Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.419
Filtrar
1.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445574

RESUMO

Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD+ synthesis, facilitates the survival of cisplatin-treated osteosarcoma cells. A high-throughput cytotoxicity screening was performed to identify novel pathways or compounds linked to the cancer-promoting role of NMNAT1. Nine compounds caused higher toxicity in the NMNAT1 KO U2OS cells compared to their wild type counterparts, and actinomycin D (ActD) was the most potent. ActD-treatment of NMNAT1 KO cells increased caspase activity and secondary necrosis. The reduced NAD+ content in NMNAT1 KO cells was further decreased by ActD, which partially inhibited NAD+-dependent enzymes, including the DNA nick sensor enzyme PARP1 and the NAD+-dependent deacetylase SIRT1. Impaired PARP1 activity increased DNA damage in ActD-treated NMNAT1 knockout cells, while SIRT1 impairment increased acetylation of the p53 protein, causing the upregulation of pro-apoptotic proteins (NOXA, BAX). Proliferation was decreased through both PARP- and SIRT-dependent pathways. On the one hand, PARP inhibitors sensitized wild type but not NMNAT1 KO cells to ActD-induced anti-clonogenic effects; on the other hand, over-acetylated p53 induced the expression of the anti-proliferative p21 protein leading to cell cycle arrest. Based on our results, NMNAT1 acts as a survival factor in ActD-treated osteosarcoma cells. By inhibiting both PARP1- and SIRT1-dependent cellular pathways, NMNAT1 inhibition can be a promising new tool in osteosarcoma chemotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/prevenção & controle , Dactinomicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Osteossarcoma/prevenção & controle , Antibióticos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células , Humanos , Nicotinamida-Nucleotídeo Adenililtransferase/antagonistas & inibidores , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Células Tumorais Cultivadas
2.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445291

RESUMO

Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility.


Assuntos
Neoplasias Ósseas/patologia , Ácido Clorogênico/farmacologia , Doxorrubicina/farmacologia , Osteossarcoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Cardiotônicos/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ácido Clorogênico/administração & dosagem , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Osteossarcoma/tratamento farmacológico , Ratos
3.
Molecules ; 26(16)2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34443394

RESUMO

This paper reports the first metabolomics study of the impact of new chelates Pt2Spm and Pd2Spm (Spm = Spermine) on human osteosarcoma cellular metabolism, compared to the conventional platinum drugs cisplatin and oxaliplatin, in order to investigate the effects of different metal centers and ligands. Nuclear Magnetic Resonance metabolomics was used to identify meaningful metabolite variations in polar cell extracts collected during exposure to each of the four chelates. Cisplatin and oxaliplatin induced similar metabolic fingerprints of changing metabolite levels (affecting many amino acids, organic acids, nucleotides, choline compounds and other compounds), thus suggesting similar mechanisms of action. For these platinum drugs, a consistent uptake of amino acids is noted, along with an increase in nucleotides and derivatives, namely involved in glycosylation pathways. The Spm chelates elicit a markedly distinct metabolic signature, where inverse features are observed particularly for amino acids and nucleotides. Furthermore, Pd2Spm prompts a weaker response from osteosarcoma cells as compared to its platinum analogue, which is interesting as the palladium chelate exhibits higher cytotoxicity. Putative suggestions are discussed as to the affected cellular pathways and the origins of the distinct responses. This work demonstrates the value of untargeted metabolomics in measuring the response of cancer cells to either conventional or potential new drugs, seeking further understanding (or possible markers) of drug performance at the molecular level.


