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1.
BMC Complement Med Ther ; 20(1): 68, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32126993

RESUMO

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and has also been associated with a high degree of malignancy and enhanced metastatic capacity. Curcumin (CUR) is well known for its anti-osteosarcoma activity. However, both demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are natural curcumin analogues/congeners from turmeric whose role in osteosarcoma development remains unknown. METHODS: To evaluate the growth inhibitory effects of CUR, DMC and BDMC on osteosarcoma (HOS and U2OS), breast (MDA-MB-231), and melanoma (A2058) cancer cells, we employed the MTT assay, annexin V-FITC /7-AAD staining, and clonogenic assay. RESULTS: CUR,DMC, and BDMC all decreased the viability of HOS, U2OS, MDA-MB-231, and A2058 cancer cells. Additionally, CUR,DMC, and BDMC induced the apoptosis of HOS cells through activation of Smad 2/3 or repression of Akt signaling pathway. Furthermore, the combination of CUR,DMC, and BDMC synergistically reduced cell viability, colony formation and increased apoptosis than either two or a single agent in HOS cells. CONCLUSIONS: The combination of these three compounds could be used as a novel target for the treatment of osteosarcoma.

2.
Mol Carcinog ; 59(3): 293-303, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31916307

RESUMO

Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High-grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell-cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox-treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral-mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X-ray repair cross-complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.

3.
Int J Oncol ; 55(4): 949-959, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485602

RESUMO

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Despite advances in surgery, radiotherapy and chemotherapy, the overall 5­year survival rate of patients with OSCC has not significantly improved. In addition, the prognosis of patients with advanced­stage OSCC remains poor. Therefore, it is necessary to develop novel therapeutic modalities. Vincristine (VCR), a naturally occurring vinca alkaloid, is a classical microtubule­destabilizing agent and is widely used in the treatment of a number of cancers. Despite the proven antitumor benefits of VCR treatment, one of the major reasons for the failure of treatment is drug resistance. Changes in the tumor microenvironment are responsible for cross­talk between cells, which may facilitate drug resistance in cancers; secreted proteins may promote communication between cancer cells to induce the development of resistance. To identify the secreted proteins involved in VCR resistance, conditioned media was obtained, and an antibody array was conducted to screen a comprehensive secretion profile between VCR­resistant (SAS­VCR) and parental (SAS) OSCC cell lines. The results showed that amphiregulin (AREG) was highly expressed and secreted in SAS­VCR cells. Pretreatment with exogenous recombinant AREG markedly increased drug resistance against VCR in OSCC cells, as assessed by an MTT assay. Colony formation, MTT and western blot assays were performed to investigate the effects of AREG knockdown on VCR sensitivity. The results indicated that AREG expression can regulate VCR resistance in OSCC cells; overexpression of AREG increased VCR resistance in parental cells, whereas AREG knockdown decreased the VCR resistance of resistant cells. In addition, it was also demonstrated that the glycogen synthase kinase­3ß pathway may be involved in AREG­induced VCR resistance. These findings may provide rationale to combine VCR with blockade of AREG­related pathways for the effective treatment of OSCC.


Assuntos
Anfirregulina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Bucais/metabolismo , Anfirregulina/genética , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Prognóstico , Transdução de Sinais , Regulação para Cima , Vincristina/farmacologia
4.
BMC Cancer ; 19(1): 756, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370819

