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Cuprotosis, an emerging mode of cell death, has recently caught the attention of researchers worldwide. However, its impact on low-grade glioma (LGG) patients has not been fully explored. To gain a deeper insight into the relationship between cuprotosis and LGG patients' prognosis, we conducted this study in which LGG patients were divided into two clusters based on the expression of 18 cuprotosis-related genes. We found that LGG patients in cluster A had better prognosis than those in cluster B. The two clusters also differed in terms of immune cell infiltration and biological functions. Moreover, we identified differentially expressed genes (DEGs) between the two clusters and developed a cuprotosis-related prognostic signature through the least absolute shrinkage and selection operator (LASSO) analysis in the TCGA training cohort. This signature divided LGG patients into high- and low-risk groups, with the high-risk group having significantly shorter overall survival (OS) time than the low-risk group. Its predictive reliability for prognosis in LGG patients was confirmed by the TCGA internal validation cohort, CGGA325 cohort and CGGA693 cohort. Additionally, a nomogram was used to predict the 1-, 3-, and 5-year OS rates of each patient. The analysis of immune checkpoints and tumor mutation burden (TMB) has revealed that individuals belonging to high-risk groups have a greater chance of benefiting from immunotherapy. Functional experiments confirmed that interfering with the signature gene TNFRSF11B inhibited LGG cell proliferation and migration. Overall, this study shed light on the importance of cuprotosis in LGG patient prognosis. The cuprotosis-related prognostic signature is a reliable predictor for patient outcomes and immunotherapeutic response and can help to develop new therapies for LGG.
Assuntos
Apoptose , Glioma , Humanos , Reprodutibilidade dos Testes , Morte Celular , Glioma/genética , Glioma/terapia , ImunoterapiaRESUMO
Non-small cell lung cancer (NSCLC) is a prevalent form of lung cancer. Patients with advanced NSCLC are currently being treated with various therapies, including traditional radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. However, a considerable proportion of advance patients who cannot benefit from them. Consequently, it is essential to identify a novel research target that offers an encouraging perspective. The stimulator of interferon genes (STING) has emerged as such a target. At present, it is confirmed that activating STING in NSCLC tumor cells can impede the proliferation and metastasis of dormant tumor cells. This review focuses on the role of STING in NSCLC treatment and the factors influencing its activation. Additionally, it explores the correlation between STING activation and diverse therapy modalities for NSCLC, such as radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. Furthermore, it proposes the prospect of innovative therapy methods involving nanoparticles, with the aim of using the features of STING to develop more strategies for NSCLC therapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Imunoterapia , Terapia de Alvo MolecularRESUMO
BACKGROUND & AIMS: CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes for patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. This strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s affect pancreatic cancer initiation or recurrence after radiotherapy. METHODS: One hundred ninety-two pairs of human pancreatic adenocarcinoma and adjacent nontumor pancreatic tissues were collected from patients undergoing surgery. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time polymerase chain reaction, and immunoblot; levels were correlated with patient survival times. We studied the effects of anti-CD44s in mice with human pancreatic tumor xenografts and used flow cytometry to determine the effects on TICs. Changes in CD44s signaling were examined by real-time polymerase chain reaction, immunoblot, reporter assay, and in vitro tumorsphere formation assays. RESULTS: Levels of CD44s were significantly higher in pancreatic cancer than adjacent nontumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months compared with >43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and postradiation recurrence of pancreatic xenograft tumors in mice. The antibody reduced the number of TICs in cultured pancreatic cancer cells and xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s down-regulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited signal transducer and activator of transcription 3-mediated cell proliferation and survival signaling. CONCLUSIONS: The TIC marker CD44s is up-regulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and postradiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the tumors. Strategies to target CD44s cab be developed to block pancreatic tumor formation and post-radiotherapy recurrence in patients.
