Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros












Base de dados
Intervalo de ano de publicação
1.
Biochem Pharmacol ; 222: 116079, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38402910

RESUMO

Breast cancer is one of the main causes of malignancy-related deaths globally and has a significant impact on women's quality of life. Despite significant therapeutic advances, there is a medical need for targeted therapies in breast cancer. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor mediates responses to environment stimuli, is emerging as a unique pleiotropic target. Herein, a combined molecular simulation and in vitro investigations identified 3-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (3FPP) as a novel AhR ligand in T47D and MDA-MB-231 breast cancer cells. Its agonistic effects induced formation of the AhR-AhR nuclear translocator (Arnt) heterodimer and prompted its binding to the penta-nucleotide sequence, called xenobiotic-responsive element (XRE) motif. Moreover, 3FPP augmented the promoter-driven luciferase activities and expression of AhR-regulated genes encoding cytochrome P450 1A1 (CYP1A1) and microRNA (miR)-212/132 cluster. It reduced cell viability, migration, and invasion of both cell lines through AhR signaling. These anticancer properties were concomitant with reduced levels of B-cell lymphoma 2 (BCL-2), SRY-related HMG-box4 (SOX4), snail family zinc finger 2 (SNAI2), and cadherin 2 (CDH2). In vivo, 3FPP suppressed tumor growth and activated AhR signaling in an orthotopic mouse model. In conclusion, our results introduce the fused pyrazolopyridine 3FPP as a novel AhR agonist with AhR-specific anti-breast cancer potential in vitro and in vivo.


Assuntos
Neoplasias da Mama , Pirazóis , Receptores de Hidrocarboneto Arílico , Animais , Camundongos , Feminino , Humanos , Receptores de Hidrocarboneto Arílico/metabolismo , Ligantes , Qualidade de Vida , Citocromo P-450 CYP1A1/metabolismo , Neoplasias da Mama/genética , Piridinas/farmacologia , Piridinas/uso terapêutico , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Fatores de Transcrição SOXC/metabolismo
2.
Molecules ; 28(10)2023 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-37241719

RESUMO

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse agonistic ligands and regulates complicated transcriptional processes through its canonical and non-canonical pathways in normal and malignant cells. Different classes of AhR ligands have been evaluated as anticancer agents in different cancer cells and exhibit efficiency, which has thrust AhR into the limelight as a promising molecular target. There is strong evidence demonstrating the anticancer potential of exogenous AhR agonists including synthetic, pharmaceutical, and natural compounds. In contrast, several reports have indicated inhibition of AhR activity by antagonistic ligands as a potential therapeutic strategy. Interestingly, similar AhR ligands exert variable anticancer or cancer-promoting potential in a cell- and tissue-specific mode of action. Recently, ligand-mediated modulation of AhR signaling pathways and the associated tumor microenvironment is emerging as a potential approach for developing cancer immunotherapeutic drugs. This article reviews advances of AhR in cancer research covering publication from 2012 to early 2023. It summarizes the therapeutic potential of various AhR ligands with an emphasis on exogenous ligands. It also sheds light on recent immunotherapeutic strategies involving AhR.


Assuntos
Receptores de Hidrocarboneto Arílico , Transdução de Sinais , Receptores de Hidrocarboneto Arílico/metabolismo , Ligantes
3.
Phytomedicine ; 96: 153817, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34782204

RESUMO

BACKGROUND: Despite the significant advances in diagnosis and treatment, breast cancer remains the most common malignancy and the second cause of death in women. Increasingly, preclinical evidence has suggested aryl hydrocarbon receptor (Ahr), a ligand activated transcription factor, a promising therapeutic target in breast cancer. PURPOSE: This study aims at screening a number of phenolic compounds to identify an Ahr ligand with suppressive effects on human breast cancer. METHODS: Potential interactions between Ahr and phenolic compounds were predicted in silico, and physical interaction was examined by ligand competitive binding in vitro. The MDA-MB-231 and T47D breast cancer cell lines were used to examine the expression of Ahr downstream genes and progression of breast cancer cells in vitro. Binding of Ahr/Ahr nuclear transporter (Arnt) complex to the xenobiotic-responsive element (XRE)-box was examined by DNA-protein interaction (DPI)-ELISA, promoter activity was assessed using luciferase reporter system, and RNA interreference was carried out using electroporation. The real-time PCR and/or immunoblotting were used to quantify gene expressions. Tumor growth in vivo was assessed using a murine orthotopic model. RESULTS: A combined computational modeling and in vitro approaches identified gallic acid (GA) as an Ahr ligand with agonistic properties. It induced binding of Ahr/Arnt to the XRE-box, enhanced the promoter activity and expression of Ahr downstream genes including cytochrome P450 1A1 (CYP1A1), and SRY-related HMG-box4 (SOX4)-targeting miR-212/132 cluster and miR-335 in both MDA-MB-231 and T47D cells. GA increased apoptosis while decreased proliferation, migration and invasion capacities of breast cancer cells in an Ahr-dependent fashion. Furthermore, it reduced the levels of B-cell lymphoma 2 (BCL-2), cyclooxygenase-2 (COX-2) and SOX4, while selectively increased that of tumor protein 53 (P53), in an Ahr-dependent and -independent fashions. In an in vivo orthotopic model, GA activated Ahr signaling and reduced the growth of breast cancer cells. CONCLUSION: We identified GA as an Ahr phenolic ligand, and provided evidence on the role of Ahr in mediating its anti-breast cancer effects, indicating that GA, and possibly other phenolic compounds, have important therapeutic implications in human breast cancer through activation of Ahr signaling.


Assuntos
Neoplasias da Mama , MicroRNAs , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Feminino , Ácido Gálico/farmacologia , Humanos , Camundongos , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição SOXC , Transdução de Sinais
4.
Eur J Cancer ; 110: 74-85, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30772656

RESUMO

Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available. Therefore priority should be given to developing treatment for patients with relapsed and refractory mature B-cell lymphomas. The consensus of the clinicians attending the meeting was that CAR T-cells, T-cell engagers and antibody drug conjugates (excluding those with a vinca alkaloid-like drug) presently have the greatest probability of providing benefit in relapse in view of their mechanism of action. However, as producing autologous CAR T-cells currently takes at least 4 weeks, they are not products which could be quickly employed initially at relapse in rapidly progressing mature B-cell malignancies but only for the consolidation phase of the treatment. Global, industry-supported, academic-sponsored studies testing compounds from different pharmaceutical companies simultaneously should be considered in rare populations, and it was proposed that an international working group be formed to develop an overarching clinical trials strategy for these disease groups. Future Forums are planned for other relevant paediatric oncologic diseases with a high unmet medical need and relevant molecular targets.


Assuntos
Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Linfoma de Células B/tratamento farmacológico , Adolescente , Adulto , Linfócitos B/efeitos dos fármacos , Criança , Europa (Continente) , Órgãos Governamentais , Humanos , Avaliação das Necessidades , América do Norte , Planejamento de Assistência ao Paciente
5.
J Clin Virol ; 53(3): 208-13, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22237003

RESUMO

BACKGROUND: The IMPACT study was a randomized, double-blind study comparing 100 to 200 days of VGCV prophylaxis (900 mg once daily) in D+/R- kidney transplant recipients. Although extending the duration of prophylaxis resulted in a significant reduction in confirmed cytomegalovirus (CMV) disease (100-day: 36.8% vs 200-day: 16.1%(1)), the consequence of extending the duration of prophylaxis on the development of viral resistance remains unknown. OBJECTIVE: To determine whether extending valganciclovir prophylaxis from 100 days to 200 days increased the incidence of ganciclovir resistance. STUDY DESIGN: Genotypic analysis of CMV UL97 and UL54 was conducted on virus isolated from patients meeting the predefined resistance analysis criteria (RAC). RESULTS: A greater number of patients met the RAC in the 100 day prophylaxis arm (50/163; 31%) compared to the 200 day prophylaxis arm (22/155; 14%). Sequence data were successfully generated for all 200-day patients and 48/50 100-day patients. Three patients in each treatment arm (100 day: 3/163 (1.8%) vs 200 day: 3/155 (1.9%)) had a single known valganciclovir resistance mutation detected (100 day: UL97 gene: M460V, C592G twice; 200 day: UL97 gene: C603W, M460V and UL54 gene: P522S). Overall, a resistance mutation was more likely to be detected if the patient met the RAC during prophylaxis (5/12 (42%)) compared to post-prophylaxis (1/58 (2%)). All six patients with known ganciclovir resistance mutations cleared the virus; three cleared virus without treatment and three cleared virus following treatment. CONCLUSIONS: Extending valganciclovir prophylaxis from 100 days to 200 days did not significantly affect the incidence of ganciclovir resistance.


