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1.
Zhonghua Er Ke Za Zhi ; 57(11): 863-869, 2019 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-31665841

RESUMO

Objective: To analyze the clinical characteristics of newly treated high-risk group neuroblastoma (NB) patients with bone marrow metastasis and to explore the prognostic factors. Methods: The clinical features (sex, age, stage, risk group, pathological type, metastatic site, etc.) of 203 newly treated high-risk NB patients with bone marrow metastasis admitted to Hematology Oncology Center, Beijing Children's Hospital from January 2007 to December 2016 were analyzed retrospectively. There were 118 males (58.1%) and 85 females (41.9%). Kaplan-Meier method was used for survival analysis and Cox regression was used to analyze the prognostic factors. Results: The age at onset of the 203 patients was 41 months (9-147 months). The metastatic sites at diagnosis were as follows: bone in 195 cases (96.1%), distant lymph nodes in 104 cases (51.2%), skull and endomeninx in 61 cases (30.0%), orbit in 30 cases (14.8%), pleura in 16 cases (7.9%), liver in 13 cases(6.4%), canalis spinalis in 13 cases (6.4%), other sites in 11 cases (5.4%) and skin and soft tissue in 10 cases (4.9%). In all, 194 cases were enrolled for prognostic analysis. The follow-up time was 36 months (1 day-138 months) , and the 5-years event free survival (EFS) and overall survival (OS) were 36.1% and 39.7%, respectively. A total of 118 patients (60.8%) had events (first relapse or death) with the time to event occurrence was 15 months (1 day-72 months), whereas 112 patients (57.7%) died with the event occurrence to death time was 3 months (1 day-21 months). There was no significant difference in 5-years OS between radiotherapy group and non-radiotherapy group (42.3% vs. 38.3%, χ(2)=3.671, P=0.055). The 5-years OS in transplantation group was significantly better than the non-transplantation group (44.3% vs. 35.5%, χ(2)=8.878, P=0.003), and the radiotherapy combined transplantation group also had a better 5-years OS rate than the non-radiotherapy combined transplantation group (45.8% vs. 37.3%, χ(2)=5.945, P=0.015). Univariate survival analysis showed lactate dehydrogenase ≥ 1 500 U/L, the amplification of MYCN, the metastatic sites of orbit, canalis spinalis and pleura were associated with poor prognosis of newly diagnosed high-risk NB patients (χ(2)=21.064, 13.601, 3.998, 6.183, 15.307, all P<0.05). The amplification of MYCN and the metastatic sites of pleura were risk factors for prognosis of newly diagnosed high-risk NB patients by Cox regression models (HR=1.896,1.100, 95%CI: 1.113-3.231, 1.020-1.187, both P<0.05). Conclusions: The prognosis is unfavorable in high-risk group NB patients with BM metastasis. Radiotherapy combined with transplantation can further improve the prognosis of these patients. The amplification of MYCN and the metastatic sites of pleura were the poor prognostic factors for high-risk NB patients with bone marrow metastasis.


Assuntos
Neoplasias da Medula Óssea/patologia , Neuroblastoma/patologia , Neoplasias da Medula Óssea/mortalidade , Neoplasias da Medula Óssea/radioterapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Metástase Neoplásica , Neuroblastoma/mortalidade , Neuroblastoma/radioterapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
2.
Zhonghua Zhong Liu Za Zhi ; 41(10): 748-752, 2019 Oct 23.
Artigo em Chinês | MEDLINE | ID: mdl-31648496