Assuntos
Antineoplásicos/farmacologia , Quelantes/farmacologia , Desenho de Fármacos , Osteossarcoma/patologia , Paládio/química , Platina/química , Antineoplásicos/química , Linhagem Celular Tumoral , Quelantes/química , Humanos
4.
Medicine (Baltimore) ; 100(34): e26681, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449453

RESUMO

RATIONALE: Recently, the number of osteosarcomas has been increasing in elderly patients due to human longevity. Lung metastases are the primary cause of death from osteosarcomas. Complete resection of lung metastases can prolong the survival. However, complete resection in elderly patients is often difficult due to high risk of operative complications. Computed tomography (CT) guided radiofrequency ablation (RFA) is a minimally invasive technique to destroy tumor nodules using heat. In this report, we present the first case older than 65 years applying RFA for lung metastases due to osteosarcoma. PATIENT CONCERNS: A 74-year-old male presented with 1-year history of heel pain. A conventional high-grade osteosarcoma in his calcaneus was diagnosed. Below-knee amputation was performed. However, lung metastases were found in both lungs 1 year after amputation. CT-guided lung RFA was chosen since surgical intervention for lung metastases was abandoned because of tumor multiplicity and medical comorbidities. A total of 18 lung metastases were treated by CT-guided RFA. The most frequent complication was pneumothoraxes in 4 of 8 (50%) procedures and chest tube drainage was required in 2 of these (2 of 8 (25%) procedures). DIAGNOSES: Six lung metastases of osteosaroma were found in both lungs at 1 year after surgery. INTERVENTIONS: CT-guided lung RFA was performed. A total of 18 lung metastases were treated in 8 lung RF procedures. OUTCOMES: The patient has been alive with disease for 5.5 years after the initial surgery. LESSONS: CT-guided lung RFA is effective for elderly patients with osteosarcoma lung metastases in spite of discouragement of lung metastasectomy due to multiplicity of metastases and medical-comorbidities.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Osteossarcoma/patologia , Ablação por Radiofrequência/métodos , Idoso , Calcâneo/patologia , Humanos , Masculino , Radiografia Intervencionista , Tomografia Computadorizada por Raios X
5.
Aging (Albany NY) ; 13(13): 17316-17327, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34238763

RESUMO

Anoctamin 5 (ANO5) is a member of the Anoctamin (ANO) family of calcium-activated chloride channels. Although ANO5 expression is upregulated in various cancers, its role in osteosarcoma remains largely unknown. In this study, bioinformatics analysis, western blot, and immunohistochemical staining revealed that ANO5 was upregulated in osteosarcoma cell lines and osteosarcoma tissues, and ANO5 expression was positively associated with tumor size, tumor grade, and metastasis. Functional experiments demonstrated that inhibition of ANO5 decreased, while ANO5 overexpression increased, osteosarcoma cell proliferation and mobility in vitro. Immunoprecipitation, western blot, and confocal microscopy experiments showed that ANO5 bound to and promoted the degradation of Nel-like proteins 1 (NELL1) and 2 (NELL2). Moreover, a subcutaneous tumor transplantation model revealed that ANO5 knockdown reduced osteosarcoma cell proliferation and increased NELL1 and NELL2 expression in vivo. Finally, rescue experiments showed that knockdown of NELL1 or NELL2 reversed the inhibitory effects of ANO5 knockdown on osteosarcoma cell proliferation and migration. These results demonstrated that upregulation of ANO5 promoted osteosarcoma development by decreasing the stability of the NELL1 and NELL2 proteins and that ANO5 may be an effective target for the treatment of osteosarcoma.


Assuntos
Anoctaminas/genética , Neoplasias Ósseas/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas do Tecido Nervoso/genética , Osteossarcoma/genética , Adolescente , Adulto , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/genética , Transplante de Neoplasias , Osteossarcoma/patologia , Regiões Promotoras Genéticas , Cicatrização , Adulto Jovem
6.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200964

RESUMO

For osteosarcoma (OS), the most common primary malignant bone tumor, overall survival has hardly improved over the last four decades. Especially for metastatic OS, novel therapeutic targets are urgently needed. A hallmark of cancer is aberrant metabolism, which justifies targeting metabolic pathways as a promising therapeutic strategy. One of these metabolic pathways, the NAD+ synthesis pathway, can be considered as a potential target for OS treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the classical salvage pathway for NAD+ synthesis, and NAMPT is overexpressed in OS. In this study, five OS cell lines were treated with the NAMPT inhibitor FK866, which was shown to decrease nuclei count in a 2D in vitro model without inducing caspase-driven apoptosis. The reduction in cell viability by FK866 was confirmed in a 3D model of OS cell lines (n = 3). Interestingly, only OS cells with low nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1) RNA expression were sensitive to NAMPT inhibition. Using a publicly available (Therapeutically Applicable Research to Generate Effective Treatments (TARGET)) and a previously published dataset, it was shown that in OS cell lines and primary tumors, low NAPRT1 RNA expression correlated with NAPRT1 methylation around the transcription start site. These results suggest that targeting NAMPT in osteosarcoma could be considered as a novel therapeutic strategy, where low NAPRT expression can serve as a biomarker for the selection of eligible patients.