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Adenocarcinoma/terapia , Anticorpos/farmacologia , Biomarcadores Tumorais/imunologia , Receptores de Hialuronatos/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/terapia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares , Fatores de Tempo , Fatores de Transcrição/metabolismo , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Purpose: This study aims to explore the prognostic values of routine pre-treatment hematological parameters in patients with nasopharyngeal carcinoma (NPC). Methods: The hematological parameters and clinical data of patients with NPC were collected from January 2012 to December 2013 at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The survival statistics were obtained by regularly following-up the patients. The cut-off values for the hematological parameters were calculated using X-tile software. SPSS version 24.0 was used for the statistical analysis. The relationship between the hematological parameters and the prognosis of patients with NPC was analyzed using the Kaplan-Meier method and Cox multivariate regression. The discriminating abilities of the factors, which predict the prognosis, were evaluated by utilizing the receiver operating characteristic (ROC) area under the curve (AUC). Results: This study included 179 patients with NPC. Multivariate analysis shows that pretreatment platelet-to-lymphocyte ratio (PLR; hazard ratio; HR = 0.44, 95% CI [0.21-0.91], p = 0.029), serum albumin (ALB; HR = 2.49, 95% CI [1.17-5.30], p = 0.018), and globulin (GLO; HR = 0.44, 95% CI [0.21-0.90], p = 0.024) are independent predictors for 5-year overall survival (OS) in patients with NPC. In addition, pre-treatment PLR (HR = 0.47, 95% CI [0.25-0.90], p = 0.022) and pre-treatment GLO (HR = 0.37, 95% CI [0.19-0.72], p = 0.001) are associated with 5-year progression-free survival (PFS) in patients with NPC. Based on the results of the multivariate analysis, we proposed a new biomarker GLO-PLR, which is observably correlated with the T stage, N stage and clinical stage in patients with NPC. The OS resolving ability of the GLO-PLR evaluated by AUC is 0.714, which is better than those of GLO and PLR. The PFS resolving ability of the GLO-PLR evaluated by AUC was 0.696, which is also better than those of GLO and PLR. Conclusion: Pre-treatment PLR, ALB, and GLO are independent predictors of 5-year OS in patients with NPC, where PLR and GLO are also independent predictors of 5-year FPS. Compared with other hematological parameters, the proposed GLO-PLR is an inexpensive, effective, objective, and easy-to-measure marker for predicting the prognosis of NPC.
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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/patologia , Estudos Retrospectivos , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/patologia , Prognóstico , Adulto , Idoso , Albumina Sérica/análise , Albumina Sérica/metabolismo , Contagem de Plaquetas , Curva ROC , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Plaquetas/patologiaRESUMO
A method was developed by hydride generation atomic fluorescence spectrometry (HG-AFS)for the determination of selenium in plant samples. Effects of reagent and pre-reduction method on the fluorescence intensity of selenium were studied. The influence of coexisting foreign ions on the determination of selenium was also investigated. Under the optimized digestive and experimental conditions, the linear regression equation was I = 139.98c + 27.71 for Se. The linear range, the correlation coefficient,and the detection limit of Se was 0-10 ng x mL(-1), 1.0000, and 1.45 ng x g(-1) respectively. The recovery of Se (98.9%-101%, mean=100%) was determined through the use of standard reference material. The relative standard deviation for nine replicate analyses was 0.73% for Se content in shrub leaves. This method was verified by analyzing the national reference material (GSV-1)and the found value was in good agreement with the certified value. The proposed method that was successfully used for the determination of Se in plant samples has the advantages of simple operation, low cost, and high efficiency.
