23)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766540

RESUMO

Four novel xanthohumol (XN) cocrystals with pharmaceutically acceptable coformers, such as nicotinamide (NIC), glutarimide (GA), acetamide (AC), and caffeine (CF) in the 1:1 stoichiometry were obtained by the slow evaporation solution growth technique. The structure of the cocrystals was determined by single crystal X-ray diffraction. The analysis of packing and interactions in the crystal lattice revealed that molecules in the target cocrystals were packed into almost flat layers, formed by the O-HO, O-HN, and N-HO-type contacts between the xanthohumol and coformer molecules. The results provided details about synthons responsible for crystal net stabilization and all hydrogen bonds observed in the crystal lattice. The main synthon was formed via the hydrogen bond between the hydroxyl group in the B ring of XN and coformers. The three-dimensional crystal lattice was stabilized by the hydrogen XN-XN interactions whereas the π-π stacking interactions played an additional role in layer binding, with the exception of low quality cocrystals formed with caffeine. Application of FTIR and Raman spectroscopy confirmed that the crystalline phase of obtained cocrystals was not a simple combination of individual components and completely different crystal phases resulted from the effect of intermolecular interactions. The multivariate analysis showed the changes in the spectra, and this technique can be applied in a combination with vibrational spectroscopy for fast screening of new crystal phases. Additionally, the solubility studies of pure XN and its cocrystals exhibited a 2.6-fold enhancement in XN solubility in aqueous solution for XN-AC and, to a lesser extent, for other cocrystals.


Assuntos
Chalconas/química , Cristalografia por Raios X/métodos , Flavonoides/química , Modelos Moleculares , Prenilação , Propiofenonas/química , Análise Espectral Raman/métodos , Acetamidas/química , Cafeína/química , Varredura Diferencial de Calorimetria , Cristalização , Niacinamida/química , Piperidonas/química , Vibração
9.
Transplant Proc ; 51(10): 3444-3448, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31733799

RESUMO

BACKGROUND: Gemigliptin is a potent, selective dipeptidyl peptidase (DPP)-4 inhibitor that does not require any dosage adjustment based on renal function. It is also known to have no apparent interaction with commonly used drugs. In the present study, we aimed to evaluate the glucose-lowering efficacy and safety of gemigliptin in post-transplant patients with type 2 diabetes mellitus (T2D). METHODS: A total of 84 patients who were prescribed gemigliptin for more than 180 days after transplantation were analyzed retrospectively. Six-month changes in blood glucose and glycated hemoglobin (HbA1c) levels were checked to assess glycemic efficacy. Safety was evaluated by examining its influence on immunosuppressive treatment, as determined by the blood trough level and dosage of calcineurin inhibitors, as well as changes in parameters related to liver and renal function. RESULTS: Six months of gemigliptin treatment significantly lowered blood glucose level (HbA1c: 8.16 ± 1.69 to 7.44 ± 1.26%; P < .001). There were no significant changes in blood trough levels of immunosuppressants, including tacrolimus, cyclosporine, and sirolimus. The dosage of immunosuppressants was also stable. In addition, there were no significant changes in the levels of liver enzymes and renal function during 6 months of treatment. CONCLUSION: Gemigliptin robustly lowered blood glucose levels without exerting any significant effect on immunosuppressive treatment, renal function, and liver enzymes in post-transplant patients with T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Transplante de Órgãos , Piperidonas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Molecules ; 24(21)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671767