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most severe type of primary brain tumor with a high mortality rate. Although extensive treatments for GBM, including resection, irradiation, chemotherapy and immunotherapy, have been tried, the prognosis is still poor. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug for the clinical treatment of GBM; however, its effects are very limited because of the chemoresistance. Valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitor activity, has been shown to have synergistic effects with TMZ against GBM. The mechanism of action of VPA on TMZ combination therapy is still unclear. Accumulating evidence has shown that secreted proteins are responsible for the cross talking among cells in the tumor microenvironment, which may play a critical role in the regulation of drug responses. METHODS: To understand the effect of VPA on secreted proteins in GBM cells, we first used the antibody array to analyze the cell culture supernatant from VPA-treated and untreated GBM cells. The results were further confirmed by lentivirus-mediated knockdown and exogenous recombinant administration. RESULTS: Our results showed that amphiregulin (AR) was highly secreted in VPA-treated cells. Knockdown of AR can sensitize GBM cells to TMZ. Furthermore, pretreatment of exogenous recombinant AR significantly increased EGFR activation and conferred resistance to TMZ. To further verify the effect of AR on TMZ resistance, cells pre-treated with AR neutralizing antibody markedly increased sensitivity to TMZ. In addition, we also observed that the expression of AR was positively correlated with the resistance of TMZ in different GBM cell lines. CONCLUSIONS: The present study aimed to identify the secreted proteins that contribute to the modulation of drug response. Understanding the full set of secreted proteins present in glial cells might help reveal potential therapeutic opportunities. The results indicated that AR may potentially serve as biomarker and therapeutic approach for chemotherapy regimens in GBM.


Assuntos
Anfirregulina/metabolismo , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Temozolomida/farmacologia , Ácido Valproico/farmacologia , Anfirregulina/genética , Anticorpos Bloqueadores/farmacologia , Biomarcadores Tumorais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Técnicas de Silenciamento de Genes , Humanos , Lentivirus/genética
5.
Mol Carcinog ; 57(12): 1816-1824, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30230033

RESUMO

Chondrosarcoma is characterized by the ability to produce extracellular matrix of cartilage. Curative surgical resection becomes difficult when high-grade chondrosarcoma metastasizes to other parts of the body. Doxorubicin (Dox) has been widely used clinically to treat many different types of cancers, including chondrosarcomas. However, chondrosarcoma is often resistant to chemotherapy and radiotherapy. New systemic treatment regimens are needed to improve the prognosis. Amphiregulin (AR) has been reported to be involved in cancer metastasis and drug resistance. The aim of the present study was to investigate the role of AR on cell migration and Dox sensitivity. To gain insight into the mechanisms used by AR to mediate its effects, we generated two chondrosarcoma cell lines, migration-prone JJ012 and Dox-resistant SW1353, to analyze the relationship between AR levels and cell functions. AR was highly expressed and secreted in mobile and drug-resistant cells. Next, we used the lentivirus-mediated RNAi system to knock down AR expression and found that AR silencing was significantly attenuated in cell migration and drug resistance. In addition, we used exogenous recombinant AR (r-AR) to confirm cell function and we introduced antibody array analysis to investigate pathways of AR activation. The results showed that AR can promote migratory activity and Dox resistance through activation of the MAPK pathway. Whereas the inhibition of the MAPK pathway has the potential to inhibit chondrosarcoma cell migration, p38 inhibition, and ERK activation may render cells more sensitive to Dox. These findings suggest that combining AR with MAPK blockade may effectively treat chondrosarcoma.


Assuntos
Anfirregulina/metabolismo , Neoplasias Ósseas/metabolismo , Condrossarcoma/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Condrossarcoma/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Regulação para Cima
6.
BMC Complement Altern Med ; 18(1): 248, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30189898

RESUMO

BACKGROUND: Persistent hepatitis B virus (HBV) infection causes liver cirrhosis and hepatocellular carcinoma and constitutes a major worldwide health problem. Currently, anti-HBV drugs are limited to peginterferon and nucleos(t)ide analogs, which are costly and have considerable side effects; the development of novel, effective anti-HBV agents is crucial. METHODS: Catechins are a major group of compounds found in green tea extract and epigallocatechin gallate (EGCG) has been shown to have antiviral properties, including inhibition of cellular entry by HBV. FRG (Fah-/-/ Rag2-/-/ IL-2Rγ/-) mice were used in this study to generate chimeras carrying human primary hepatocytes, to facilitate investigation of the inhibitory effect of EGCG on HBV infection. RESULTS: Here, we show the inhibitory effect of EGCG on HBV infection and replication in HuS-E/2 cells. The inhibitory effect of EGCG on HBV infection in vivo was confirmed by monitoring HBV DNA and HBsAg in serum and immunostaining the liver tissues of the human liver chimeric mice. CONCLUSIONS: The effects of EGCG suggest a robust strategy for the treatment of HBV infection and EGCG may have therapeutic potential for the treatment of HBV-associated liver diseases.