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Plantas/química , Selênio/análise , Espectrometria de Fluorescência , Íons , Isótopos , Limite de Detecção , Compostos de SelênioRESUMO
The present study aimed to reveal the amount per application of facial sheet masks and its influencing factors in Chinese population to form the base for an accurate exposure assessment. A total of 175 healthy subjects aged 18 years or older were recruited and divided into two subgroups: one group of 35 subjects were asked to apply same mask for 5, 10, 15, 20, 25, and 30 min respectively, and the other 140 subjects were instructed to apply one of four types of facial sheet masks presented in the market for 15 min. Furthermore, phenoxyethanol and methylparaben were measured to reflect actual exposure to chemicals. The sharp increase in the relative exposure to phenoxyethanol (CAS NO.122-99-6) and methylparaben at 25 min and longer suggests applying facial sheet masks for longer than 20 min may drive the exposure to hazardous chemicals to increase significantly. The 90th percentile of amount per application for plant-cellulose, bamboo charcoal fiber, bio-cellulose, and binchotan charcoal fiber-based masks was 5.753, 5.371, 5.017, and 4.821 g respectively. In addition, men and subjects with sebaceous skin demonstrated lower amount per application compared to women and subjects with dry skin, respectively. Finally, our data showed that the larger the contacting area between face and mask, the more amount per application. We concluded that the appropriate time of application should be less than 20 min. And mask fabrics, gender, sebum content, and contacting area could significantly impact the risk assessment of facial sheet masks. Our data for the first time provides insights into a realistic risk assessment of facial sheet masks in Chinese population.
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Cosméticos/administração & dosagem , Face , Pele/efeitos dos fármacos , Administração Cutânea , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de RiscoRESUMO
In the title compound, C(15)H(14)N(2)O(7), the planes of the two benzene rings form a dihedral angle of 33.16â (17)°. In the crystal, inter-molecular hydrogen bonds involveing the OH group and nitro O atoms link the mol-ecules into chains propagating along the a axis.
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There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefitinib. The anti-tumor activity of these novel Gefitinib analogues in 6 human cancer cell lines was examined. Compared with the parental Gefitinib, most of the new compounds show a markedly increased cytotoxicity to cancer cells. Furthermore, several of the series B compounds that side chains at position 7 contain either a methyl or ethyl group are potent pan-RTK inhibitors. Two representative compounds in this class, 15 and 17, have an enhanced capability to inhibit cancer cell growth and induce apoptosis in vitro and inhibit tumor formation in vivo in human cancer cells with high HER-2, as compared with the parental Gefitinib. Thus they may be promising lead compounds to be developed as an alternative for current Gefitinib therapy or for Gefitinb-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.
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Antineoplásicos/química , Quinazolinas/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Receptores ErbB , Gefitinibe , Humanos , Quinazolinas/química , Quinazolinas/uso terapêutico , Receptor ErbB-2RESUMO
The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1alpha, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Melanoma/enzimologia , Inibidores de Proteases/farmacologia , Inibidores de Proteassoma , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirazinas/farmacologia , Neoplasias Cutâneas/enzimologia , Apoptose/genética , Sítios de Ligação , Bortezomib , Desenho de Fármacos , Fator de Transcrição E2F1/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Interferência de RNA , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Concurrent cisplatin with radiotherapy (CRT) or concurrent cetuximab with radiotherapy (BRT) improves outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) compared with radiotherapy alone. Nevertheless, a detailed comparison between CRT and BRT in locally advanced HNSCC is required due to inconclusive results. METHODS: A comprehensive literature search was conducted on PubMed, Web of Science, Cochrane databases, and EMBASE. Studies that evaluated CRT vs BRT in locally advanced HNSCC were included. The primary outcome that was overall survival (OS), whereas the secondary outcomes were progression-free survival (PFS), locoregional control (LRC), and distant metastasis-free survival (DMFS). Pooled hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to evaluate prognosis. All the analyses were performed using Stata Statistical Software 12.0. RESULTS: Twenty-three studies, with a total of 8701 patients, were considered eligible and included in this meta-analysis. Our results revealed that patients treated with CRT had longer OS (HRâ=â0.51, 95%CI, 0.41-0.64, Pâ<â.001), PFS (HRâ=â0.37, 95%CI, 0.23-0.60, Pâ<â.001), LRC (HRâ=â0.46, 95%CI, 0.37-0.57, Pâ<â.001), and DMFS (HRâ=â0.56, 95%CI, 0.40-0.77, Pâ<â.001) than those treated with BRT. Furthermore, the results of the subgroup analyses were consistent with the primary analysis. CONCLUSIONS: CRT has a better OS, PFS, LRC, and DMFS than BRT in locally advanced HNSCC, and should be the preferred treatment for patients with the disease.