RESUMO

In this study, we investigated whether the curcuminoids, CLEFMA and EF24, improved cisplatin efficacy and reduced cisplatin ototoxicity. We used the lung cancer cell line, A549, to determine the effects of the curcuminoids and cisplatin on cell viability and several apoptotic signaling mechanisms. Cellular viability was measured using the MTT assay. A scratch assay was used to measure cell migration and fluorescent spectrophotometry to measure reactive oxygen species (ROS) production. Western blots and luminescence assays were used to measure the expression and activity of apoptosis-inducing factor (AIF), caspases-3/7, -8, -9, and -12, c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK), and proto-oncogene tyrosine-protein kinase (Src). A zebrafish model was used to evaluate auditory effects. Cisplatin, the curcuminoids, and their combinations had similar effects on cell viability (IC50 values: 2-16 µM) and AIF, caspase-12, JNK, MAPK, and Src expression, while caspase-3/7, -8, and -9 activity was unchanged or decreased. Cisplatin increased ROS yield (1.2-fold), and curcuminoid and combination treatments reduced ROS (0.75-0.85-fold). Combination treatments reduced A549 migration (0.51-0.53-fold). Both curcuminoids reduced auditory threshold shifts induced by cisplatin. In summary, cisplatin and the curcuminoids might cause cell death through AIF and caspase-12. The curcuminoids may potentiate cisplatin's effect against A549 migration, but may counteract cisplatin's effect to increase ROS production. The curcuminoids might also prevent cisplatin ototoxicity.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Benzilideno/uso terapêutico , Cisplatino/efeitos adversos , Diarileptanoides/uso terapêutico , Ototoxicidade/tratamento farmacológico , Piperidonas/uso terapêutico , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Benzilideno/química , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Cisplatino/química , Diarileptanoides/química , Diarileptanoides/farmacologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ototoxicidade/fisiopatologia , Piperidonas/química , Peixe-Zebra
11.
Nat Commun ; 10(1): 4967, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672972

RESUMO

To build or dissect complex pathways in bacteria and mammalian cells, it is often necessary to recur to at least two plasmids, for instance harboring orthogonal inducible promoters. Here we present SiMPl, a method based on rationally designed split enzymes and intein-mediated protein trans-splicing, allowing the selection of cells carrying two plasmids with a single antibiotic. We show that, compared to the traditional method based on two antibiotics, SiMPl increases the production of the antimicrobial non-ribosomal peptide indigoidine and the non-proteinogenic aromatic amino acid para-amino-L-phenylalanine from bacteria. Using a human T cell line, we employ SiMPl to obtain a highly pure population of cells double positive for the two chains of the T cell receptor, TCRα and TCRß, using a single antibiotic. SiMPl has profound implications for metabolic engineering and for constructing complex synthetic circuits in bacteria and mammalian cells.


Assuntos
Antibacterianos , Bactérias/enzimologia , Farmacorresistência Bacteriana , Inteínas , Engenharia Metabólica/métodos , Plasmídeos/genética , Processamento de Proteína , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/metabolismo , Resistência a Ampicilina , Linhagem Celular , Resistência ao Cloranfenicol , Cinamatos , Humanos , Higromicina B/análogos & derivados , Piperidonas , Puromicina , Trans-Splicing
12.
J Exp Clin Cancer Res ; 38(1): 453, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694672

RESUMO

BACKGROUND: The first line therapy for patients with diffuse large B cell (DLBCL) is R-CHOP. About half of DLBCL patients are either refractory to, or will relapse, after the treatment. Therefore, identifying novel drug targets and effective therapeutic agents is urgently needed for improving DLBCL patient survival. b-AP15, a selective small molecule inhibitor of proteasomal USP14 and UCHL5 deubiquitinases (DUBs), has shown selectivity and efficacy in several other types of cancer cells. This is the first study to report the effect of b-AP15 in DLBCL. METHODS: Cell lines of two DLBCL subtypes, Germinal Center B Cell/ GCB (SU-DHL-4, OCI-LY-1, OCI-LY-19) and Activated B Cell/ABC (SU-DHL-2), were used in the current study. Cell viability was measured by MTS assay, proliferation by trypan blue exclusion staining assay, cellular apoptosis by Annexin V-FITC/PI staining and mitochondrial outer membrane permeability assays, the activities of 20S proteasome peptidases by cleavage of specific fluorogenic substrates, and cell migration was detected by transwell assay in these GCB- and ABC-DLBCL cell lines. Mouse xenograft models of SU-DHL-4 and SU-DHL-2 cells were used to determine in vivo effects of b-AP15 in DLBCL tumors. RESULTS: b-AP15 inhibited proteasome DUB activities and activated cell death pathway, as evident by caspase activation and mitochondria apoptosis in GCB- and ABC- DLBCL cell lines. b-AP15 treatment suppressed migration of GCB- and ABC-DLBCL cells via inhibiting Wnt/ß-catenin and TGFß/Smad pathways. Additionally, b-AP15 significantly inhibited the growth of GCB- and ABC DLBCL in xenograft models. CONCLUSIONS: These results indicate that b-AP15 inhibits cell migration and induces apoptosis in GCB- and ABC-DLBCL cells, and suggest that inhibition of 19S proteasomal DUB should be a novel strategy for DLBCL treatment.