Assuntos
Acrilamidas/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , NAD/metabolismo , Osteossarcoma/tratamento farmacológico , Pentosiltransferases/antagonistas & inibidores , Piperidinas/farmacologia , Apoptose , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células , Glioma/metabolismo , Glioma/patologia , Humanos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Células Tumorais Cultivadas
7.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202300

RESUMO

Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Comunicação Celular , Osteoclastos/metabolismo , Osteossarcoma/complicações , Osteossarcoma/patologia , Animais , Neoplasias Ósseas/diagnóstico por imagem , Remodelação Óssea , Reabsorção Óssea/diagnóstico , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Osteogênese
8.
Cancer Sci ; 112(9): 3769-3783, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34181803

RESUMO

The large-conductance Ca2+ -activated K+ channel KCa 1.1 plays a pivotal role in tumor development and progression in several solid cancers. The three-dimensional (3D) in vitro cell culture system is a powerful tool for cancer spheroid formation, and mimics in vivo solid tumor resistance to chemotherapy in the tumor microenvironment (TME). KCa 1.1 is functionally expressed in osteosarcoma and chondrosarcoma cell lines. KCa 1.1 activator-induced hyperpolarizing responses were significantly larger in human osteosarcoma MG-63 cells isolated from 3D spheroid models compared with in those from adherent 2D monolayer cells. The present study investigated the mechanisms underlying the upregulation of KCa 1.1 and its role in chemoresistance using a 3D spheroid model. KCa 1.1 protein expression levels were significantly elevated in the lipid-raft-enriched compartments of MG-63 spheroids without changes in its transcriptional level. 3D spheroid formation downregulated the expression of the ubiquitin E3 ligase FBXW7, which is an essential contributor to KCa 1.1 protein degradation in breast cancer. The siRNA-mediated inhibition of FBXW7 in MG-63 cells from 2D monolayers upregulated KCa 1.1 protein expression. Furthermore, a treatment with a potent and selective KCa 1.1 inhibitor overcame the chemoresistance of the MG-63 and human chondrosarcoma SW-1353 spheroid models to paclitaxel, doxorubicin, and cisplatin. Among several multidrug resistance ATP-binding cassette transporters, the expression of the multidrug resistance-associated protein MRP1 was upregulated in both spheroids and restored by the inhibition of KCa 1.1. Therefore, the pharmacological inhibition of KCa 1.1 may be an attractive new strategy for acquiring resistance to chemotherapeutic drugs in the TME of KCa 1.1-positive sarcomas.


Assuntos
Neoplasias Ósseas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Osteossarcoma/metabolismo , Esferoides Celulares/metabolismo , Regulação para Cima/genética , Antineoplásicos/farmacologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Humanos , Indóis/farmacologia , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/antagonistas & inibidores , Osteossarcoma/patologia , Paclitaxel/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , RNA Interferente Pequeno/genética , Transfecção , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
9.
Medicine (Baltimore) ; 100(23): e26021, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114989

RESUMO

ABSTRACT: The present study aimed to develop nomograms to predict survival in patients with chondroblastic osteosarcoma (COS).An analysis was conducted of 320 cases of COS collected from the surveillance, epidemiology, and end results (SEER) database between 2004 and 2015. Independent prognostic factors were screened using univariate and multivariate Cox analyses. Subsequently, nomograms were established to predict the patients' cancer-specific survival (CSS) and overall survival (OS) rates. The prediction accuracy and discriminative ability of the nomograms were examined using calibration curves and the concordance index (C-index).As revealed in the univariate and multivariate Cox regression analysis, age, tumor size, the primary site, the presence of metastasis, a history of having undergone surgery, and a history of having received radiotherapy were found to be independent prognostic factors associated with survival in patients with COS (all P < .05). Furthermore, age >39 years, the presence of distant metastasis, no history of having undergone any surgery, and tumor size >103 mm were found to be associated with poor prognosis in patients, while the primary site of the mandible and no history of having undergone radiotherapy showed associations with a more favorable prognosis in patients. Next, nomograms were constructed to predict the OS and CSS in patients with COS.We constructed nomograms that can provide accurate survival predictions in patients with chondroblastic osteosarcoma. These nomograms can help surgeons customize the treatment strategies for patients with chondroblastic osteosarcoma.