RESUMO

Objective: To investigate the effect and mechanisms of CHL1 gene overexpression on cell viability, invasiveness and apoptosis in neuroblastoma cells. Methods: The empty plasmid (pcDNA3.1 group) and CHL1 recombinant plasmid (pcDNA3.1-CHL1 group) were transfected into SK-N-SH human neuroblastoma cells, and the untransfected cells were used as blank control. Forty-eight hours after transfection, the protein expressions of CHL1, PCNA, MMP-2, Bax, STAT3 and p-STAT3 were detected by western blot. Meanwhile, cell viability, invasion and apoptosis were detected by MTT, transwell and flow cytometry assays, respectively. Results: The expression level of CHL1 protein in pcDNA3.1-CHL1 group was 0.612±0.052, which was higher than that of pcDNA3.1 group 0.122±0.014 and blank control group 0.120±0.013, with statistically significant difference (P<0.05). After 24, 48 and 72 hours of transfection, the absorbance (A) values of SK-N-SH cells in the pcDNA3.1-CHL1 group were 0.328±0.035, 0.502±0.051 and 0.688±0.064, respectively, whereas those in the pcDNA3.1 group were 0.562±0.050, 0.796±0.065 and 0.973±0.077, respectively. The differences were statistically significant (P<0.05). The invaded cells in the pcDNA3.1-CHL1 group were 104.9±3.7, which were lower than that in the pcDNA3.1 group (175.6±4.6), with statistically significant difference (P<0.05). Additionally, the apoptotic rate of pcDNA3.1-CHL1 cells was (23.46±1.22)%, which was higher than that in pcDNA3.1 group (3.45±0.20)%(P<0.05). Furthermore, the levels of PCNA, MMP-2, Bax and p-STAT3 proteins in pcDNA3.1-CHL1 group were 0.156±0.018, 0.122±0.015, 0.285±0.032 and 0.023±0.004, respectively, whereas those in pcDNA3.1 group were 0.542±0.053, 0.196±0.021, 0.073±0.009 and 0.057±0.007, respectively. There were statistically significant differences between two groups (P<0.05). Conclusion: Overexpression of CHL1 inhibits the cell viability and invasion, as well as induces apoptosis of neuroblastoma cells, which is related to the inhibition of STAT3 signaling pathway.


Assuntos
Apoptose , Proliferação de Células , Sobrevivência Celular , Invasividade Neoplásica , Neuroblastoma/patologia , Proteínas Supressoras de Tumor/metabolismo , Moléculas de Adesão Celular , Linhagem Celular Tumoral , Humanos , Transfecção , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologia
3.
Medicine (Baltimore) ; 98(36): e17038, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490393

RESUMO

RATIONALE: Neuroblastoma is one of the most common tumors found in children, and mostly arises in the adrenal gland and paravertebral regions. Orbital neuroblastoma metastasis is relatively rare, and is associated with poor prognosis. Since the symptoms and signs of orbital neuroblastoma are not specific, its diagnosis remains challenging. PATIENT CONCERNS: A 3-year-old girl presented with periorbital ecchymoses (raccoon eyes) and proptosis for 40 days. DIAGNOSES: Abdominal magnetic resonance imaging (MRI) and sonography analysis revealed a large mass in the left adrenal gland (primary tumor). The computed tomography and MRI further revealed multiple soft tissue masses in the skull and both orbits with erosion of the adjacent bones (the metastasis). The histological analysis of the tumor removed from the right orbit confirmed the diagnosis of neuroblastoma. INTERVENTIONS: The mass on the right face was surgically removed. OUTCOMES: The patient exhibited no deteriorative signs at the 6-month follow-up. LESSONS: Clinical manifestations, such as periorbital ecchymoses and proptosis, in combination with radiological analysis and histological findings, are important for the diagnosis of orbital neuroblastoma metastasis.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Equimose/etiologia , Exoftalmia/etiologia , Neuroblastoma/diagnóstico por imagem , Neoplasias Orbitárias/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/patologia , Pré-Escolar , Feminino , Humanos , Neuroblastoma/complicações , Neuroblastoma/patologia , Neuroblastoma/secundário , Neoplasias Orbitárias/complicações , Neoplasias Orbitárias/patologia , Neoplasias Orbitárias/secundário
4.
Medicine (Baltimore) ; 98(34): e16752, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441848