Assuntos
Apoptose/efeitos dos fármacos , Enzimas Desubiquitinantes/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/metabolismo , Piperidonas/farmacologia , Inibidores de Proteassoma/farmacologia , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Caspases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505816

RESUMO

Due to the poor prognosis of metastatic osteosarcoma, chemotherapy is usually employed in the adjuvant situation to improve the prognosis and the chances of long-term survival. 4-[3,5-Bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid (CLEFMA) is a synthetic analog of curcumin and possesses anti-inflammatory and anticancer properties. To further obtain information regarding the apoptotic pathway induced by CLEFMA in osteosarcoma cells, microculture tetrazolium assay, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. CLEFMA dose-dependently decreased the cell viabilities of human osteosarcoma U2OS and HOS cells and significantly induced apoptosis in human osteosarcoma cells. In addition to the effector caspase 3, CLEFMA significantly activated both extrinsic caspase 8 and intrinsic caspase 9 initiators. Moreover, CLEFMA increased the phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2 and p38. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), CLEFMA's increases of cleaved caspases 3, 8, and 9 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Conclusively, CLEFMA activates both extrinsic and intrinsic apoptotic pathways in human osteosarcoma cells through JNK and p38 signaling. These findings contribute to a better understanding of the mechanisms responsible for CLEFMA's apoptotic effects on human osteosarcoma cells.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Benzilideno/farmacologia , Proliferação de Células/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Piperidonas/farmacologia , Caspases/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética
14.
Res Vet Sci ; 126: 113-117, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31445397

RESUMO

Caprine alphaherpesvirus 1 (CpHV-1) induces genital lesions in its natural host similar to those caused by Human alphaherpesvirus 2 (HHV-2), commonly named herpes simplex virus 2 (HSV-2) in human patients. CpHV-1 infection in goats could represent a useful homologous animal model for the study of HSV-2 infection, chiefly for the assessment of antiviral drugs in in vivo studies. PHA767491 is a potent inhibitor of HSV-1 and HSV-2, being able to limit replication of HHVs both in vitro and in the mouse model. In the present study the antiviral efficacy of PHA767491 against CpHV-1 was evaluated in vitro in MDBK cells. PHA767491 inhibited significantly CpHV-1 replication in a dose-dependent fashion by up to 2.50 log10 TCID50/50 µl and was able to decrease viral DNA by nearly 8 log10. These findings confirm that PHA767491 is highly effective not only against simplexviruses (HSV-1 and HSV-2), but also against the varicellovirus CpHV-1. Experiments will be necessary to assess whether PHA767491 is suitable for treatment of vaginal lesions in CpHV-1-goat model. This could provide hints for the therapy of genital alphaherpesvirus infections in humans.