Assuntos
Antivirais/farmacologia , Catequina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B , Animais , Catequina/farmacologia , DNA Viral/sangue , Feminino , Células Hep G2 , Hepatite B/imunologia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/sangue , Humanos , Fígado/efeitos dos fármacos , Fígado/virologia , Camundongos , Replicação Viral/efeitos dos fármacos
8.
Sci Rep ; 7: 45039, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28327651

RESUMO

Oral cancer is one of the most common cancers in the world. Approximately 90% of oral cancers are subtyped to oral squamous cell carcinoma (OSCC). Despite advances in diagnostic techniques and improvement in treatment modalities, the prognosis remains poor. Therefore, an effective chemotherapy mechanism that enhances tumor sensitivity to chemotherapeutics is urgently needed. Methyl protodioscin (MP) is a furostanol bisglycoside with a wide range of beneficial effects, including anti-inflammatory and anti-cancer properties. The aim of the present study was to determine the antitumor activity of MP on OSCC and its underlying mechanisms. Our results show that treatment of OSCC cells with MP potently inhibited cell viability. Moreover, MP leading to cell cycle arrest at G2/M phase, which subsequently activates caspase-3, -8, -9 and PARP to induce cell apoptosis. Meanwhile, we also demonstrate that MP induces a robust autophagy in OSCC cells. The results indicate cathepsin S (CTSS) is involved in MP-induced apoptosis and autophagy by modulation of p38 MAPK and JNK1/2 pathways. These findings may provide rationale to combine MP with CTSS blockade for the effective treatment of OSCC.


Assuntos
Catepsinas/antagonistas & inibidores , Diosgenina/análogos & derivados , Sistema de Sinalização das MAP Quinases , Neoplasias Bucais/metabolismo , Saponinas/farmacologia , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Pontos de Checagem do Ciclo Celular/genética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diosgenina/química , Diosgenina/farmacologia , Humanos , Neoplasias Bucais/genética , Saponinas/química
9.
Biochem Pharmacol ; 130: 10-20, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28131848

RESUMO

BACKGROUND AND PURPOSE: Oral cancer is a type of head and neck cancer that is characterized by cancerous tissue growth in the oral cavity. Andrographolide and dehydroandrographolide (DA) are the two principal components of Andrographis paniculata (Burm.f.) Nees and are the main contributors to its therapeutic properties. However, the pharmacological activities of DA remain unclear. EXPERIMENTAL APPROACH: In this study, we used wound closure assay and Boyden chamber assay to determine the effects of DA on oral cancer cell migration and invasion. KEY RESULTS: DA treatment significantly inhibited the migration and invasion abilities of SCC9 cells in vitro. Gelatin zymography and Western blotting results revealed that DA inhibited MMP-2 activity and reduced its protein levels. DA inhibited the phosphorylation of ERK1/2, p38, and JNK 1/2 in SCC9 cells. According to the mRNA levels detected using real-time PCR, DA inhibited MMP-2 expression in SCC9 cells. This inhibitory effect was associated with the upregulation of the TIMP-2 and downregulation of NF-κB, AP-1, and SP-1 expression. In addition, DA suppressed carcinoma-associated epithelial-mesenchymal transition in SCC9 cells. Finally, DA administration effectively suppressed MMP-2 expression and tumor metastases in the oral carcinoma xenograft mouse model in vivo. CONCLUSIONS & IMPLICATIONS: DA inhibits the invasion of human oral cancer cells and is a potential chemopreventive agent against oral cancer metastasis.