RESUMO

RATIONALE: Tumor rupture and bleeding at initial presentation of infants with neuroblastoma (NBL) is a rare, but life threatening condition and challenge in pediatric oncology. Here, we report successful multidisciplinary management of an abdominal compartment syndrome as a result of tumor rupture and bleeding in an infant with bilateral high risk stage 4 NBL. PATIENT CONCERNS: The patient was admitted to a cooperating hospital with vomiting, failure to thrive and a large mass in the abdomen and was then referred to our center. DIAGNOSES: Stage 4 NBL with MYC-N amplification and 1p36 deletion was diagnosed in an 11 months old girl. Due to rapid and massive tumor growth she developed abdominal compression with renal failure, severe bleeding, and tumor lysis syndrome (TLS). INTERVENTIONS: Surgical decompression by enterostomy, local, and systemic bleeding control with platelets and coagulation factors, antiinfective and TLS therapy were effective in stabilizing the patient's condition. This allowed initiation of the multimodal antineoplastic treatment according to protocol NB 2004. OUTCOMES: Mechanical ventilation was stopped after 11 days, the abdominal wall was closed 3 months after the start of therapy, and treatment according to the protocol be started and successfully completed. LESSONS: Only the immediate, coordinated multidisciplinary intervention managed to overcome the life-threatening abdominal compartment syndrome and its associated problems, eventually enabling successful curative treatment.


Assuntos
Hemorragia/complicações , Hipertensão Intra-Abdominal/etiologia , Hipertensão Intra-Abdominal/terapia , Neuroblastoma/complicações , Anti-Infecciosos/uso terapêutico , Fatores de Coagulação Sanguínea , Enterostomia/métodos , Feminino , Hemorragia/terapia , Humanos , Lactente , Estadiamento de Neoplasias , Neuroblastoma/patologia
5.
Medicine (Baltimore) ; 98(30): e16564, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348281

RESUMO

RATIONALE: Neuroblastoma is one of the most common malignant tumors in childhood, which mainly occurs in adrenal glands and peripheral sympathetic nerve system. Neuroblastoma occurring in adulthood is rare, and adults with neuroblastoma arising from thorax are exceedingly rare. A case of neuroblastoma that originated from thorax was reported, and was treated by resection operation. PATIENT CONCERNS: A 46-year-old woman was admitted to our hospital with left side chest pain for 5 days. Laboratory examinations were all normal. Chest computerized tomogram (CT) showed a lesion with clear boundary that was located at the left dorsal pleura. The nature of the mass was heterogeneous, showing slight heterogeneous enhancement after contrast and there was no obvious necrosis. DIAGNOSES: Based on the morphologic and immunohistochemical features, the tumor diagnosis was favorable for neuroblastoma. INTERVENTIONS: A resection operation was carried out. OUTCOMES: Three years postoperative, no sign of recurrence or metastasis has been observed. LESSONS: Primary neuroblastoma in adulthood is rare and has poor prognosis. Resection can be an important treatment option, and combining with other methods like chemotherapy, stem cell transplantation, the survival rate may be improved.


Assuntos
Neuroblastoma/cirurgia , Neoplasias Torácicas/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Neuroblastoma/patologia , Neoplasias Torácicas/patologia , Procedimentos Cirúrgicos Torácicos/métodos , Resultado do Tratamento
6.
Zhonghua Zhong Liu Za Zhi ; 41(7): 516-521, 2019 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-31357838

