RESUMO
Antibodies targeting insulin-like growth factor 1 receptor (IGF-1R) induce objective responses in only 5% to 15% of children with sarcoma. Understanding the mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R-targeted antibodies. Sensitivity to the IGF-1R-targeting antibody TZ-1 was determined in rhabdomyosarcoma and Ewing sarcoma cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. The BRD4 inhibitor, JQ1, was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of receptor tyrosine kinases (RTK) was assessed. Sensitivity to TZ-1 in vivo was determined in Rh41 parental and TZ-1-resistant xenografts. Of 20 sarcoma cell lines, only Rh41 was sensitive to TZ-1. Cells intrinsically resistant to TZ-1 expressed multiple (>10) activated RTKs or a relatively less complex set of activated RTKs (â¼5). TZ-1 decreased the phosphorylation of IGF-1R but had little effect on other phosphorylated RTKs in all resistant lines. TZ-1 rapidly induced activation of RTKs in Rh41 that was partially abrogated by knockdown of SOX18 and JQ1. Rh41/TZ-1 cells selected for acquired resistance to TZ-1 constitutively expressed multiple activated RTKs. TZ-1 treatment caused complete regressions in Rh41 xenografts and was significantly less effective against the Rh41/TZ-1 xenograft. Intrinsic resistance is a consequence of redundant signaling in pediatric sarcoma cell lines. Acquired resistance in Rh41 cells is associated with rapid induction of multiple RTKs, indicating a dynamic response to IGF-1R blockade and rapid development of resistance. The TZ-1 antibody had greater antitumor activity against Rh41 xenografts compared with other IGF-1R-targeted antibodies tested against this model.
Assuntos
Proteínas Nucleares , Sarcoma , Criança , Humanos , Fatores de Transcrição , Receptor IGF Tipo 1 , Sarcoma/tratamento farmacológico , Receptores de Somatomedina , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Proteínas de Ciclo Celular , Fatores de Transcrição SOXFRESUMO
Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease-switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy-which utilizes strategies to reenergize or alter the immune system to target cancer-have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-ß signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Médicos , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Humanos , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , Imunoterapia/métodos , Linfócitos TRESUMO
BACKGROUND AND STUDY AIMS: The clinical significance of serum parameters of iron metabolism and hepcidin in liver disease remains unknown. Therefore, this study aimed to evaluate the association of serum hepcidin levels with fibrosis stage and serum iron parameters in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS: This cross-sectional study included 126 treatment-naïve patients with CHB (median age, 39.0 years; 64.3% males) who were positive for hepatitis B surface antigen and 23 healthy controls (median age, 33.0 years; 52.2% males). Data on patient demographics, serum hepcidin levels, liver function tests and serum iron parameters and liver biopsy findings including fibrosis grade, histological activity index (HAI) and liver iron level were recorded. RESULTS: The median (minimum-maximum) serum hepcidin levels were significantly lower in the CHB group than in the control group [71.2 (13.3-672.7) vs. 657.5 (201.7-2714.2) pg/mL, p < 0.001]. Higher fibrosis stage was associated with higher transferrin saturation (p = 0.029), serum ferritin level (p < 0.001) and viral load (p < 0.001). Fibrosis stage and HAI were positively correlated with ferritin (r = 0.407, p < 0.001 and r = 0.415, p < 0.001, respectively) and transferrin saturation (r = 0.219, p = 0.026 and r = 0.290, p = 0.003, respectively) levels, whereas hepcidin level was negatively correlated with fibrosis stage (r = -0.175, p = 0.051), viral load (r = -0.209, p = 0.020) and ferritin level (r = -0.244, p = 0.006) level. There were no significant differences in serum iron level, total iron binding capacity and liver iron level among patients with different stages of fibrosis. CONCLUSION: Reduced hepcidin levels and elevated transferrin saturation and ferritin levels are linked to fibrosis severity and HAI in patients with CHB.