Assuntos
Antivirais/farmacologia , Piperidonas/farmacologia , Pirróis/farmacologia , Varicellovirus/efeitos dos fármacos , Animais , Linhagem Celular , DNA Viral , Cães , Replicação Viral/efeitos dos fármacos
16.
Oxid Med Cell Longev ; 2019: 1659468, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281566

RESUMO

Inhibitors of the 20S proteasome such as bortezomib are cytotoxic to tumor cells and have been proven to be valuable for the clinical management of multiple myeloma. The therapeutic efficacy of bortezomib is, however, hampered by the emergence of acquired resistance. Available data suggest that blocking proteasome activity at the level of proteasome-associated deubiquitinases (DUBs) provides a mechanism to overcome resistance to bortezomib and also to other cancer therapies. The small molecule b-AP15 is an inhibitor of proteasome-associated DUB activity that induces both proteotoxic stress and increases in the levels of reactive oxygen species (ROS) in tumor cells. Antioxidants have been shown to decrease apoptosis induction by b-AP15 and we here addressed the question of the mechanism of redox perturbation by this compound. We show that oxidative stress induction by b-AP15 is abrogated in cells deprived of mitochondrial DNA (ρ 0 cells). We also show associations between the level of proteotoxic stress, the degree of mitochondrial dysfunction, and the extent of induction of hemeoxygenase-1 (HO-1), a target of the redox-regulated Nrf-2 transcription factor. Decreased expression of COX5b (cytochrome c oxidase subunit 5b) and TOMM34 (translocase of outer mitochondrial membrane 34) was observed in b-AP15-treated cells. These findings suggest a mitochondrial origin of the increased levels of ROS observed in cells exposed to the DUB inhibitor b-AP15.


Assuntos
Mitocôndrias/efeitos dos fármacos , Piperidonas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Células HeLa , Humanos , Mitocôndrias/metabolismo , Estresse Oxidativo , Piperidonas/farmacologia , Inibidores de Proteases/farmacologia
17.
Molecules ; 24(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261921

RESUMO

Piplartine (PPL), also known as piperlongumine, is a biologically active alkaloid extracted from the Piper genus which has been found to have highly effective anticancer activity against several tumor cell lines. This study investigates in detail the antitumoral potential of a PPL analogue; (E)-N-(4-fluorobenzyl)-3-(3,4,5-trimethoxyphenyl) acrylamide (NFBTA). The anticancer potential of NFBTA on the glioblastoma multiforme (GBM) cell line (U87MG) was determined by 3-(4,5-dimethyl-2-thia-zolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT), and lactate dehydrogenase (LDH) release analysis, and the selectivity index (SI) was calculated. To detect cell apoptosis, fluorescent staining via flow cytometry and Hoechst 33258 staining were performed. Oxidative alterations were assessed via colorimetric measurement methods. Alterations in expressions of key genes related to carcinogenesis were determined. Additionally, in terms of NFBTA cytotoxic, oxidative, and genotoxic damage potential, the biosafety of this novel agent was evaluated in cultured human whole blood cells. Cell viability analyses revealed that NFBTA exhibited strong cytotoxic activity in cultured U87MG cells, with high selectivity and inhibitory activity in apoptotic processes, as well as potential for altering the principal molecular genetic responses in U87MG cell growth. Molecular docking studies strongly suggested a plausible anti-proliferative mechanism for NBFTA. The results of the experimental in vitro human glioblastoma model and computational approach revealed promising cytotoxic activity for NFBTA, helping to orient further studies evaluating its antitumor profile for safe and effective therapeutic applications.


Assuntos
Acrilamidas/química , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Piperidonas/síntese química , Piperidonas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dioxolanos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Piperidonas/química
18.
Int J Pharm ; 567: 118460, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31247278