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Cetuximab/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Quimiorradioterapia/métodos , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidadeRESUMO
The N-deficient porous g-C3N4 with broadband white light emission was constructed by supramolecular copolymerization design, which combined organic copolymers cyanuric acid and 2,4,6-triaminopyrimidine with melamine upon the mixture gas environment of (95%)N2/(5%)H2. Herein, we achieved great breakthrough in narrowing the band gap of g-C3N4 from 2.64 to 1.39 eV. Furthermore, in contrast to pristine g-C3N4, we demonstrated that the emission wavelengths of N-deficient porous g-C3N4 can be tuned from narrow blue to broadband white range, where the optimal white light coordinate position is (0.297, 0.345). The prepared N-deficient porous g-C3N4 overcomes the limitation of the narrow adjusting range of optical properties while using conventional g-C3N4 and makes it more promising for applications in solid-state displays.
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Abundant studies have been conducted to identify how B-cell translocation gene 1 protein (BTG1) gene affects the differentiation, proliferation, metastasis of cancer cells, and how it further regulates the generation or development of diseases to influence the prognosis of patients. However, the data from single research were not powerful enough. The correlations between BTG1 expression and mechanisms of tumorigenesis or prognosis of patients are still in controversial. Our system review and meta-analysis provided a complete explanation about the association between BTG1 expression and clinicopathological features or prognosis of patients, which further laid a foundation for future research on BTG1. Fifteen eligible studies consisting of 1992 participants were included. We uncovered that BTG1 expression in solid tumors was associated with lymph node status (RR=0.66, 95% CI: 0.58-0.75, P=0.142), TMN stage status (RR=2.13, 95% CI: 1.71-2.65, P=0.001), T category (RR=1.90, 95% CI: 1.20-3.00, P=0.000), histological differentiation (RR=1.91, 95% CI: 1.55-2.37, P=0.012), vascular invasion (RR=0.90, 95% CI: 0.57-1.41, P=0.001). BTG1 low expression was significantly associated with overall survival (OS) (HR=0.47, 95% CI: 0.38-0.67, P=0.000). It concluded that BTG1 possessed the potential value for future research and could be recommended as a significant biomarker in solid tumor.
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Biomarcadores Tumorais/genética , Regulação para Baixo , Proteínas de Neoplasias/genética , Neoplasias/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Neoplasias/genética , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for human cancer therapy, prostate cancer still remains resistant to TRAIL. Both X-linked inhibitor of apoptosis (XIAP) and nuclear factor-kappaB function as key negative regulators of TRAIL signaling. In this study, we evaluated the effect of SH122, a small molecule mimetic of the second mitochondria-derived activator of caspases (Smac), on TRAIL-induced apoptosis in prostate cancer cells. METHODS: The potential of Smac-mimetics to bind XIAP or cIAP-1 was examined by pull-down assay. Cytotoxicity of TRAIL and/or Smac-mimetics was determined by a standard cell growth assay. Silencing of XIAP or cIAP-1 was achieved by transient transfection of short hairpin RNA. Apoptosis was detected by Annexin V-PI staining followed by flow cytometry and by Western Blot analysis of caspases, PARP and Bid. NF-kappaB activation was determined by subcellular fractionation, real time RT-PCR and reporter assay. RESULTS: SH122, but not its inactive analog, binds to XIAP and cIAP-1. SH122 significantly sensitized prostate cancer cells to TRAIL-mediated cell death. Moreover, SH122 enhanced TRAIL-induced apoptosis via both the death receptor and the mitochondrial pathway. Knockdown of both XIAP and cIAP-1 sensitized cellular response to TRAIL. XIAP-knockdown attenuated sensitivity of SH122 to TRAIL-induced cytotoxicity, confirming that XIAP is an important target for IAP-inhibitor-mediated TRAIL sensitization. SH122 also suppressed TRAIL-induced NF-kappaB activation by preventing cytosolic IkappaB-alpha degradation and RelA nuclear translocation, as well as by suppressing NF-kappaB target gene expression. CONCLUSION: These results demonstrate that SH122 sensitizes human prostate cancer cells to TRAIL-induced apoptosis by mimicking Smac and blocking both IAPs and NF-kappaB. Modulating IAPs may represent a promising approach to overcoming TRAIL-resistance in human prostate cancer with constitutively active NF-kappaB signaling.
Assuntos
Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/agonistas , Proteínas Mitocondriais/agonistas , NF-kappa B/metabolismo , Neoplasias da Próstata/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Humanos , Proteínas Inibidoras de Apoptose/genética , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Masculino , Proteínas Mitocondriais/farmacologia , NF-kappa B/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Ligação Proteica , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismoRESUMO
PURPOSE: The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor both in vitro and in vivo in androgen-independent prostate cancer and the possible mechanism of radiosensitization. EXPERIMENTAL DESIGN: Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-kappaB activation was detected by luciferase reporter assay and quantitative real-time PCR. RESULTS: SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-alpha- and radiation-induced nuclear factor-kappaB activation in DU-145 cells. CONCLUSIONS: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.
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Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/metabolismo , Oligopeptídeos/farmacologia , Neoplasias da Próstata/terapia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos da radiação , Western Blotting , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Humanos , Imunoprecipitação , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/efeitos dos fármacos , Masculino , Camundongos , NF-kappa B/efeitos dos fármacos , NF-kappa B/efeitos da radiação , Radioterapia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Antiapoptotic members of the Bcl-2 family proteins are overexpressed in prostate cancer and are promising molecular targets for modulating chemoresistance of prostate cancer. (-)-Gossypol, a natural BH3 mimetic, is a small-molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 currently in phase II clinical trials as an adjuvant therapy for human prostate cancer. Our objective is to examine the chemosensitization potential of (-)-gossypol in prostate cancer and its molecular mechanisms of action. (-)-Gossypol inhibited cell growth and induced apoptosis through mitochondria pathway in human prostate cancer PC-3 cells and synergistically enhanced the antitumor activity of docetaxel both in vitro and in vivo in PC-3 xenograft model in nude mouse. (-)-Gossypol blocked the interactions of Bcl-xL with Bax or Bad in cancer cells by fluorescence resonance energy transfer assay and overcame the Bcl-xL protection of FL5.12 model cells on interleukin-3 withdrawal. Western blot and real-time PCR studies showed that a dose-dependent increase of the proapoptotic BH3-only proteins Noxa and Puma contributed to the cell death induced by (-)-gossypol and to the synergistic effects of (-)-gossypol and docetaxel. The small interfering RNA knockdown studies showed that Noxa and Puma are required in the (-)-gossypol-induced cell death. Taken together, these data suggest that (-)-gossypol exerts its antitumor activity through inhibition of the antiapoptotic protein Bcl-xL accompanied by an increase of proapoptotic Noxa and Puma. (-)-Gossypol significantly enhances the antitumor activity of chemotherapy in vitro and in vivo, representing a promising new regime for the treatment of human hormone-refractory prostate cancer with Bcl-2/Bcl-xL/Mcl-1 overexpression.