Assuntos
Diterpenos/farmacologia , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Metástase Neoplásica/prevenção & controle , Inibidores de Proteases/farmacologia , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Bucais/enzimologia , Neoplasias Bucais/metabolismo
10.
Oncotarget ; 8(64): 108006-108019, 2017 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29296219

RESUMO

Background and Purpose: Nasopharyngeal carcinoma (NPC) belongs to squamous cell carcinoma that occurs in the epithelial lining of the nasopharynx. Because of the anatomical position close to the cervical lymph node, some patients have a distant metastasis at the time of diagnosis that leads to treatment failure. Although early stages have a high curability and excellent prognosis, advanced NPC urgently requires new drugs developed to reinforce the effectiveness of therapy without noticeable side effects. Experimental approach: Coronarin D (CD), a natural product extracted from the rhizomes of Hedychium coronarium, has been reported to possess anticancer potential. The aim of the present study was to determine the anticancer activity of CD and further elucidate the underlying molecular mechanisms. Key Results: In this study, we first demonstrated that CD potently suppressed cell viability in various NPC cell lines. Treatment of cells with CD induced G2/M arrest, apoptosis, and autophagy. Further studies showed that CD increased the production of reactive oxygen species and subsequently activated both autophagy and apoptosis. Moreover, we found that CD-induced activation of p38 and JNK constituted major mechanisms involved in the apoptosis and autophagy triggered by CD. In particular, inhibition of autophagy could strengthen the cytotoxicity of CD, implying that autophagy seems to play a valuable survival and protective role in cancer cells. Conclusions & Implications: These findings provide a promise for the use of CD in combination with autophagy inhibitors for treatment of human NPC cell lines.

11.
Oncotarget ; 7(43): 70276-70289, 2016 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-27602962

RESUMO

Polyphyllin G (also call polyphyllin VII), extract from rhizomes of Paris yunnanensis Franch, has been demonstrated to have strong anticancer activities in a wide variety of human cancer cell lines. Previous studies found that Polyphyllin G induced apoptotic cell death in human hepatoblastoma cancer and lung cancer cells. However, the underlying mechanisms of autophagy in human nasopharyngeal carcinoma (NPC) remain unclear. In this study, Polyphyllin G can potently induced apoptosis dependent on the activations of caspase-8, -3, and -9 and the changes of Bcl-2, Bcl-xL and Bax protein expression in different human NPC cell lines (HONE-1 and NPC-039). The amount of both LC3-II and Beclin-1 was intriguingly increased suggest that autophagy was induced in Polyphyllin G-treated NPC cells. To further clarify whether Polyphyllin G-induced apoptosis and autophagy depended on AKT/ERK/JNK/p38 MAPK signaling pathways, cells were combined treated with AKT inhibitor (LY294002), ERK1/2 inhibitor (U0126), p38 MAPK inhibitor (SB203580), or JNK inhibitor (SP600125). These results demonstrated that Polyphyllin G induced apoptosis in NPC cells through activation of ERK, while AKT, p38 MAPK and JNK were responsible for Polyphyllin G-induced autophagy. Finally, an administration of Polyphyllin G effectively suppressed the tumor growth in the NPC carcinoma xenograft model in vivo. In conclusion, our results reveal that Polyphyllin G inhibits cell viability and induces apoptosis and autophagy in NPC cancer cells, suggesting that Polyphyllin G is an attractive candidate for tumor therapies. Polyphyllin G may promise candidate for development of antitumor drugs targeting nasopharyngeal carcinoma.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Saponinas/farmacologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno , Neoplasias Nasofaríngeas/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
12.
BMC Anesthesiol ; 15: 92, 2015 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-26077473