RESUMO

As a new strategy for treatment of ductal carcinoma in situ, biocompatible and bioadhesive nanoemulsions for intraductal administration of the cytotoxic agent piplartine (piperlongumine) were optimized in this study. To confer bioadhesive properties, the nanoemulsion was modified with chitosan or hyaluronic acid. Tricaprylin was selected as the nanoemulsion non-polar phase due to its ability to dissolve larger drug amounts compared to isopropyl myristate and monocaprylin. Use of phosphatidylcholine as sole surfactant did not result in a homogeneous nanoemulsion, while its association with polysorbate 80 and glycerol (in a surfactant blend) led to the formation of nanoemulsions with droplet size of 76.5 ±â€¯1.2 nm. Heating the aqueous phase to 50 °C enabled sonication time reduction from 20 to 10 min. Inclusion of either chitosan or hyaluronic acid resulted in nanoemulsions with similar in vitro bioadhesive potential, and comparable ability to prolong mammary tissue retention (to 120 h) in vivo without causing undesirable histological alterations. Piplartine was stable in both nanoemulsions for 60 days; however, the size of loaded NE-HA was maintained at a similar range for longer periods of time, suggesting that this nanoemulsion may be a stronger candidate for intraductal delivery.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Dioxolanos/administração & dosagem , Glândulas Mamárias Animais/metabolismo , Nanopartículas/administração & dosagem , Piperidonas/administração & dosagem , Adesividade , Animais , Antineoplásicos Fitogênicos/química , Galinhas , Quitosana/administração & dosagem , Quitosana/química , Membrana Corioalantoide/efeitos dos fármacos , Dioxolanos/química , Vias de Administração de Medicamentos , Emulsões , Feminino , Glicerol/administração & dosagem , Glicerol/química , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Nanopartículas/química , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/química , Piperidonas/química , Polissorbatos/administração & dosagem , Polissorbatos/química , Ratos Wistar , Pele/química , Suínos
19.
Molecules ; 24(12)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31212829

RESUMO

BACKGROUND: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. METHOD AND RESULTS: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 ± 2.4 µM and 4.9 ± 2.8 µM for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/ß-catenin, NF-κB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. CONCLUSION: This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models.


Assuntos
Antineoplásicos/farmacologia , Compostos de Benzilideno/farmacologia , Curcumina/química , Curcumina/farmacologia , Mitotano/farmacologia , Piperidonas/farmacologia , Neoplasias do Córtex Suprarrenal , Animais , Antineoplásicos/química , Compostos de Benzilideno/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Camundongos , Estrutura Molecular , Piperidonas/química , Espécies Reativas de Oxigênio/metabolismo
20.
Neoplasia ; 21(7): 653-664, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31132676

RESUMO

The ubiquitin-proteasome system is elementary for cellular protein degradation and gained rising attention as a new target for cancer therapy due to promising clinical trials with bortezomib, the first-in class proteasome inhibitor meanwhile approved for multiple myeloma and mantle cell lymphoma. Both bortezomib and next-generation proteasome inhibitors mediate their effects by targeting the 20S core particle of the 26S proteasome. The novel small molecule inhibitor b-AP15 affects upstream elements of the ubiquitin-proteasome cascade by suppressing the deubiquitinase activity of both proteasomal regulatory 19S subunits and showed promising anticancer activity in preclinical models. Nonetheless, effects of inhibitors on the ubiquitin-proteasome system are not exclusively restricted to malignant cells: alteration of natural killer cell-mediated immune responses had already been described for drugs targeting either 19S or 20S proteasomal subunits. Moreover, it has been shown that bortezomib impairs dendritic cell (DC) phenotype and function at different levels. In the present study, we comparatively analyzed effects of bortezomib and b-AP15 on monocyte-derived DCs. In line with previous results, bortezomib exposure impaired maturation, antigen uptake, migration, cytokine secretion and immunostimulation, whereas treatment with b-AP15 had no compromising effects on these DC features. Our findings warrant the further investigation of b-AP15 as an alternative to clinically approved proteasome inhibitors in the therapy of malignancies, especially in the context of combinatorial treatment with DC-based immunotherapies.


Assuntos
Enzimas Desubiquitinantes/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Ubiquitina/genética , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Enzimas Desubiquitinantes/genética , Humanos , Monócitos/metabolismo , Neoplasias/genética , Neoplasias/patologia , Piperidonas/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA