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1.
JCI Insight ; 5(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33208553

RESUMO

BACKGROUNDSurgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%-40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib.METHODSccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment.RESULTSTwenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations.CONCLUSIONNeoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response.FUNDINGSupport was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study.

2.
Nat Commun ; 11(1): 2135, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358509

RESUMO

A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/microbiologia , Fatores de Transcrição/metabolismo , Animais , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/metabolismo , Carcinoma de Células Renais/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutação , Fosforilação , Fator de Transcrição STAT1/metabolismo , Análise Serial de Tecidos , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcriptoma/genética
3.
Cancer Lett ; 487: 10-20, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470488

RESUMO

A common feature of many solid tumors is low oxygen conditions due to inadequate blood supply. Hypoxia induces hypoxia inducible factor (HIF) stabilization and downstream signaling. This signaling has pleiotropic roles in cancers, including the promotion of cellular proliferation, changes in metabolism, and induction of angiogenesis. In addition, hypoxia is becoming recognized as an important driver of epithelial-to-mesenchymal (EMT) in cancer. During EMT, epithelial cells lose their typical polarized states and transition to a more mobile mesenchymal phenotype. Hypoxia induces this transition by modulating EMT signaling pathways, inducing EMT transcription factor activity, and regulating miRNA networks. As both hypoxia and EMT modulate the tumor microenvironment (TME) and are associated with immunosuppression, we also explore how these pathways may impact response to immuno-oncology therapeutics.

4.
JCI Insight ; 5(2)2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31873073

RESUMO

Integrins, the extracellular matrix receptors that facilitate cell adhesion and migration, are necessary for organ morphogenesis; however, their role in maintaining adult tissue homeostasis is poorly understood. To define the functional importance of ß1 integrin in adult mouse lung, we deleted it after completion of development in type 2 alveolar epithelial cells (AECs). Aged ß1 integrin-deficient mice exhibited chronic obstructive pulmonary disease-like (COPD-like) pathology characterized by emphysema, lymphoid aggregates, and increased macrophage infiltration. These histopathological abnormalities were preceded by ß1 integrin-deficient AEC dysfunction such as excessive ROS production and upregulation of NF-κB-dependent chemokines, including CCL2. Genetic deletion of the CCL2 receptor, Ccr2, in mice with ß1 integrin-deficient type 2 AECs impaired recruitment of monocyte-derived macrophages and resulted in accelerated inflammation and severe premature emphysematous destruction. The lungs exhibited reduced AEC efferocytosis and excessive numbers of inflamed type 2 AECs, demonstrating the requirement for recruited monocytes/macrophages in limiting lung injury and remodeling in the setting of a chronically inflamed epithelium. These studies support a critical role for ß1 integrin in alveolar homeostasis in the adult lung.


Assuntos
Células Epiteliais Alveolares/metabolismo , Integrina beta1/genética , Integrina beta1/metabolismo , Pneumonia/metabolismo , Envelhecimento/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Adesão Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Modelos Animais de Doenças , Epitélio , Pulmão/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptores CCR2/genética
5.
Urol Oncol ; 35(3): 102-110, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28089416

RESUMO

BACKGROUND: Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist. METHODS AND PURPOSE: In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/terapia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/terapia , Recidiva Local de Neoplasia/terapia , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Citotoxicidade Imunológica/efeitos dos fármacos , Progressão da Doença , Intervalo Livre de Doença , Humanos , Imunoterapia/métodos , Rim/irrigação sanguínea , Rim/patologia , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neovascularização Patológica/patologia , Nefrectomia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
6.
Cancer ; 123(2): 200-209, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27861752

RESUMO

The treatment of advanced renal cell carcinoma has posed a challenge for decades, in part because of common themes related to intrinsic resistance to cytotoxic chemotherapy and the obscure biology of these cancer types. Forward movement in the treatment of the renal cell carcinomas thus can be approached in 2 ways: by splitting the tumor types along histologic and molecular features, in the hopes of coupling highly precision-focused therapy on a subset of patients who have disease with the most potential for benefit; or by lumping the various biologies and histologies together, to include the rarer renal cell carcinoma types with the more common types. The former strategy satisfies the desire for customized precision in treatment delivery, whereas the latter strategy allows clinicians to offer a wider therapeutic menu in a set of diseases we are continuing to learn about on a physiologic and molecular level. Cancer 2017;123:200-209. © 2016 American Cancer Society.


Assuntos
Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Tomada de Decisões/fisiologia , Humanos
7.
Mol Cancer Res ; 14(7): 589-98, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27330105

RESUMO

The renal cell carcinomas (RCC), clear cell, papillary, and chromophobe, have recently undergone an unmatched genomic characterization by The Cancer Genome Atlas. This analysis has revealed new insights into each of these malignancies and underscores the unique biology of clear cell, papillary, and chromophobe RCC. Themes that have emerged include distinct mechanisms of metabolic dysregulation and common mutations in chromatin modifier genes. Importantly, the papillary RCC classification encompasses a heterogeneous group of diseases, each with highly distinct genetic and molecular features. In conclusion, this review summarizes RCCs that represent a diverse set of malignancies, each with novel biologic programs that define new paradigms for cancer biology. Mol Cancer Res; 14(7); 589-98. ©2016 AACR.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Animais , Carcinoma de Células Renais/patologia , Genoma , Humanos , Neoplasias Renais/patologia
8.
Clin Cancer Res ; 22(22): 5605-5616, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27220961

RESUMO

PURPOSE: Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. EXPERIMENTAL DESIGN: Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed. RESULTS: Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets. CONCLUSIONS: Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. ©2016 AACR.


Assuntos
Carcinoma Papilar/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/fisiologia , Tirosina/metabolismo , Carcinoma Papilar/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Neoplasias Renais/tratamento farmacológico , Espectrometria de Massas/métodos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteômica/métodos , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Urol Oncol ; 34(3): 122.e1-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26546482

RESUMO

PURPOSE: The 34-gene classifier, ClearCode34, identifies prognostically distinct molecular subtypes of clear cell renal cell carcinoma (ccRCC) termed clear cell A (ccA) and clear cell B (ccB). The primary objective of this study was to describe clinical characteristics and comorbidities of relevance in patients stratified by ClearCode34. PATIENTS AND METHODS: In this retrospective analysis, 282 patients from Moffitt Cancer Center with ccRCC with gene expression analyses of the primary tumor were identified and ClearCode34 was applied to identify tumors as ccA or ccB. The medical record and institutional databases were queried to define patient characteristics, comorbidities, and outcomes. RESULTS: We validated in this external cohort the superior overall survival, cancer-specific survival, and recurrence-free survival of ccA patients relative to ccB patients (P<0.001). Addressing other clinical characteristics, the ccA patients were more likely to be obese (48% vs. 34%, P = 0.021) and diabetic (26% vs. 13%, P = 0.035). The ccA patients also trended toward having been more frequent users of angiotensin system inhibitors (71% vs. 52%, P = 0.055). In multivariate analyses, ccB status is independently associated with inferior cancer-specific survival (hazard ratio = 3.26, 95% confidence interval: 1.84-5.79) and overall survival (hazard ratio = 2.50, 95% confidence interval: 1.53-4.08). CONCLUSIONS: ClearCode34, after considering distinct patterns of comorbidities in each molecular subtype, remains a strong prognostic tool in patients with ccRCC. Obesity and diabetes mellitus emerged as factors that may influence ccRCC phenotypes and further studies investigating the effect of these metabolic conditions functionally onto tumor biology are warranted. Additionally, use of angiotensin system inhibitors could be studied in the context of ccRCC molecular classification in future studies to better understand its effect on ccRCC outcomes.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Recidiva Local de Neoplasia/genética , Idoso , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/secundário , Comorbidade , Feminino , Seguimentos , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transcriptoma
10.
Sci Signal ; 8(359): ra4, 2015 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-25587191

RESUMO

Strategies to measure functional signaling-associated protein complexes have the potential to augment current molecular biomarker assays, such as genotyping and expression profiling, used to annotate diseases. Aberrant activation of epidermal growth factor receptor (EGFR) signaling contributes to diverse cancers. We used a proximity ligation assay (PLA) to detect EGFR in a complex with growth factor receptor-bound protein 2 (GRB2), the major signaling adaptor for EGFR. We used multiple lung cancer cell lines to develop and characterize EGFR:GRB2 PLA and correlated this assay with established biochemical measures of EGFR signaling. In a panel of patient-derived xenografts in mice, the intensity of EGFR:GRB2 PLA correlated with the reduction in tumor size in response to the EGFR inhibitor cetuximab. In tumor biopsies from three cohorts of lung cancer patients, positive EGFR:GRB2 PLA was observed in patients with and without EGFR mutations, and the intensity of EGFR:GRB2 PLA was predictive of overall survival in an EGFR inhibitor-treated cohort. Thus, we established the feasibility of using PLA to measure EGFR signaling-associated protein complexes in patient-based materials, suggesting the potential for similar assays for a broader array of receptor tyrosine kinases and other key signaling molecules.


Assuntos
Biomarcadores Tumorais/metabolismo , Receptores ErbB/metabolismo , Imunoensaio/métodos , Neoplasias Pulmonares/diagnóstico , Complexos Multiproteicos/metabolismo , Mapeamento de Interação de Proteínas/métodos , Transdução de Sinais/fisiologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linhagem Celular Tumoral , Cetuximab , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Proteína Adaptadora GRB2/metabolismo , Xenoenxertos/efeitos dos fármacos , Xenoenxertos/patologia , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Complexos Multiproteicos/fisiologia
11.
Eur Urol ; 61(2): 258-68, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22030119

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) displays molecular and histologic heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multigene expression profiles, but it is unclear whether these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histologic descriptions or gender. OBJECTIVE: Determine whether additional subtypes of ccRCC exist and whether these subtypes are related to von Hippel-Lindau (VHL) inactivation, hypoxia-inducible factor (HIF) 1 and 2 expression, tumor histology, or gender. DESIGN, SETTING, AND PARTICIPANTS: Six large, publicly available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation. MEASUREMENTS: Unsupervised consensus clustering was performed on the meta-arrays. Tumors were examined for the relationship of multigene-defined consensus subtypes and expression signatures of VHL mutation and HIF status, tumor histology, and gender. RESULTS AND LIMITATIONS: Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed that correlated strongly with a wild type (WT) VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by the potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information. CONCLUSIONS: The ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified that may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that it could have implications regarding current treatments and future drug development.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Neoplasias Renais/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Análise por Conglomerados , Feminino , Humanos , Fator 1 Induzível por Hipóxia/genética , Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Fatores Sexuais , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
12.
Cochlear Implants Int ; 11 Suppl 1: 42-55, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21756583

RESUMO

HYPOTHESIS: Dexamethasone (DXM) protects hearing against trauma-induced loss. MATERIALS: in vivo: A guinea pig model of electrode induced trauma (EIT)-induced hearing loss was used to locally deliver dexamethasone. In vitro: TNF-α-challenged organ of Corti explants treated with DXM or polymer-eluted DXM +/- PI3K/Akt/PkB/NFkB inhibitors were used for hair cells count and gene expression studies. RESULTS: in vivo: local DXM treatment of EIT-animals prevents trauma-induced loss of ABR thresholds that occurs in EIT-animals and EIT-animals treated with the carrier solution (i.e., AP), and prevented loss of auditory hair cells. In vitro: DXM and polymer-eluted DXM were equally effective in protecting hair cells from ototoxic levels of TNF-α Inhibitor treated explants demonstrated that DXM treatment requires both Akt/PKB and NFkB signalling for otoprotection. DXM treatment of explants showed up regulation of anti-apoptosis related genes (i.e., Bcl-2, Bcl-xl) and down regulation of pro-apoptosis related genes (i.e., Bax, TNFR-1). CONCLUSIONS: DXM exert its otoprotective action by activation of cell signal molecules (e.g., NFkB) that alter the expression of anti- and pro-apoptosis genes.


Assuntos
Dexametasona/farmacologia , Proteínas Ativadoras de GTPase/metabolismo , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva/prevenção & controle , Fator de Necrose Tumoral alfa/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Limiar Auditivo/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Eletrodos Implantados/efeitos adversos , Proteínas Ativadoras de GTPase/genética , Regulação da Expressão Gênica , Cobaias , Células Ciliadas Auditivas/citologia , Perda Auditiva/etiologia , Técnicas In Vitro , Órgão Espiral/efeitos dos fármacos , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima , Ferimentos e Lesões/complicações
13.
Hear Res ; 255(1-2): 22-32, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19442713

RESUMO

BACKGROUND: Tumor necrosis factor alpha (TNFalpha) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment). HYPOTHESIS: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival. MATERIALS AND METHODS: Organ of Corti explants challenged with an ototoxic level of TNFalpha was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFalpha-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFalpha ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity. RESULTS: The general caspase inhibitor Boc-d-fmk prevented TNFalpha-induced AHC death. There was a significant reduction (p<0.05) in the efficacy of Dex otoprotection against TNFalpha ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFkappaB (NFkappaB-I). CONCLUSION: Dex treatment protects hair cells against TNFalpha apoptosis in vitro by activation of PI3K/Akt and NFkappaB signaling.


Assuntos
Apoptose/efeitos dos fármacos , Dexametasona/farmacologia , Células Ciliadas Auditivas/citologia , Células Ciliadas Auditivas/efeitos dos fármacos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/fisiologia , Compostos de Benzil/farmacologia , Inibidores de Caspase , Relação Dose-Resposta a Droga , Células Ciliadas Auditivas/metabolismo , Hidrocarbonetos Fluorados/farmacologia , Técnicas In Vitro , NF-kappa B/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagem
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