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Proteínas Reguladoras de Apoptose/metabolismo , Gossipol/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dimerização , Docetaxel , Relação Dose-Resposta a Droga , Humanos , Interleucina-3/metabolismo , Masculino , Camundongos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , RNA Interferente Pequeno/metabolismo , Taxoides/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Glioblastoma is a common malignant tumor in the central nervous system with an extremely poor outcome; understanding the mechanisms of glioblastoma at the molecular level is essential for clinical treatment. In the present study, we used bioinformatics analysis to identify potential biomarkers associated with prognosis in glioblastoma and elucidate the underlying mechanisms. The result revealed that 552 common genes were differentially expressed between glioblastoma and normal tissues based on TCGA, GSE4290, and GSE 50161 datasets. Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interaction (PPI) network were carried out to gain insight into the actions of differentially expressed genes (DEGs). As a result, 20 genes (CALB1, CDC20, CDCA8, CDK1, CEP55, DLGAP5, KIF20A, KIF4A, NDC80, PBK, RRM2, SYN1, SYP, SYT1, TPX2, TTK, VEGFA, BDNF, GNG3, and TOP2A) were found as hub genes via CytoHubba in Cytoscape and functioned mainly by participating in cell cycle and p53 signaling pathway; among them, RRM2 and CEP55 were considered to have relationship with the prognosis of glioblastoma, especially RRM2. High expression of RRM2 was consistent with shorter overall survival time. In conclusion, our study displayed the bioinformatic analysis methods in screening potential oncogenes in glioblastoma and underlying mechanisms. What is more is that we successfully identified RRM2 as a novel biomarker linked with prognosis, which might be expected to be a promising target for the therapy of glioblastoma.
Assuntos
Biomarcadores Tumorais/genética , Glioblastoma/genética , Proteínas de Neoplasias/genética , Prognóstico , Proteínas de Ciclo Celular/genética , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Glioblastoma/patologia , Humanos , Proteínas Nucleares/genética , Ribonucleosídeo Difosfato Redutase/genéticaRESUMO
Background: Pre-treatment serum lactate dehydrogenase (LDH) has emerged as prognostic factor for many cancers. In this study, we evaluated the value of LDH in predicting distant metastasis and poor survival for patients with nasopharyngeal carcinoma (NPC). Methods: Clinical data from 172 non-metastatic NPC patients were retrospectively collected and serum LDH levels were routinely measured before treatment. The independent-samples t test was used to calculate differences between serum LDH levels from the various patient groups. Receiver-operating characteristic (ROC) curve analysis was performed to select the optimal cutoff points. The Kaplan-Meier method and log-rank test were adopted to calculate and compare the distant metastasis free survival (DMFS) and overall survival (OS) rates. The Cox proportional hazards model was used to carry out univariate and multivariate analyses. Results: NPC patients progressed with distant metastasis often have higher pre-treatment serum LDH levels than those did not develop distant metastasis (mean LDH level was 237.1U/L and 108.8U/L, respectively, p=0.001). Elevated LDH level was identified as an independent prognostic factor for poor DMFS (hazard ratio (HR), 8.31; 95% confidence interval (CI), 2.44-28.32; p=0.001) and OS (HR, 4.45; 95% CI, 1.77-11.21; p=0.002). Moreover, subgroup analyses revealed significant associations between serum LDH level and worse survival in advanced stage patients. Conclusions: Pre-treatment serum LDH level can predict distant metastasis and associate with the poor survival in patients with NPC.
RESUMO
An effective and facile "on-off" fluorescence sensing approach for the determination of Fe3+ ion using a large area and relatively uniform size graphitic carbon nitride nanosheets (GCNS) was developed. The prepared GCNS have blue and stable emission, as well as excellent water dispersion, and were applied as an effective fluorescent probe that based on the quenched fluorescence for selective and sensitive detection of Fe3+ ion. Herein, we explain the ambiguous fluorescence quenching mechanism between the GCNS and Fe3+, which mainly springs from the redox potential and empty d orbital of Fe3+. The redox potential and unfilled d orbit of Fe3+ endow it excellent binding force with GCNS, which generates most obvious fluorescence quenching effect with respect to other metal ions. The limit of detection (LOD) for Fe3+ was found to be about 2.06⯵M. Therefore, the prepared GCNS has the potential to be used as a fluorescent probe for detection.
RESUMO
Correction for 'Core-shell like glass containing lanthanide doped nanocrystals for efficient luminescence' by Qunhuo Liu et al., Chem. Commun., 2018, 54, 13092-13095.