Assuntos
Condroblastoma , Nomogramas , Osteossarcoma , Risco Ajustado/métodos , Programa de SEER/estatística & dados numéricos , Fatores Etários , Condroblastoma/mortalidade , Condroblastoma/patologia , Condroblastoma/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Osteossarcoma/terapia , Valor Preditivo dos Testes , Prognóstico , Radioterapia/métodos , Radioterapia/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/métodos , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Análise de Sobrevida , Carga Tumoral
10.
Aging (Albany NY) ; 13(13): 17901-17913, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34170850

RESUMO

BACKGROUND: Osteosarcoma (OS) is characterized by a high rate of metastasis. It has been found that tumor cells can bypass apoptosis which leads to an uncontrolled proliferation, but chloroquine (CQ) can have an effect on the tumors by inducing apoptosis. We aimed to explore the effects and the hypothetical mechanism of CQ effects on OS. METHODS: We first estimated the CQ effects on proliferation, apoptosis, migration, invasion, and lamellipodia formation of OS cells. Mice bearing xenograft model were used to test the anti-tumor growth and lung metastasis effects of CQ in OS. Western blot and immunohistochemistry were used to explore the mechanism of CQ effects and the association between p-STAT3 expression and lung metastasis of OS patients. RESULTS: CQ induces the apoptosis and suppressed the viability, proliferation, migration, invasion, and lamellipodia formation of OS cells in vitro. In vivo experiments demonstrated that CQ inhibited tumor growth and lung metastasis. CQ induced apoptosis was dependent on the lysosomal inhibition and inhibition of protein turnover. The lung metastasis was associated with the p-STAT3 expression in OS patients. CONCLUSION: CQ inhibited progression of OS cells in vitro, and suppressed tumor growth and lung metastasis in vivo. p-STAT3 can be a predictive biomarker for lung metastasis in osteosarcoma patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Cloroquina/farmacologia , Invasividade Neoplásica/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Fator de Transcrição STAT3/metabolismo , Adulto , Animais , Neoplasias Ósseas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/prevenção & controle , Osteossarcoma/metabolismo , Fosforilação , Pseudópodes/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
11.
ACS Appl Mater Interfaces ; 13(27): 31542-31553, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34191477

RESUMO

Conventional biomaterial-mediated osteosarcoma therapy mainly focuses on its antitumor effect yet often fails to overcome the problem of post-treatment bone tissue defect repair. Simultaneously, minimally invasive drug delivery methods are becoming spotlights for normal tissue preservation. Herein, an injectable curcumin-microsphere/IR820 coloaded hybrid methylcellulose hydrogel (Cur-MP/IR820 gel) platform was designed for osteosarcoma therapy and bone regeneration. In vitro, the K7M2wt osteosarcoma cells were eradicated by hyperthermia and curcumin. Later, the sustained release of curcumin promoted alkaline phosphatase expression and calcium deposition of bone mesenchymal stem cells. In vivo, this hybrid hydrogel could reach tumor site via injection and turned into hydrogel due to heat sensitivity. Under the irradiation of an 808 nm laser, localized hyperthermia (∼51 °C) generated in 5 min to ablate the tumor. Meanwhile, the thermal-accelerated curcumin release and thermal-increased cell membrane permeability led to tumor cell apoptosis. Tumors in photothermal-co-chemotherapy group were successfully restrained from day 2 after treatment. After that, bone reconstruction was promoted because of sustained released curcumin. The chemo-co-thermal efficacy and osteogenic capacity of Cur-MP/IR820 hydrogel suggest a promising approach to the treatment of osteosarcoma and provide provoking inspiration for treating bone tumors and repairing bone tissue.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Curcumina/química , Curcumina/farmacologia , Hidrogéis/química , Hipertermia Induzida , Verde de Indocianina/análogos & derivados , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Terapia Combinada , Curcumina/metabolismo , Curcumina/uso terapêutico , Humanos , Verde de Indocianina/química , Microesferas , Osteossarcoma/patologia
12.
Aging (Albany NY) ; 13(12): 16425-16444, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34156352