RESUMO

BACKGROUND: The application of pulsed radiofrequency (PRF) close to the dorsal root ganglia, or peripheral nerves, has been demonstrated to be effective for the treatment of chronic neuropathic pain conditions. The goal of this study was to investigate the analgesic effect of immediate PRF treatment after nerve injury and its possible cellular alterations in the dorsal horn of the spinal cord in rats with spared nerve injury (SNI). METHODS: Neuropathic pain was achieved in a SNI neuropathic pain model by ligating and cutting the common peroneal and tibial branches of the left sciatic nerve, leaving the sural nerve intact. Wistar rats were divided into four groups that received different treatments, i.e., SNI and PRF for 6 min at 45 V (SNI + PRF-45 V), at 60 V (SNI + PRF-60 V), SNI alone, and sham groups. After the SNI surgery, each rat was immediately given the PRF treatment (500 kHz, rate of 2 Hz, 20 ms duration, temperature below 42 °C) on the left sciatic nerve 0.3-0.4 cm proximal to the injured site. The behavioral measurements included mechanical allodynia and cold allodynia of the ipsilateral hind paw and were performed during the 28 days that followed the SNI surgery and PRF treatment. Total extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phospho-ERK1/2 were measured using Western blot in the ipsilateral spinal cord from animals in the different groups. RESULTS: The three groups of rats with nerve injuries manifested a lower paw withdrawal threshold (PWT) in the behavioral measurement of mechanical allodynia and a shorter painful-behavior duration in the cold allodynia test over 28 days. Mechanical allodynia measurement showed that both the PRF-45 V and PRF-60 V treatment groups exhibited a more prominent antiallodynic effect than did the SNI group from days 1 to 28 after surgery. Similarly, in comparison with the SNI group, both the SNI + PRF-45 V and SNI + PRF-60 V groups had significant inhibition on the cold allodynia measurement from days 1 to 28 after surgery. Furthermore, the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the ipsilateral spinal dorsal horn of SNI rats was effectively inhibited in the SNI + PRF-45 V and SNI + PRF-60 V groups for 28 days after surgery. CONCLUSIONS: Immediate PRF application on the proximal nerve injury site provided a significant inhibition of neuropathic pain formation, accompanied by the inhibition of ERK activation.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/genética , Hiperalgesia/terapia , Neuralgia/terapia , Tratamento por Radiofrequência Pulsada/métodos , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Nervo Isquiático/lesões , Medula Espinal/metabolismo , Nervo Sural/metabolismo , Fatores de Tempo
13.
Oncotarget ; 6(13): 11434-46, 2015 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-25825984

RESUMO

Chondrosarcoma is a malignant tumor that produces cartilage matrix. The most lethal aspect is its metastatic property. We demonstrated that amphiregulin (AR) is significantly upregulated in highly aggressive cells. AR silencing markedly suppressed cell migration. Exogenous AR markedly increased cell migration by transactivation of α6ß1 integrin expression. A neutralizing α6ß1 integrin antibody can abolish AR-induced cell motility. Knockdown of AR inhibits metastasis of cells to the lung in vivo. Furthermore, elevated AR expression is positively correlated with α6ß1 integrin levels and higher grades in patients. These findings can potentially serve as biomarker and therapeutic approach for controlling chondrosarcoma metastasis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/enzimologia , Movimento Celular/efeitos dos fármacos , Condrossarcoma/enzimologia , Família de Proteínas EGF/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Integrina alfa6beta1/metabolismo , MAP Quinase Quinase 1/metabolismo , Fator de Transcrição AP-1/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismo , Anfirregulina , Animais , Anticorpos/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Condrossarcoma/secundário , Relação Dose-Resposta a Droga , Família de Proteínas EGF/genética , Família de Proteínas EGF/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Integrina alfa6beta1/antagonistas & inibidores , Integrina alfa6beta1/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , MAP Quinase Quinase 1/genética , Masculino , Camundongos Nus , Gradação de Tumores , Invasividade Neoplásica , Fosforilação , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Fator de Transcrição AP-1/genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/genética , Proteínas ras/genética
14.
PLoS One ; 9(11): e112636, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25390068