Assuntos
Hepatite B Crônica , Hepcidinas/sangue , Cirrose Hepática , Adulto , Biomarcadores/sangue , Correlação de Dados , Estudos Transversais , Feminino , Ferritinas/sangue , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/epidemiologia , Humanos , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Testes de Função Hepática/métodos , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Transferrina/metabolismo , Turquia/epidemiologiaRESUMO
The pre-metastatic niche (PMN) represents an abnormal microenvironment devoid of cancer cells, but favoring tumor growth. Little is known about the mechanisms that generate the PMN or their effects on host cells within metastasis-prone organs. Here, we investigated by using spontaneous metastatic models whether lung epithelial cells are essential for primary tumor induced neutrophil recruitment in lung and subsequently initiating PMN formation in osteosarcoma. We found that serum levels of ANGPTL2 in osteosarcoma patients are significantly higher compared to those in healthy controls and that ANGPTL2 secretion by tumor cells plays an essential role in osteosarcoma metastasis. We determined that tumor-derived ANGPTL2 stimulates lung epithelial cells, which is essential for primary tumor-induced neutrophil recruitment in lung and subsequent pre-metastatic niche formation. Lastly, we identified that a p63 isoform, ΔNp63, drives high level of ANGPTL2 secretion and pharmaceutical inhibition of ANGPTL2 signaling by a non-RGD-based integrin binding peptide (ATN-161) diminished metastatic load in lungs likely due to reduction of the lung pre-metastatic niche formation.
RESUMO
BACKGROUND: Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isoform of TP73, and to evaluate targeting of its downstream mediators, the angiopoietin 1 (ANGPT1)/tunica interna endothelial cell kinase 2 (Tie2) axis, by using a highly potent, orally available small-molecule inhibitor (rebastinib) in GBM. METHODS: ΔNp73 expression was assessed in glioma sphere cultures, xenograft glioblastoma tumors, and glioblastoma patients by western blot, quantitative reverse transcription PCR, and immunohistochemistry. Immunoprecipitation, chromatin immunoprecipitation (ChiP) and sequential ChIP were performed to determine the interaction between ΔNp73 and E26 transformation-specific (ETS) proto-oncogene 2 (ETS2) proteins. The oncogenic consequences of ΔNp73 expression in glioblastomas were examined by in vitro and in vivo experiments, including orthotopic zebrafish and mouse intracranial-injection models. Effects of rebastinib on growth of established tumors and survival were examined in an intracranial-injection mouse model. RESULTS: ΔNp73 upregulates both ANGPT1 and Tie2 transcriptionally through ETS conserved binding sites on the promoters by interacting with ETS2. Elevated expression of ΔNp73 promotes tumor progression by mediating angiogenesis and survival. Therapeutic targeting of downstream ΔNp73 signaling pathways by rebastinib inhibits growth of established tumors and extends survival in preclinical models of glioblastoma. CONCLUSION: Aberrant expression of ΔNp73 in GBM promotes tumor progression through autocrine and paracrine signaling dependent on Tie2 activation by ANGPT1. Disruption of this signaling by rebastinib improves tumor response to treatment in glioblastoma.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Proteína Proto-Oncogênica c-ets-2/metabolismo , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Quinolinas/administração & dosagem , Proteína Tumoral p73/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral/efeitos dos fármacos , Modelos Animais de Doenças , Glioblastoma/tratamento farmacológico , Humanos , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Proto-Oncogene Mas , Análise de Sobrevida , Peixe-ZebraRESUMO
Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2-specific, CAR-reengineered T-cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR-T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Receptores de Antígenos Quiméricos/imunologia , Sarcoma de Ewing/tratamento farmacológico , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Terapia Baseada em Transplante de Células e Tecidos/métodos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Imunoterapia Adotiva/métodos , Camundongos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/imunologia , Sarcoma de Ewing/patologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Osteosarcoma (OS), a malignant tumor of bone, kills through aggressive metastatic spread almost exclusively to the lung. Mechanisms driving this tropism for lung tissue remain unknown, though likely invoke specific interactions between tumor cells and other cells within the lung metastatic niche. Aberrant overexpression of ΔNp63 in OS cells directly drives production of IL-6 and CXCL8. All these factors were expressed at higher levels in OS lung metastases than in matched primary tumors from the same patients. Expression in cell lines correlated strongly with lung colonization efficiency in murine xenograft models. Lentivirus-mediated expression endowed poorly metastatic OS cells with increased metastatic capacity. Disruption of IL-6 and CXCL8 signaling using genetic or pharmaceutical inhibitors had minimal effects on tumor cell proliferation in vitro or in vivo, but combination treatment inhibited metastasis across multiple models of metastatic OS. Strong interactions occurred between OS cells and both primary bronchial epithelial cells and bronchial smooth muscle cells that drove feed-forward amplification of IL-6 and CXCL8 production. These results identify IL-6 and CXCL8 as primary mediators of OS lung tropism and suggest pleiotropic, redundant mechanisms by which they might effect metastasis. Combination therapy studies demonstrate proof of concept for targeting these tumor-lung interactions to affect metastatic disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/patologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neoplasias Pulmonares/patologia , Adolescente , Adulto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osso e Ossos/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Receptor gp130 de Citocina/antagonistas & inibidores , Receptor gp130 de Citocina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Seguimentos , Humanos , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Pulmão/patologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/prevenção & controle , Osteossarcoma/secundário , Cultura Primária de Células , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Receptores de Interleucina-8A/antagonistas & inibidores , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
BACKGROUND: STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5. METHODS AND FINDINGS: An in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization. LY5 was evaluated in vitro demonstrating good biologic activity against rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma cell lines at high nanomolar/low micromolar concentrations, as well as specific inhibition of STAT3 phosphorylation without effects on other STAT3 family members. LY5 exhibited excellent oral bioavailability in both mice and healthy dogs, and drug absorption was enhanced in the fasted state with tolerable dosing in mice at 40 mg/kg BID. However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines. Moreover, concentrations needed to inhibit ex vivo metastasis growth using the PuMA assay were significantly higher than those needed to inhibit STAT3 phosphorylation in vitro. Lastly, LY5 treatment did not inhibit the growth of sarcoma xenografts or prevent pulmonary metastasis in mice. CONCLUSIONS: LY5 is a novel small molecule inhibitor that effectively inhibits STAT3 phosphorylation and cell proliferation at nanomolar concentrations. LY5 demonstrates good oral bioavailability in mice and dogs. However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects. These data suggest that the anti-cancer effects of LY5 identified in vitro were not mediated through STAT3 inhibition.
Assuntos
Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Osteossarcoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Sarcoma de Ewing/tratamento farmacológico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Aminopiridinas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/farmacologia , Cães , Feminino , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Osteossarcoma/patologia , Fosforilação/efeitos dos fármacos , Rabdomiossarcoma/patologia , Fator de Transcrição STAT3/metabolismo , Sarcoma de Ewing/patologia , Sulfonamidas/farmacologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
p63 is a structural homolog within the 53 family encoding two isoforms, ΔNp63 and TAp63. The oncogenic activity of ΔNp63 has been demonstrated in multiple cancers, however the underlying mechanisms that contribute to tumorigenesis are poorly characterized. Osteosarcoma (OSA) is the most common primary bone tumor in dogs, exhibiting clinical behavior and molecular biology essentially identical to its human counterpart. The purpose of this study was to evaluate the potential contribution of ΔNp63 to the biology of canine OSA. As demonstrated by qRT-PCR, nearly all canine OSA cell lines and tissues overexpressed ΔNp63 relative to normal control osteoblasts. Inhibition of ΔNp63 by RNAi selectively induced apoptosis in the OSA cell lines overexpressing ΔNp63. Knockdown of ΔNp63 upregulated expression of the proapoptotic Bcl-2 family members Puma and Noxa independent of p53. However the effects of ΔNp63 required transactivating isoforms of p73, suggesting that ΔNp63 promotes survival in OSA by repressing p73-dependent apoptosis. In addition, ΔNp63 modulated angiogenesis and invasion through its effects on VEGF-A and IL-8 expression, and STAT3 phosphorylation. Lastly, the capacity of canine OSA cell lines to form pulmonary metastasis was directly related to expression levels of ΔNp63 in a murine model of metastatic OSA. Together, these data demonstrate that ΔNp63 inhibits apoptosis and promotes metastasis, supporting continued evaluation of this oncogene as a therapeutic target in both human and canine OSA.