RESUMO

To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 (CDK1) and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. In vitro, MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.


Assuntos
Biologia Computacional , Simulação de Acoplamento Molecular , Osteossarcoma/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sítios de Ligação , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Ligantes , Osteossarcoma/genética , Osteossarcoma/patologia , Mapas de Interação de Proteínas/genética , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida
13.
Aging (Albany NY) ; 13(11): 15501-15510, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34102610

RESUMO

Growing studies noted that lncRNA was closely related with the initiation and progression of tumors. However, the role of BCRT1 in the progression of osteosarcoma remains unknown. We noted that BCRT1 is significantly upregulated in osteosarcoma specimens and cells. Elevated expression of BCRT1 promotes cell growth and cell cycle in osteosarcoma cell. Moreover, BCRT1 induces EMT and secretion of inflammatory mediators in osteosarcoma cell. We illustrated that elevated expression of BCRT1 decreases miR-1303 expression in MG-63 cell. The expression of miR-1303 is lower in osteosarcoma specimens than in non-tumor specimens. There is an inverse interrelation between miR-1303 levels and BCRT1 levels in osteosarcoma specimens. Furthermore, we identified FGF7 is one direct target gene of miR-1303 in osteosarcoma cell. Ectopic expression of miR-1303 suppresses FGF7 expression and elevated expression of BCRT1 enhanced FGF7 expression in MG-63 cell. Finally, we illustrated that BCRT1 induces osteosarcoma cell cycle and proliferation and promotes EMT progression and inflammatory mediators secretion via modulating FGF7 expression. Our study suggested that BCRT1 acts as one oncogene in osteosarcoma progression.


Assuntos
Neoplasias Ósseas/genética , Progressão da Doença , Fator 7 de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/metabolismo , Sequência de Bases , Neoplasias Ósseas/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Fator 7 de Crescimento de Fibroblastos/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Regulação para Cima/genética
14.
Anticancer Res ; 41(6): 2993-2999, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083290

RESUMO

BACKGROUND/AIM: The delayed initiation of treatment is not associated with good clinical outcomes in patients with malignancies. However, few previous studies have examined prognostic factors, including the delayed initiation of treatment, in malignant bone tumors. PATIENTS AND METHODS: One hundred and one patients with malignant bone tumors were enrolled. Univariate and multivariate analyses were performed to identify factors predicting metastasis, including factors that delay the initiation of treatment. RESULTS: The multivariate analysis revealed that high-grade bone malignancy (p<0.01), a >30-day delay in referral to a specialized hospital by a general practitioner (p=0.03), and large tumor size (>77 mm) (p=0.04), were independently associated with metastasis of malignant bone tumors. CONCLUSION: When general practitioners notice a patient with a >77 mm bone tumor, early referral to a specialized hospital within one month might be essential for preventing metastasis.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Metástase Neoplásica , Osteossarcoma/patologia , Osteossarcoma/terapia , Tempo para o Tratamento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Encaminhamento e Consulta , Análise de Sobrevida , Adulto Jovem
15.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070338