RESUMO

Bone morphogenic protein (BMP)-7 is a member of the transforming growth factor (TGF)-beta superfamily, which is originally identified based on its ability to induce cartilage and bone formation. In recent years, BMP-7 is also defined as a potent promoter of cell motility, invasion, and metastasis. However, there is little knowledge of the role of BMP-7 and its cellular function in chondrosarcoma cells. In the present study, we investigated the biological impact of BMP-7 on cell motility using transwell assay. In addition, the intracellular signaling pathways were also investigated by pharmacological and genetic approaches. Our results demonstrated that treatment with exogenous BMP-7 markedly increased cell migration by activating c-Src/PI3K/Akt/IKK/NF-κB signaling pathway, resulting in the transactivation of αvß3 integrin expression. Indeed, abrogation of signaling activation, by chemical inhibition or expression of a kinase dead form of the protein attenuated BMP-7-induced expression of integrin αvß3 and cell migration. These findings may provide a useful tool for diagnostic/prognostic purposes and even therapeutically in late-stage chondrosarcoma as an anti-metastatic agent.


Assuntos
Proteína Morfogenética Óssea 7/farmacologia , Neoplasias Ósseas/metabolismo , Movimento Celular/efeitos dos fármacos , Condrossarcoma/metabolismo , Genes src/fisiologia , Integrina alfaVbeta3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima/efeitos dos fármacos
15.
Oncotarget ; 5(21): 10718-31, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25301739

RESUMO

Chondrosarcoma is the second most common primary malignant bone cancer, with potential for local invasion and distant metastasis. Chemokine CCL5 (formerly RANTES) of the CC-chemokine family plays a crucial role in metastasis. Angiogenesis is essential for the cancer metastasis. However, correlation of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is still unknown. CCL5-mediated VEGF expression was assessed by qPCR, ELISA, and Western blotting. CCL5-induced angiogenesis was examined by migration and tube formation in endothelial progenitor cells in vitro. CCL5 increased VEGF expression and also promoted chondrosarcoma conditional medium-mediated angiogenesis in vitro and in vivo. Stimulation of chondrosarcoma with CCL5 augmented PI3K and Akt phosphorylation, while PI3K and Akt inhibitor or siRNA abolished CCL5-induced VEGF expression and angiogenesis. We also demonstrated CCL5 inhibiting miR-200b expression and miR-200b mimic reversing the CCL5-enhanced VEGF expression and angiogenesis. Moreover, in chondrosarcoma patients showed the positive correlation between CCL5 and VEGF; negative correlation between CCL5 and miR-200b. Taken together, results demonstrate CCL5 promoting VEGF-dependent angiogenesis in human chondrosarcoma cells by down-regulating miR-200b through PI3K/Akt signaling pathway.


Assuntos
Neoplasias Ósseas/irrigação sanguínea , Quimiocina CCL5/metabolismo , Condrossarcoma/irrigação sanguínea , MicroRNAs/genética , Neovascularização Patológica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Western Blotting , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Quimiocina CCL5/genética , Embrião de Galinha , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Membrana Corioalantoide , Regulação para Baixo , Células Progenitoras Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Biochim Biophys Acta ; 1840(12): 3483-93, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25230157

RESUMO

BACKGROUND: Leptin, 16kDa product of obese gene, is adipocytokine playing critical role in regulation of body weight. In recent years, leptin is also defined as potent angiogenic factor involving in tumorigenesis, angiogenesis, and metastasis. However, it is unknown whether leptin regulates VEGF production in human chondrosarcoma and contributing the tumor-associated angiogenesis. METHODS: We analyzed protein level of leptin and VEGF in human chondrosarcoma tissues. Effects of leptin on chondrosarcoma cells were examined by in vitro and in vivo assays. In addition, intracellular signal pathways were investigated by pharmacological and genetic approaches. RESULTS: We found that both leptin and VEGF are highly expressed in human chondrosarcoma tissues, and positively correlated with tumor stage. Leptin increases VEGF production by activating OBRl receptor and MAPKs (p38, ERK, and JNK), which in turn enhances binding of AP-1 transcription factor to VEGF promoter, resulting in the transactivation of VEGF expression and subsequently promoting migration and tube formation in endothelial progenitor cells (EPCs). In vivo, knockdown leptin significantly reduces angiogenesis and tumor growth. CONCLUSION: Leptin may be a therapeutic target of angiogenesis and metastasis in chondrosarcoma. GENERAL SIGNIFICANCE: These findings provide better understanding of pathogenesis of chondrosarcoma and can utilize this knowledge to design new therapeutic strategy.

17.
Antiviral Res ; 111: 100-11, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25260897

RESUMO

Hepatitis B virus (HBV) is a major cause of liver disease and hepatocellular carcinoma. Chronic HBV infection is currently managed with either nucleoside/nucleotide-based or interferon-based therapies, but fails to clear infection in a substantial proportion of cases, and antiviral strategies targeting the early stages of infection are therefore required for the prevention of HBV infection. In this study, we examined some common phytochemicals and identified epigallocatechin-3-gallate (EGCG) as a new inhibitor of HBV entry. EGCG, a flavonoid present in green tea extract, belongs to the subclass of catechins. We demonstrated that EGCG at a concentration of 50µM inhibited HBV entry into immortalized human primary hepatocytes by more than 80%, whereas the other four catechins tested had much weaker inhibitory effects. DMSO-differentiated HuS-E/2 cells expressed sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. Application of EGCG during HBV inoculation markedly inhibited infection in both DMSO-differentiated HuS-E/2 cells and HA-NTCP-expressing Huh7 cells. Interestingly, EGCG induced clathrin-dependent endocytosis of NTCP from the plasma membrane followed by protein degradation. In addition, EGCG inhibited the clathrin-mediated endocytosis of transferrin. Treatment of cells with EGCG had no effect on HBV genome replication or virion secretion. Moreover, the characteristic of HBV virion and the expression of known HBV entry factors were unaltered by EGCG. Finally, the antiviral activity of EGCG on HBV entry was observed using four different genotypes, A to D. These results show that the green tea-derived molecule EGCG potently inhibits HBV entry and could be used in prevention of HBV reinfection.


Assuntos
Antivirais/farmacologia , Catequina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatócitos/virologia , Extratos Vegetais/farmacologia , Catequina/farmacologia , Linhagem Celular , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatócitos/efeitos dos fármacos , Humanos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
18.
Ann Surg Oncol ; 21 Suppl 4: S555-63, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24723223

RESUMO

BACKGROUND: Accumulating evidence is revealing an important role of microRNA (miRNA) in tumor progression and chemotherapeutic resistance. Dicer is a cytoplasmic endoribonuclease type III crucial for production of mature miRNAs. The aberrant expression of Dicer has also been reportedly associated with clinical aggressiveness, prognosis, and patient survival in various cancer types. However, the molecular mechanisms of Dicer in acquired gefitinib resistance are still not clear. METHODS: In this study, we analyzed the protein level of Dicer between gefitinib-sensitive (PC9) and gefitinib-resistant (PC9/GR) non-small-cell lung cancer (NSCLC) cell lines by Western blot analysis. Silence and overexpression of the Dicer were performed to investigate the effects on gefitinib sensitivity, as assessed by (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and sub-G1 assay of flow cytometry. To further explore the mechanism of chemoresistance, we examined whether Dicer knockdown led to modulating specific miRNAs and its miRNA target genes. RESULTS: Dicer expression was significantly increased in PC9/GR compared with PC9 cells. Knockdown of Dicer restores gefitinib sensitivity in resistant cells, and overexpression of Dicer enhances resistance to gefitinib in sensitive cells. Silencing of Dicer induces sensitivity to gefitinib in NSCLC cells through the downregulation of miR-30b/c and miR-221/222 to increase the protein level of caspase-3, resulting in an increase in gefitinib-induced apoptosis. CONCLUSIONS: Dicer contributes to the resistance to gefitinib in lung cancer. These results indicate that Dicer may be a target for diagnosis and therapy of patients with resistance to gefitinib.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Quinazolinas/uso terapêutico , Ribonuclease III/metabolismo , Adenocarcinoma/genética , Idoso , Idoso de 80 Anos ou mais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Gefitinibe , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Ribonuclease III/genética
19.
PLoS One ; 9(3): e92741, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24667577