Assuntos
Neoplasias Ósseas/patologia , Neoplasias Pulmonares/patologia , Osteossarcoma/patologia , Fator de Transcrição STAT3/metabolismo , Sarcoma Experimental/patologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose , Neoplasias Ósseas/veterinária , Linhagem Celular Tumoral , Sobrevivência Celular , Cães , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Interleucina-8/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos SCID , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Osteoblastos , Osteossarcoma/veterinária , Fosforilação , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sarcoma Experimental/secundário , Fatores de Transcrição/genética , Proteína Tumoral p73/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND/AIMS: This study is designed to determine which drug forms provide ideal pharyngeal anesthesia when used during upper gastrointestinal system endoscopy. MATERIALS AND METHODS: A total of 180 patients were included in the study. Using the random number table, these patients were divided into three groups. Group 1, lidocaine gel+isotonic spray; Group 2, base lubricant gel+lidocaine spray; and Group 3: lidocaine gel+lidocaine spray. Data were collected from the patient identification form, compliance to operation form, and State Anxiety Inventory. RESULTS: Anesthetization and compliance to procedure scores were higher and anxiety scores were lower in Group 3 than in other groups (p<0.05). It was observed that as the compliance score increased, the anesthetization and satisfaction scores also increased; however, coughing during the procedure, duration of the procedure, and anxiety scores decreased (p<0.05). It was determined that as anesthetization scores increased, discomfort in the throat caused by the device, coughing during the procedure, and anxiety scores decreased (p<0.05). CONCLUSION: Lidocaine gel and spray combination is the most ideal pharyngeal anesthesia to ensure the adaptation of the patient to the procedure and to decrease anxiety and discomfort during the procedure.
Assuntos
Anestésicos Combinados/administração & dosagem , Anestésicos Locais/administração & dosagem , Endoscopia Gastrointestinal/métodos , Soluções Isotônicas/administração & dosagem , Lidocaína/administração & dosagem , Adulto , Ansiedade/epidemiologia , Ansiedade/etiologia , Tosse/epidemiologia , Tosse/etiologia , Método Duplo-Cego , Endoscopia Gastrointestinal/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Satisfação do Paciente , Faringe/cirurgiaRESUMO
Under conditions of DNA damage, the mammalian target of rapamycin complex 1 (mTORC1) is inhibited, preventing cell cycle progression and conserving cellular energy by suppressing translation. We show that suppression of mTORC1 signaling to 4E-BP1 requires the coordinated activity of two tumor suppressors, p53 and p63. In contrast, suppression of S6K1 and ribosomal protein S6 phosphorylation by DNA damage is Akt-dependent. We find that loss of either p53, required for the induction of Sestrin 1/2, or p63, required for the induction of REDD1 and activation of the tuberous sclerosis complex, prevents the DNA damage-induced suppression of mTORC1 signaling. These data indicate that the negative regulation of cap-dependent translation by mTORC1 inhibition subsequent to DNA damage is abrogated in most human cancers.
Assuntos
Dano ao DNA , Complexos Multiproteicos/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Neoplasias/genética , Neoplasias/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63, which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63-, and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of ΔNp63; however, there is no correlation of ΔNp63 expression with p53 mutation status. Our data suggest that ΔNp63 itself endows cells with a gain-of-function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that ΔNp63 overexpression, independent of p53, increases secretion of interleukin (IL)-6 and IL-8, leading to elevated phosphorylation of STAT3 (Tyr-705). We show that elevated phosphorylation of STAT3 leads to stabilization of hypoxia-inducible factor 1α (HIF-1α) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis.
Assuntos
Neoplasias Ósseas/irrigação sanguínea , Proteínas de Membrana/metabolismo , Neuroblastoma/irrigação sanguínea , Osteossarcoma/irrigação sanguínea , Adolescente , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Criança , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos SCID , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fatores de Transcrição , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Eisenmenger syndrome is associated with irreversible increase in pulmonary vascular resistance causing reduced survival. Bosentan, a non-selective endothelin receptor antagonist is the commonly used specific pulmonary arterial hypertension drug in Eisenmenger syndrome. In this paper, we present a case of recurrent gastrointestinal bleeding in a 23-year-old female with Eisenmenger syndrome who was only under bosentan treatment, which has not been reported previously. Most common adverse effect of bosentan is elevation in the liver enzymes however, bleeding complication is very rare. On the contrary, it was proposed that bosentan might be a potential protector against hyperacidity and mucosal erosion that occur as a consequence of stress. Although the mechanistic relationship of bleeding tendency and role of Eisenmenger syndrome concomitant with bosentan treatment is far from conclusive statement for now, this association warrants and should draw attention of clinicians and researches in this field.
Assuntos
Anti-Hipertensivos/efeitos adversos , Complexo de Eisenmenger/complicações , Hemorragia Gastrointestinal/etiologia , Sulfonamidas/efeitos adversos , Anti-Hipertensivos/farmacologia , Bosentana , Complexo de Eisenmenger/tratamento farmacológico , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Recidiva , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Adulto JovemRESUMO
The Interferon (IFN) which is the standard treatment for Hepatitis C, may cause a lot of side effects including dermatological anomalies. This paper presents a psoriasis case which occurred in relation with the treatment of acute hepatitis C (AHC) with peginterferon alfa (peg-IFN-α). A 60-year-old male patient came to the hospital with symptoms of high liver enzymes. The patient with history of a recent operation showed anti-HCV(+), HCVRNA 3.5 million IU/mL and HCV genotype 1b in the tests. Without any other etiological factors found in the patient, we started a treatment of peg-IFNα-2b with the diagnosis of AHC. After 3 weeks, psoriatic plaques were observed in various parts of the body. Antiviral treatment of the patient was concluded within 6 months. His psoriasis treatment initially commenced with local agents followed by phototherapy. Permanent viral response was seen in the patient and his lesions recovered rapidly after the antipsoriatic and antiviral treatment. Psoriasis and other autoimmune diseases should be considered even though they are encountered rarely,and the patients should be informed of the possible risks before planning treatment with peg-IFN-α.
Assuntos
Toxidermias/diagnóstico , Toxidermias/etiologia , Hepatite C/tratamento farmacológico , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Psoríase/induzido quimicamente , Psoríase/diagnóstico , Diagnóstico Diferencial , Toxidermias/prevenção & controle , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/prevenção & controle , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly, mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA-damaging agents; however, the molecular mechanism is not well understood. We found that an mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft to radiotherapy and sensitized rhabdomyosarcoma cells to the DNA interstrand cross-linker (ICL) melphalan. Sensitization correlated with drug-induced downregulation of a key component of the Fanconi anemia pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2-deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2-deficient cells showed impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by reintroduction of wild-type FANCD2. Pharmacologic inhibition of PI3K-mTOR-AKT pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double-strand breaks by sustaining FANCD2 and provide a novel mechanism of how the Fanconi anemia pathway modulates DNA damage response and repair.