RESUMO

The high mortality rate together with an ever-growing number of annual cases have defined neoplastic disorders as "the real 21st-century disease". Its dubious distinction also results from conventional therapy failure, which has made cancer an orphan disease. Therefore, innovative and alternative therapeutic strategies are mandatory. The ability to leverage human naturally occurring anti-tumor defenses has always represented a fascinating perspective, and the immuno blockage approval in cancer treatment represents in timeline the latest success. As a multifunctional organ, adipose tissue releases a large amount of adipokines having both carcinogenic and antitumor properties. The negative correlation between serum levels and risk for developing malignancies, as well as the huge number of existing preclinical studies, have identified adiponectin as a potential anticancer adipokine. Nevertheless, its usage in clinical has constantly clashed with the inability to reproduce a mimic synthetic compound. Between 2011 and 2013, two distinct adiponectin receptor agonists were recognized, opening new scenarios even in cancer. Here, we review the first orally active adiponectin receptor agonists AdipoRon, from the discovery to the anticancer evidence. Including our latest findings in osteosarcoma models, we summarize AdipoRon and other existing agonists state-of-art, questioning about the feasibility assessment of this strategy in cancer treatment.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Proteínas de Neoplasias/agonistas , Osteossarcoma/tratamento farmacológico , Piperidinas/uso terapêutico , Receptores de Adiponectina/agonistas , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Humanos , Proteínas de Neoplasias/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Receptores de Adiponectina/metabolismo
16.
J Photochem Photobiol B ; 221: 112235, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34126589

RESUMO

The investigation of in-vitro response of cell cultures derived from tumor material of individual patients with similar tumor localizations to photodynamic treatment is presented. Tumor types included in the research were renal cell carcinoma, melanoma and alveolar, synovial, lypo- and osteo- sarcomas. Long-term observations of treatment-induced morphological changes in cells were performed by means of digital holographic microscopy. A substantial variance in response of cells of individual patients with similar tumor types and localizations to photodynamic treatment with the same dose has been observed. These peculiarities are indicative of the demand to personalized protocols of photodynamic treatment. The elevated resistance of cells of some patients to treatment at high doses highlights potential limitations of photodynamic therapy for some patients. Digital holographic microscopy is shown to be an informative label-free noninvasive tool allowing for long-term monitoring of cell samples in vitro and providing quantitative information on necrosis rate and loss of cellular dry mass. The developed methodology can be generalized for analysis of cellular response to various therapies.


Assuntos
Proliferação de Células/efeitos dos fármacos , Holografia/métodos , Fármacos Fotossensibilizantes/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Humanos , Melanoma/metabolismo , Melanoma/patologia , Microscopia de Fluorescência , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fármacos Fotossensibilizantes/química , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas
17.
Front Immunol ; 12: 623762, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959121

RESUMO

Osteosarcoma (OSA) is the most common bone malignancy and displays high heterogeneity of molecular phenotypes. This study aimed to characterize the molecular features of OSA by developing a classification system based on the gene expression profile of the tumor microenvironment. Integrative analysis was performed using specimens and clinical information for OSA patients from the TARGET program. Using a matrix factorization method, we identified two molecular subtypes significantly associated with prognosis, S1 (infiltration type) and S2 (escape type). Both subtypes displayed unique features of functional significance features and cellular infiltration characteristics. We determined that immune and stromal infiltrates were abundant in subtype S1 compare to that in subtype S2. Furthermore, higher expression of immune checkpoint PDCD1LG2 and HAVCR2 was associated with improved prognosis, while a preferable chemotherapeutic response was associated with FAP-positive fibroblasts in subtype S1. Alternatively, subtype S2 is characterized by a lack of effective cytotoxic responses and loss of major histocompatibility complex class I molecule expression. A gene classifier was ultimately generated to enable OSA classification and the results were confirmed using the GSE21257 validation set. Correlations between the percentage of fibroblasts and/or fibrosis and CD8+ cells, and their clinical responses to chemotherapy were assessed and verified based on 47 OSA primary tumors. This study established a new OSA classification system for stratifying OSA patient risk, thereby further defining the genetic diversity of OSA and allowing for improved efficiency of personalized therapy.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Linfócitos T CD8-Positivos/imunologia , Fibroblastos Associados a Câncer/patologia , Perfilação da Expressão Gênica , Linfócitos do Interstício Tumoral/imunologia , Osteossarcoma/genética , Transcriptoma , Microambiente Tumoral , Adolescente , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linfócitos T CD8-Positivos/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Criança , Bases de Dados Genéticas , Feminino , Fibrose , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Osteossarcoma/imunologia , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Adulto Jovem
18.
Aging (Albany NY) ; 13(10): 14258-14276, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34015762