RESUMO

Objective: To investigate the effects and mechanisms of miR-144 on proliferation, apoptosis and cisplatin (DDP) resistance of neuroblastoma cells. Methods: Real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the mRNA expressions of miR-144 and MYCN in neuroblastoma cell lines, including SH-SY5Y and SK-N-SH, and human umbilical vein endothelial cells HUVEC. The miR-negative control, miR-144 mimics, si-negative control, si-MYCN, miR-144 mimics and pcDNA, miR-144 mimics and pcDNA-MYCN co-transfected SH-SY5Y cells were described as miR-NC, miR-144, si-NC, si-MYCN, miR-144+ pcDNA and miR-144+ pcDNA-MYCN group, respectively. The half maximal inhibitory concentration (IC(50)) and cell proliferation were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay. The protein expressions of MYCN, p21, cyclin D1, Bax, Bcl-2 were analyzed by western blot. Cell apoptosis was detected by flow cytometry. The cell fluorescence activity was detected by double luciferase reporter gene assay. Results: Compared with HUVEC cells, the expressions of miR-144 in neuroblastoma cells SH-SY5Y and SK-N-SH significantly decreased, while the mRNA and protein expression of MYCN significantly increased. The IC(50) of DDP was 9.16 µg/ml in SH-SY5Y cells. The absorbance value in 490nm (A(490) value) of miR-144 group was 0.30±0.03, significantly lower than 0.46±0.03 of miR-NC group. The cell apoptotic rate of miR-144 group was 26.94%±2.01%, significantly higher than 9.68%±0.52% of miR-NC group. The IC(50) value of DDP in miR-144 group was 2.95±0.26, significantly lower than 9.23±0.61 of miR-NC group. The expressions of p21, cyclin D1, Bax, Bcl-2 in miR-NC and miR-144 group were 2.67±0.19, 0.41±0.04, 2.12±0.21, 0.18±0.01 and 1.01±0.07, 1.00±0.06, 1.00±0.05, 1.00±0.06, respectively, with statistical significance (all P<0.05). Knockdown of MYCN showed the similar effects with those of miR-144 overexpression in SH-SYSY cells. MiR-144 significantly inhibited the fluorescence activity of ectopic MYCN expressing cells and negatively regulated the expression of MYCN. Overexpression of MYCN can reverse the effects of miR-144 on proliferation inhibition, apoptosis promotion and sensitization of SH-SY5Y cells to DDP. Conclusion: MiR-144 inhibits proliferation, promotes apoptosis and enhances the sensitivity of neuroblastoma cells to DDP through targeting MYCN, which provides a potential treatment for neuroblastoma.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Antineoplásicos/farmacologia , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Criança , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
Anticancer Res ; 39(7): 3487-3492, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262872

RESUMO

BACKGROUND/AIM: Despite intensive chemotherapy, the survival rates for high-risk neuroblastoma, most of which have MYCN amplification, remain low. Overexpression of N-myc oncoprotein promotes expression of cancer-associated properties. We recently found that combination of all-trans retinoic acid (ATRA) with the ß1-integrin-activating peptide TNIIIA2 attenuated cancer-associated properties of neuroblastoma cells through N-Myc degradation. However, ATRA has serious side-effects and there are concerns about late adverse effects. The aim of this study was to examine the effects of the combination of acyclic retinoid (ACR) with TNIIIA2 on neuroblastoma. MATERIALS AND METHODS: The effects of ACR and TNIIIA2 were examined by neuroblastoma cell proliferation and survival assays as well as by using a neuroblastoma xenograft model. The levels of N-Myc and cancer-associated malignant properties were assayed by western blot and colony formation assay, respectively. RESULTS: Combining ACR, which is clinically safe, with TNIIIA2 induced proteasomal degradation of N-Myc and reduction of neuroblastoma cell malignant properties. An in vivo experiment showed therapeutic potential. CONCLUSION: ACR-TNIIIA2 combination treatment may be efficacious and clinical safe chemotherapy for high-risk neuroblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Peptídeos/uso terapêutico , Tenascina/uso terapêutico , Tretinoína/análogos & derivados , Animais , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Peptídeos/farmacologia , Fenótipo , Tenascina/farmacologia , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Carga Tumoral/efeitos dos fármacos
8.
Cell Physiol Biochem ; 53(1): 258-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31313541

RESUMO

BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells. METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells. RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells. CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.


Assuntos
Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Receptores da Transferrina , Antígenos CD/genética , Antígenos CD/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Células HEK293 , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Vorinostat/farmacologia , Xantonas/farmacologia
9.
Chem Biol Interact ; 310: 108688, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173752

RESUMO

Glucagon-like peptide 1 (GLP-1) has neuroprotective properties in Alzheimer's disease (AD). In this study, our aim is to explore the neuroprotective effects of liraglutide, a GLP-1 analogue, on AD-like neurodegeneration induced by H2O2 in human neuroblastoma SH-SY5Y cells. Cytotoxicity was determined by MTT assay and lactate dehydrogenase level was monitored by LDH assay. The level of lipid peroxidation and cell apoptosis rate were measured by malondialdehyde (MDA) assay and Annexin V-FITC/propidium iodide (PI) staining. Western blotting was used to assess the expression of Bcl-2, Bax, caspase-3, tau and the Akt/GSK-3ß. Liraglutide pre-treatment enhanced cell viability with reduced cytotoxicity, lipid peroxidationand and apoptosis. In addition, pre-treatment of liraglutide displayed that increased the expression of the pro-survival Bcl-2 and reduced pro-apoptotic Bax with ameliorated the hyperphosphorylation of tau and Akt/GSK-3ß signaling pathway in H2O2 stressed SH-SY5Y cells. These finding provided evidences that liraglutide protected the H2O2 induced AD-like neurodegeneration through improving Akt/GSK-3ß signaling pathway. These results suggest that liraglutide may have potential values for the treatment for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Liraglutida/uso terapêutico , Neuroblastoma/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo , Linhagem Celular Tumoral , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Neuroblastoma/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/etiologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
10.
Chem Biol Interact ; 310: 108728, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254498

RESUMO

Disruption of the mitochondrial function has been associated with redox impairment and triggering of cell death in nucleated human cells, as observed in several diseases. The administration of chemicals that would prevent mitochondrial dysfunction is an attractive strategy in cases of neurodegeneration, cardiovascular diseases, and metabolic disorders. Methylglyoxal (MG) is a dicarbonyl compound that exhibits an important role as a mitochondrial toxicant in neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease) and diabetes mellitus. On the other hand, naringenin (NGN; C15H12O5) is a natural antioxidant that also presents anti-inflammatory effects in mammalian cells. In this context, we have evaluated whether and how NGN would be able to prevent the mitochondria-related bioenergetics and redox dysfunctions induced by MG in the human neuroblastoma SH-SY5Y cells. The cells were pretreated (for 2 h) with NGN (at 10-80 µM) and then challenged with MG at 500 µM for 24 h. NGN significantly attenuated the effects of MG on the mitochondrial function and redox environment in this experimental model. Moreover, NGN prevented the MG-triggered mitochondria-related cell death in SH-SY5Y cells. Nonetheless, the inhibition of the synthesis of glutathione (GSH, a major non-enzymatic antioxidant) suppressed the promotion of mitochondrial protection by NGN in MG-treated cells. We also found that the synthesis of GSH was induced by NGN through a mechanism associated with the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Therefore, NGN caused mitochondrial protection by an Nrf2/GSH-dependent manner in SH-SY5Y cells exposed to MG.


Assuntos
Flavanonas/farmacologia , Glutationa/metabolismo , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Neuroblastoma/patologia , Fármacos Neuroprotetores/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Flavanonas/uso terapêutico , Humanos , Oxirredução/efeitos dos fármacos , Aldeído Pirúvico/efeitos adversos
11.
Int J Oncol ; 55(1): 93-102, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180520

RESUMO

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children, which has complex molecular mechanisms. Increasing evidence has suggested that long noncoding RNAs (lncRNAs) account for NB pathogenesis. However, the function of small nucleolar RNA host gene 16 (SNHG16) in NB is currently unclear. In the present study, publically available data and clinical specimens were employed to verify the expression of SNHG16 in NB. Colony formation, real­time cell proliferation and migration assays were performed to demonstrate the status of cellular proliferation and migration. Flow cytometry was used to examine cell cycle progression in SH­SY5Y cells, and acridine orange/ethidium bromide staining and caspase­3/7 activity measurements were applied to study cell apoptosis. To explore the underlying mechanism of SNHG16 function, an online database was used to identify potential RNA­binding proteins that bind SNHG16. The expression of SNHG16 was revealed to be in line with the clinical staging of NB, and high SNHG16 expression was positively associated with poor clinical outcome. Furthermore, SNHG16 silencing inhibited cell proliferation, repressed migration, and induced cell cycle arrest at the G0/G1 phase in SH­SY5Y cells. Additionally, apoptosis was undetectable in SH­SY5Y cells following SNHG16 silencing. Bioinformatics analysis revealed that SNHG16 regulated cell proliferation in NB through transcriptional and translational pathways. These results suggested that SNHG16 may serve important roles in the development and progression of NB, and could represent a potential target for NB therapy.


Assuntos
Neuroblastoma/genética , RNA Longo não Codificante/genética , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Inativação Gênica , Humanos , Lactente , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oncogenes , RNA Longo não Codificante/biossíntese , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transfecção
12.
Med Oncol ; 36(8): 66, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31183633

RESUMO

Nuclear receptor subfamily 4, group A, member 3 (NR4A3) is a member of the NR4A subgroup of orphan nuclear receptors, implicated in the regulation of diverse biological functions, including metabolism, angiogenesis, inflammation, cell proliferation, and apoptosis. Although many reports have suggested the involvement of NR4A3 in the development and/or progression of tumors, its role varies among tumor types. Previously, we reported that DNA hypomethylation at NR4A3 exon 3 is associated with lower survival rate of neuroblastoma (NB) patients. As hypomethylation of this region results in reduced expression of NR4A3, our observations suggested that NR4A3 functions as a tumor suppressor in NB. However, the exact mechanisms underlying its functions have not been clarified. In the present study, we analyzed public databases and showed that reduced NR4A3 expression was associated with shorter survival period of NB in two out of three datasets. An in vitro study revealed that forced expression of NR4A3 in human NB-derived cell line NB1 resulted in elongation of neurites along with overexpression of GAP43, one of the differentiation markers of NB. On the other hand, siRNA-mediated knockdown of NR4A3 suppressed the expression level of GAP43. Interestingly, the forced expression of NR4A3 induced only the GAP43 but not the other molecules involved in NB cell differentiation, such as MYCN, TRKA, and PHOX2B. These results indicated that NR4A3 directly activates the expression of GAP43 and induces differentiated phenotypes of NB cells, without affecting the upstream signals regulating GAP43 expression and NB differentiation.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Neuroblastoma/metabolismo , Receptores de Esteroides/biossíntese , Receptores dos Hormônios Tireóideos/biossíntese , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Progressão da Doença , Proteína GAP-43/biossíntese , Técnicas de Silenciamento de Genes , Humanos , Neuritos/metabolismo , Neuritos/patologia , Neuroblastoma/genética , Neuroblastoma/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Regulação para Cima
13.
Fitoterapia ; 136: 104164, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31071436

RESUMO

Five pairs of enantiomeric 8-O-4' neolignans (1a/1b-5a/5b), including seven new compounds (1a/1b, 2a, 3a, 4a/4b and 5b), were obtained from the fruits of Crataegus pinnatifida Bge. Their structures were determined by comprehensive spectroscopic analyses. The absolute configurations of the enantiomers were determined by comparison of the experimental ECD with the calculated data. Additionally, all the enantiomeric neolignans were evaluated for their neuroprotective activity against H2O2-induced cell injury in human neuroblastoma SH-SY5Y cells, and most of them showed potent selective neuroprotective activity. Especially, 3b (72.98%) showed the best protective effect, better than 3a (63.49%) and trolox (62.86%) at 25 µM.


Assuntos
Crataegus/química , Frutas/química , Lignanas/farmacologia , Neuroblastoma/patologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Lignanas/isolamento & purificação , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Estereoisomerismo
14.
Fitoterapia ; 136: 104165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075486

RESUMO

Ten new diarylheptanoids (1-10), including five diarylether-type (1-5), three biaryl-type (6-8), and two linear type (9-10), along with eighteen known ones, were isolated from the fresh pericarps of Juglans hopeiensis Hu. Their structures were settled by integrated spectroscopic techniques, and their absolute configurations were determined by a combination of circular dichroism analysis, optical rotations, and NOESY experiments. Screening results showed that some isolated diarylheptanoids exhibited moderate neuroprotective effects on H2O2-induced or CoCl2-induced cellular damage in human neuroblastoma SH-SY5Y cells.


Assuntos
Diarileptanoides/farmacologia , Juglans/química , Neuroblastoma/patologia , Fármacos Neuroprotetores/farmacologia , Linhagem Celular Tumoral , China , Diarileptanoides/isolamento & purificação , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
15.
Clin Nucl Med ; 44(9): 761-763, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31058691

RESUMO

Although increased MIBG activity in the colon is a well-described and well-known normal variant, elevated MIBG activity in the stomach is rarely seen. We describe increased I-MIBG accumulation in the stomach in a 13-year-old girl who had recurrent metastatic neuroblastoma. The activity appeared to be a new MIBG-avid lesion on the planar images. However, the SPECT/CT images revealed that the activity was inside the gastric lumen without anatomical abnormality. On a follow-up I-MIBG scan acquired 3 months later, the stomach no longer had elevated MIBG activity, while the other abnormal activity on prior study remained the same.


Assuntos
3-Iodobenzilguanidina/metabolismo , Mucosa Gástrica/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Estômago/diagnóstico por imagem , Adolescente , Transporte Biológico , Feminino , Humanos , Metástase Neoplásica , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Recidiva , Estômago/patologia
16.
Am J Chin Med ; 47(4): 895-912, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091975

RESUMO

In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood-brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24 h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Neuroblastoma/genética , Neuroblastoma/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fatores de Tempo , Células Tumorais Cultivadas
17.
Anal Bioanal Chem ; 411(19): 4963-4971, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093701

RESUMO

Cu isotope fractionation was investigated in the human neuroblastoma SH-SY5Y cell line, in a proliferating/tumor phase (undifferentiated cells), and in a differentiated state (neuron-like cells), induced using retinoic acid (RA). The SH-SY5Y cell line displays genetic aberrations due to its cancerous origin, but differentiation drives the cell line towards phenotypes suitable for the research of neurological diseases (e.g., Alzheimer's disease or Parkinson's disease). Cellular Cu distribution was first explored by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging and, subsequently, Cu isotopic analysis was performed at cellular and sub-cellular levels via multi-collector inductively coupled plasma-mass spectrometry (MC-ICP-MS). The SH-SY5Y cells showed a re-distribution of intracellular Cu upon RA differentiation. Both undifferentiated and differentiated cells became systematically enriched in the light 63Cu isotope with increasing intracellular Cu content. Differentiated neuron-like SH-SY5Y cells showed a heavier Cu isotopic composition (+ 0.3‰) than did the undifferentiated proliferating cells when exposed to Cu for 24 h. However, after a longer exposure time (72 h), no difference was observed between both cellular phenotypes. Mitochondrial fractions were enriched in the light 63Cu isotope, compared to whole cells, for both undifferentiated and differentiated cells (no significant difference). The Cu isotopic composition of the remaining cell lysates was heavier than that of the whole cells and + 0.2‰ heavier in the differentiated cells than in the undifferentiated cells. These results indicate that neuronal differentiation affects the Cu isotope fractionation accompanying Cu uptake in the cells, but this effect does not seem to be associated with the mitochondrial Cu pathway. Cu isotope fractionation can be an interesting tool for studying Cu metabolism at a (sub)-cellular level in functional neurons. Graphical abstract.


Assuntos
Fracionamento Celular , Cobre/isolamento & purificação , Isótopos/isolamento & purificação , Neuroblastoma/metabolismo , Neurônios/metabolismo , Frações Subcelulares/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Mitocôndrias/metabolismo , Neuroblastoma/patologia , Neurônios/citologia
18.
Food Chem Toxicol ; 129: 1-12, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30995514

RESUMO

Oleuropein aglycone (OleA), the most abundant polyphenol in extra virgin olive oil (EVOO), and Hydroxythyrosol (HT), the OleA main metabolite, have attracted our interest due to their multitarget effects, including the interference with amyloid aggregation path. However, the mechanistic details of their anti-amyloid effect are not known yet. We report here a broad biophysical approach and cell biology techniques that enabled us to characterize the different molecular mechanisms by which OleA and HT modulate the Aß1-42 fibrillation, a main histopathological feature of Alzheimer's disease (AD). In particular, OleA prevents the growth of toxic Aß1-42 oligomers and blocks their successive growth into mature fibrils following its interaction with the peptide N-terminus, while HT speeds up harmless fibril formation. Our data demonstrate that, by stabilizing oligomers and fibrils, both polyphenols reduce their seeding activity and aggregate/membrane interaction on human neuroblastoma SH-SY5Y cells. These findings highlight the great potential of EVOO polyphenols and offer the possibility to validate and to optimize their use for possible AD prevention and therapy.


Assuntos
Acetatos/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Fragmentos de Peptídeos/antagonistas & inibidores , Álcool Feniletílico/análogos & derivados , Piranos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Fenômenos Biofísicos , Linhagem Celular Tumoral , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Estresse Oxidativo , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Álcool Feniletílico/farmacologia
19.
Int J Mol Sci ; 20(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010127

RESUMO

In the last decades, glucosinolates (GLs), precursors of isothiocyanates (ITCs), have been studied mostly for their chemopreventive and chemotherapeutic properties. The aim of our research was to study the antiproliferative effect of 4-(α-L-rhamnopyranosyloxy) benzyl glucosinolate (glucomoringin; GMG) bioactivated by myrosinase enzyme to form the corresponding isothiocyanate 4-(α-L-rhamnopyranosyloxy) benzyl C (moringin) in SH-SY5Y human neuroblastoma cells. We found that moringin significantly reduced SH-SY5Y cell growth in a time and concentration-dependent (p < 0.05, 0.01, and 0.001 vs. ctrl, after treatment with 16.4 µM moringin for 24, 48, and 72 h, respectively) manner through a mechanism involving the activation of apoptotic machinery. In addition, it altered the normal progression of cells through the cell cycle, increasing the cell population in both G2 and S phases, as well as decreasing that in the G1 phase. Studying the drug mechanism of action, we found that moringin was able to increase the expression of p53, p21, and Bax at both the protein and transcriptional level. Moreover, exposure of SH-SY5Y cells to moringin significantly increased the gene expression of both caspase 3 and 9 and enhanced their cleavage, thereby initiating an intrinsic apoptotic cascade. Finally, moringin inhibited nuclear translocation of NF-κB. Our study demonstrates the ability of moringin to reduce the growth of SH-SY5Y cells and reveals its mechanism of action, suggesting its promising role as an anticancer drug.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Isotiocianatos/farmacologia , Moringa oleifera/química , NF-kappa B/metabolismo , Neuroblastoma/patologia , Sementes/química , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neuroblastoma/genética
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