Assuntos
Quebras de DNA de Cadeia Dupla , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Rabdomiossarcoma/genética , Serina-Treonina Quinases TOR/genética , Adolescente , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Criança , Pré-Escolar , Reparo do DNA , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos SCID , Fosforilação , Rabdomiossarcoma/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/AIMS: Intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and non-alcoholic fatty liver disease. Probiotics could modulate the gut flora and could influence the gut-liver axis. We aimed to investigate the preventive effect of two probiotic mixtures on the methionine choline-deficient diet-induced non-alcoholic steatohepatitis model in rats. METHODS: Two studies, short-term (2 weeks) and long-term (6 weeks), were carried out using 60 male Wistar rats. The 2-week study included six groups. Rats were fed with methionine choline-deficient diet or pair-fed control diet and were given a placebo or one of two probiotic mixtures (Pro-1 and Pro-2) by orogastric gavage. In the 6-week study, rats were allocated into four groups and were fed with methionine choline-deficient diet or pair-fed control diet and given a placebo or Pro-2. At the end of the 2- and 6-week periods, blood samples were obtained, the animals were sacrificed, and liver tissues were removed. Serum alanine aminotransferase activity was determined; histologic and immunohistochemical analysis was performed for steatosis, inflammation, protein expression of tumor necrosis factor-α, and apoptosis markers. RESULTS: In both studies, methionine choline-deficient diet caused an elevation of serum alanine aminotransferase activity, which was slightly reduced by Pro-1 and Pro-2. In the 2- and 6-week studies, feeding with methionine choline-deficient diet resulted in steatosis and inflammation, but not fibrosis, in all rats. In the 2-week study, in rats fed with methionine choline-deficient diet and given Pro-1, steatosis and inflammation were present in 2 of 6 rats. In rats fed with methionine choline-deficient diet and given Pro-2, steatosis was detected in 3 of 6 rats, while inflammation was present in 2 of 6 rats. In the 6-week study, in rats fed with methionine choline-deficient diet and given Pro-2, steatosis and inflammation were present in 3 of 6 rat livers. In both the 2- and 6-week studies, methionine choline-deficient diet resulted in tumor necrosis factor-α, proapoptotic Bax, caspase 3, caspase 8, and anti-apoptotic Bcl-2 expression in all rat livers. Pro-1 and Pro-2 treatment influenced protein expression involved in apoptosis and tumor necrosis factor-α in varying degrees. CONCLUSIONS: Pro-1 and Pro-2 decrease methionine choline-deficient diet-induced steatohepatitis in rats. The preventive effect of probiotics may be due, in part, to modulation of apoptosis and their anti-inflammatory activity.
Assuntos
Fígado Gorduroso/patologia , Fígado Gorduroso/terapia , Fígado/patologia , Probióticos/farmacologia , Alanina Transaminase/sangue , Animais , Caspase 3/metabolismo , Caspase 8/metabolismo , Deficiência de Colina , Dieta , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Imuno-Histoquímica , Inflamação/patologia , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
AIM: To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. METHODS: One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods. RESULTS: Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (< 70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles (*2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed (P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks. CONCLUSIONS: CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
Integration of cellular and extracellular signals maintains tissue homeostasis under conditions of normal proliferation and stress. A central player in regulating responses to stress is the serine/threonine kinase mammalian target of rapamycin (mTOR). In many cancers, mTOR complex 1 (mTORC1) signaling is enhanced, even under conditions where such signaling should be suppressed. This article reviews some of the details that are emerging on how low oxygen (hypoxia) regulates mTORC1 signaling, and the consequences for dysregulation in pediatric solid tumors.
Assuntos
Neoplasias/metabolismo , Proteínas/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Hipóxia Celular/fisiologia , Criança , Proteínas de Ligação a DNA/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteínas Supressoras de Tumor/metabolismoRESUMO
The mTOR complex-1 (mTORC1) coordinates cell growth and metabolism, acting as a restriction point under stress conditions such as low oxygen tension (hypoxia). Hypoxia suppresses mTORC1 signaling. However, the signals by which hypoxia suppresses mTORC1 are only partially understood, and a direct link between hypoxia-driven physiological stress and the regulation of mTORC1 signaling is unknown. Here we show that hypoxia results in ataxia telangiectasia mutated (ATM)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (HIF-1α) on serine(696) and mediates downregulation of mTORC1 signaling. Deregulation of these pathways in pediatric solid tumor xenografts suggests a link between mTORC1 dysregulation and solid tumor development and points to an important role for hypoxic regulation of mTORC1 activity in tumor development.