RESUMO

Osteosarcoma is a malignant tumor with high mortality in children and adolescents. The mechanism of osteosarcoma metastasis is currently unclear. Abnormal expression of long non-coding RNA (lncRNA) plays an important role in tumor metastasis. We used bioinformatics to analyze the differences in gene expression between osteosarcoma in situ and osteosarcoma lung metastases. CCK-8 was used to detect the effect of lncRNA LOC100129620 on the proliferation of osteosarcoma cells. The effect of LOC100129620 on the invasion of osteosarcoma cells was assessed by Transwell assay. The regulatory effect of LOC100129620 on miR-335-3p was examined using RNA pull-down and luciferase reporter gene assays. The effect of LOC100129620 on the polarization of macrophages was detected by quantitative real-time fluorescent PCR. The results show that LOC100129620 can promote the proliferation and migration of osteosarcoma cells. LOC100129620 can promote the proliferation of osteosarcoma in vivo. LOC100129620 can bind to miR-335-3p and regulate its function. MiR-335-3p mediates the regulatory effects of LOC100129620 on CDK6. LOC100129620 promotes the formation of blood vessels and the polarization of macrophages. The LOC100129620/miR-335-3p/CDK6 signaling pathway promotes the metastasis of osteosarcoma by regulating the proliferation of osteosarcoma cells, angiogenesis, and macrophage polarization.


Assuntos
Polaridade Celular , Quinase 6 Dependente de Ciclina/genética , Progressão da Doença , Macrófagos/patologia , Neovascularização Patológica/genética , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/metabolismo , Sequência de Bases , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Polaridade Celular/genética , Proliferação de Células/genética , Quinase 6 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/secundário , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , RNA Longo não Codificante/genética , Regulação para Cima/genética
19.
Commun Biol ; 4(1): 510, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931711

RESUMO

G-quadruplexes (G4s) are four-stranded nucleic acid structures abundant at gene promoters. They can adopt several distinctive conformations. G4s have been shown to form in the herpes simplex virus-1 (HSV-1) genome during its viral cycle. Here by cross-linking/pull-down assay we identified ICP4, the major HSV-1 transcription factor, as the protein that most efficiently interacts with viral G4s during infection. ICP4 specific and direct binding and unfolding of parallel G4s, including those present in HSV-1 immediate early gene promoters, induced transcription in vitro and in infected cells. This mechanism was also exploited by ICP4 to promote its own transcription. Proximity ligation assay allowed visualization of G4-protein interaction at the single selected G4 in cells. G4 ligands inhibited ICP4 binding to G4s. Our results indicate the existence of a well-defined G4-viral protein network that regulates the productive HSV-1 cycle. They also point to G4s as elements that recruit transcription factors to activate transcription in cells.


Assuntos
Quadruplex G , Herpes Simples/complicações , Herpesvirus Humano 1/genética , Proteínas Imediatamente Precoces/metabolismo , Osteossarcoma/virologia , Regiões Promotoras Genéticas , Transcrição Viral , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/virologia , Replicação do DNA , Herpes Simples/genética , Herpes Simples/virologia , Humanos , Proteínas Imediatamente Precoces/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Células Tumorais Cultivadas
20.
Br J Radiol ; 94(1123): 20210088, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33989031

RESUMO

The lungs are the commonest site of metastasis for primary high-grade bone and soft tissue sarcoma, but current guidelines on the management of pulmonary nodules do not specifically cater for this group of patients. The current article reviews the literature from the past 20 years that has reported the CT features of pulmonary metastases in the setting of known primary bone and soft tissue sarcoma, with emphasis on osteosarcoma, chondrosarcoma, and trunk and extremity soft tissue sarcoma, the aim being to aid radiologists who report chest CT of musculoskeletal sarcoma patients in deciding which lesions should be considered metastatic, which lesions are indeterminate and require follow-up, and which lesions are of no concern.


Assuntos
Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Sarcoma/patologia , Tomografia Computadorizada por Raios X , Humanos , Gradação de Tumores , Radiografia Torácica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...