RESUMO

Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes and is involved in energy homeostasis. Adiponectin expression is significantly high in the synovial fluid of patients with osteoarthritis (OA). Intercellular adhesion molecule-1 (ICAM-1) is an important adhesion molecule that mediates monocyte adhesion and infiltration during OA pathogenesis. Adiponectin-induced expression of ICAM-1 in human OA synovial fibroblasts (OASFs) was examined by using qPCR, flow cytometry and western blotting. The intracellular signaling pathways were investigated by pretreated with inhibitors or transfection with siRNA. The monocyte THP-1 cell line was used for an adhesion assay with OASFs. Stimulation of OASFs with adiponectin induced ICAM-1 expression. Pretreatment with AMP-activated protein kinase (AMPK) inhibitors (AraA and compound C) or transfection with siRNA against AMPKα1 and two AMPK upstream activator- liver kinase B1 (LKB1) and calmodulin-dependent protein kinase II (CaMKII) diminished the adiponectin-induced ICAM-1 expression. Stimulation of OASFs with adiponectin increased phosphorylation of LKB1, CaMKII, AMPK, and c-Jun, resulting in c-Jun binding to AP-1 element of ICAM-1 promoter. In addition, adiponectin-induced activation of the LKB1/CaMKII, AMPK, and AP-1 pathway increased the adhesion of monocytes to the OASF monolayer. Our results suggest that adiponectin increases ICAM-1 expression in human OASFs via the LKB1/CaMKII, AMPK, c-Jun, and AP-1 signaling pathway. Adiponectin-induced ICAM-1 expression promoted the adhesion of monocytes to human OASFs. These findings may provide a better understanding of the pathogenesis of OA and can utilize this knowledge to design a new therapeutic strategy.


Assuntos
Adiponectina/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Molécula 1 de Adesão Intercelular/biossíntese , Monócitos/metabolismo , Membrana Sinovial/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Feminino , Fibroblastos/patologia , Humanos , Masculino , Monócitos/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/patologia
20.
Biomed Res Int ; 2013: 396839, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24490159

RESUMO

Chondrosarcomas are a heterogeneous group of malignant bone tumors that are characterized by the production of cartilaginous extracellular matrix. They are the second most frequently occurring type of bone malignancy. Surgical resection remains the primary mode of treatment for chondrosarcomas, since conventional chemotherapy and radiotherapy are largely ineffective. Treatment of patients with high-grade chondrosarcomas is particularly challenging, owing to the lack of effective adjuvant therapies. Integrins are cell surface adhesion molecules that regulate a variety of cellular functions. They have been implicated in the initiation, progression, and metastasis of solid tumors. Deregulation of integrin expression and/or signaling has been identified in many chondrosarcomas. Therefore, the development of new drugs that can selectively target regulators of integrin gene expression and ligand-integrin signaling might hold great promise for the treatment of these cancers. In this review, we provide an overview of the current understanding of how growth factors, chemokines/cytokines, and other inflammation-related molecules can control the expression of specific integrins to promote cell migration. We also review the roles of specific subtypes of integrins and their signaling mechanisms, and discuss how these might be involved in tumor growth and metastasis. Finally, novel therapeutic strategies for targeting these molecules will be discussed.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Condrossarcoma/tratamento farmacológico , Integrinas/genética , Terapia de Alvo Molecular , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Adesão Celular/genética , Condrossarcoma/genética , Condrossarcoma/patologia , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Integrinas/uso terapêutico , Transdução de Sinais/genética
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