Assuntos
Substituição de Aminoácidos/efeitos dos fármacos , Antivirais/administração & dosagem , Infecções por Citomegalovirus/virologia , Citomegalovirus/genética , Ganciclovir/análogos & derivados , Transplante de Rim/métodos , Antibioticoprofilaxia , Antivirais/efeitos adversos , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/prevenção & controle , DNA Viral/sangue , Método Duplo-Cego , Esquema de Medicação , Farmacorresistência Viral , Ganciclovir/administração & dosagem , Ganciclovir/efeitos adversos , Humanos , Mutação , Valganciclovir , Carga Viral
6.
Transplantation ; 90(12): 1414-9, 2010 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-21076372

RESUMO

BACKGROUND: A 3-month course of prophylaxis is usually recommended for cytomegalovirus (CMV) D+/R- renal transplant recipients. Based on recent data, up to 6 months of prophylaxis may be used. A subanalysis was performed to evaluate the pharmacokinetics of ganciclovir after valganciclovir administration and to perform an exploratory pharmacokinetic/pharmacodynamic analysis. METHODS: In Improved Protection Against Cytomegalovirus in Transplant, a phase III, randomized, double blind, placebo-controlled, multicenter study, 318 CMV D+/R- kidney transplant recipients received valganciclovir prophylaxis (900 mg once daily) for 200 or 100 days. A population pharmacokinetic analysis was conducted on a subgroup of patients (n=120). The relationships between ganciclovir exposure (AUC0-24 hr) and clinical outcomes were explored. RESULTS: The final population parameter estimates (95% confidence interval) were as follows: apparent clearance of ganciclovir, 12 L/hr (11.3-12.7 L/hr); volume of distribution, 18.5 L (14.4-22.6 L); and peripheral volume, 44.4 L (40.2-48.6 L). No differences were apparent between the two treatment groups and these estimates. These results are consistent with previously published pharmacokinetic models. There were no direct correlations between the likelihood of developing hematologic adverse events and ganciclovir exposure at the time of the event. The incidence of CMV disease was not correlated with ganciclovir exposure. CONCLUSION: The pharmacokinetics of ganciclovir were similar between the two dosing groups (100 vs. 200 days), with the majority of patients achieving an area under the concentration time curve in the target therapeutic range (40-60 µg hr/mL). The fact that the majority of patients were within the target therapeutic range and the absence of a control arm (no treatment) precluded any attempt to validate a correlation with clinical parameters (i.e., CMV disease).


Assuntos
Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Transplante de Rim/fisiologia , Adolescente , Adulto , Idoso , Antivirais/farmacocinética , Antivirais/uso terapêutico , Área Sob a Curva , Creatinina/metabolismo , Infecções por Citomegalovirus/tratamento farmacológico , Feminino , Ganciclovir/farmacocinética , Ganciclovir/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/virologia , Probabilidade , Fatores de Tempo , Valganciclovir
7.
Transplantation ; 90(12): 1409-13, 2010 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-21030903

RESUMO

BACKGROUND: In a phase III controlled trial IMproved Protection Against Cytomegalovirus in Transplantation (IMPACT) comparing 200 with 100 days of valganciclovir prophylaxis in 318 cytomegalovirus D+/R- kidney transplant recipients, an equal number of patients (n=3 per arm) had known ganciclovir resistance mutations detected during viral breakthrough. In addition, many other viral sequence variants were observed that were of unknown significance for ganciclovir resistance. Recombinant phenotyping was performed to determine whether the previously uncharacterized genotypic changes affected ganciclovir susceptibility, especially in those receiving the longer duration of prophylaxis. METHODS: Sequences encoding individual amino acid substitutions in the UL97 kinase or UL54 DNA polymerase gene were transferred by recombination into a cloned cytomegalovirus laboratory strain, followed by reporter-based yield reduction phenotypic assay of the resulting virus for ganciclovir susceptibility. RESULTS: Twenty-six uncharacterized amino acid substitutions were detected, 2 in UL97 and 24 in UL54. All 10 substitutions in the 200-day arm and 9 of 17 substitutions in the 100-day arm (prioritized based on location and conservation) were selected for phenotyping; one substitution was detected in both subsets. Results were generated for nine of ten 200-day and eight of nine 100-day substitutions, with no substitution demonstrating a significant reduction in ganciclovir susceptibility. The two remaining amino acid substitutions, both in UL54, were not evaluated because of poor viral viability. CONCLUSION: Phenotypic evaluation of previously uncharacterized viral genotypes in the 200-day valganciclovir prophylaxis group showed no evidence of an increased incidence of genotypic ganciclovir resistance when compared with those in the 100-day prophylaxis group.


Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/genética , Citomegalovirus/genética , Ganciclovir/análogos & derivados , Variação Genética , Sequência de Bases , Citomegalovirus/efeitos dos fármacos , Seguimentos , Ganciclovir/uso terapêutico , Predisposição Genética para Doença , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Tempo , Valganciclovir
8.
Inflamm Bowel Dis ; 16(10): 1708-16, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20848453

RESUMO

BACKGROUND: NI-0401 is a fully human monoclonal antibody, which binds to the CD3 subunit of the T-cell receptor, causing modulation of T-cell activity. We investigated the safety and the ability to modulate the TCR-CD3 complex of NI-0401 in patients with active Crohn's disease (CD). METHODS: A double-blind, placebo-controlled, randomized, multicenter, dose-escalating trial was conducted in CD patients age 18-70 years, a Crohn's Disease Activity Index (CDAI) of 220-450, and detectable levels of C-reactive protein. The primary outcome was safety and the ability of NI-0401 to modulate the TCR-CD3 complex on T cells. Efficacy parameters included the proportion of patients achieving remission (CDAI <150), clinical response (CDAI fall ≥100), and change from baseline in the CD Endoscopy Index of Severity (CDEIS). RESULTS: Forty patients received placebo (n = 7) or NI-0401 (n = 33) 0.05-10 mg daily for 5 days. NI-0401 doses ≤1 mg were well tolerated. Infusion reactions occurred at doses ≥2 mg. The extent and duration of TCR-CD3 modulation increased with dose. No differences between groups were observed in the proportions of patients achieving clinical remission or response. The mean CDEIS at week 6 differed significantly between the 1-mg and placebo group. CONCLUSIONS: NI-0401 was tolerated at doses ≤1 mg with manageable side effects. NI-0401 induced a dose-dependent modulation of the TCR-CD3 complex. No significant improvement of CDAI was observed but 1 mg NI-0401 demonstrated an improvement in CDEIS.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
9.
Transplantation ; 90(12): 1427-31, 2010 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-21197713

RESUMO

BACKGROUND: Whether the early reduction in cytomegalovirus (CMV) disease seen at 1 year with prolongation of antiviral prophylaxis (up to 200 days) persists in the long term is unknown. METHODS: This international, randomized, prospective, double-blind study, compared 318 CMV D+/R- kidney transplant recipients receiving valganciclovir (900 mg) once daily for up to 200 days vs. 100 days. Long-term outcomes including CMV disease, acute rejection, graft loss, patient survival, and seroconversion were assessed. RESULTS: At 2 years posttransplant, CMV disease occurred in significantly less patients in the 200- vs. the 100-day group: 21.3% vs. 38.7%, respectively (P<0.001). Between year 1 and 2, there were only 10 new cases of CMV disease; 7 in the 200-day group and 3 in the 100-day group. Patient survival was 100% in the 200-day group and 97% in the 100-day group (p=not significant). Biopsy-proven acute rejection and graft loss rates were comparable in both groups (11.6% vs. 17.2%, P=0.16, and 1.9% vs. 4.3%, P=0.22, in the 200-day vs. 100-day groups, respectively). Seroconversion was delayed in the 200-day group but was similar to the 100-day group by 2 years posttransplant (IgM or IgG seroconversion; 55.5% in the 200-day group vs. 62.0% in the 100-day group at 2-years; P=0.26). Assessment of seroconversion at the end of prophylaxis was of limited utility for predicting late-onset CMV disease. CONCLUSION: Extending valganciclovir prophylaxis from 100 to 200 days is associated with a sustained reduction in CMV disease up to 2 years posttransplant.


Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Transplante de Rim/fisiologia , Antivirais/administração & dosagem , Infecções por Citomegalovirus/epidemiologia , Método Duplo-Cego , Seguimentos , Ganciclovir/administração & dosagem , Ganciclovir/uso terapêutico , Sobrevivência de Enxerto , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Funções Verossimilhança , Valor Preditivo dos Testes , Estudos Prospectivos , Testes Sorológicos/estatística & dados numéricos , Taxa de Sobrevida , Fatores de Tempo , Valganciclovir
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...