Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Free Radic Biol Med ; 104: 280-297, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28131902

RESUMO

Autophagy plays a key role in supporting cell survival against chemotherapy-induced apoptosis. In this study, we found the chemotherapy agent SN-38 induced autophagy in colorectal cancer (CRC) cells. However, inhibition of autophagy using a small molecular inhibitor 3-methyladenine (3-MA) and ATG5 siRNA did not increase SN-38-induced cytotoxicity in CRC cells. Notably, another autophagy inhibitor chloroquine (CQ) synergistically enhanced the anti-tumor activity of SN-38 in CRC cells with wild type (WT) p53. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that CQ and SN-38 acted together to trigger reactive oxygen species (ROS) burst, upregulate p53 expression, elicit the loss of lysosomal membrane potential (LMP) and mitochondrial membrane potential (∆ψm). In addition, ROS induced by CQ plus SN-38 upregulated p53 levels by activating p38, conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce CRC cell death. Moreover, we showed induction of ROS and p53 by the two agents provoked the loss of LMP and ∆ψm. Altogether, all results suggested that CQ synergistically sensitized human CRC cells with WT p53 to SN-38 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk. Lastly, we showed that CQ could enhance CRC cells response to CPT-11 (a prodrug of SN-38) in xenograft models. Thus the combined treatment might represent an attractive therapeutic strategy for the treatment of CRC.


Assuntos
Cloroquina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Irinotecano , Lisossomos/metabolismo , Lisossomos/patologia , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Oncotarget ; 8(14): 22414-22432, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-26461472

RESUMO

Here, we showed the antibiotic salinomycin (SAL) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status, with a relatively low toxicity to normal cells. Additionally, combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF. Further, we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP) and lysosomal membrane potential (LMP). And the ROS contributed the loss of MMP and LMP. We also found that GEF and SAL acted in concert to induce apoptosis via a mitochondrial-lysosomal cross-talk and caspase-independent pathway triggered by cathepsin B and D. Lastly, SAL in combination with GEF sensitized GEF-resistant cells to GEF in a nude mouse xenograft model. This novel combination treatment might provide a potential clinical application to overcome GEF resistance in colorectal cancer.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Lisossomos/efeitos dos fármacos , Piranos/uso terapêutico , Quinazolinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Catepsina B/metabolismo , Catepsina D/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe , Humanos , Lisossomos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Nus , Mitocôndrias/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cell Death Dis ; 7(11): e2454, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27809310

RESUMO

Estrogen-dependent breast cancer is often treated with the aromatase inhibitors or estrogen receptor (ER) antagonists. Tamoxifen as a major ER antagonist is usually used to treat those patients with ERα-positive breast cancer. However, a majority of patients with ERα positive fail to respond to tamoxifen due to the presence of intrinsic or acquired resistance to the drug. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. In this study, we investigated the role of miR-27b-3p in resistance of breast cancer to tamoxifen. MiR-27b-3p levels were remarkably reduced in the tamoxifen-resistant breast cancer cells compared with their parental cells. In addition, miR-27b-3p was also significantly downregulated in breast tumor tissues relative to adjacent non-tumor tissues. Moreover, the expression levels of miR-27b-3p were lower in the breast cancer tissues from tamoxifen-resistant patients compared with that from untreated-tamoxifen patients. Notably, tamoxifen repressed miR-27b-3p expression, whereas estrogen induced miR-27b-3p expression in breast cancer cells. Besides, we provided experimental evidences that miR-27b-3p enhances the sensitivity of breast cancer cells to tamoxifen in vitro and in vivo models. More importantly, we validated that miR-27b-3p directly targeted and inhibited the expression of nuclear receptor subfamily 5 group A member 2 (NR5A2) and cAMP-response element binding protein 1 (CREB1) and therefore augmented tamoxifen-induced cytotoxicity in breast cancer. Lastly, miR-27b-3p levels were found to be significantly negatively correlated with both NR5A2 and CREB1 levels in breast cancer tissues. Our findings provided further evidence that miR-27b-3p might be considered as a novel and potential target for the diagnosis and treatment of tamoxifen-resistant breast cancer.


Assuntos
Neoplasias da Mama/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Receptores Citoplasmáticos e Nucleares/genética , Tamoxifeno/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cell Death Dis ; 7(11): e2463, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27831559

RESUMO

Chemoresistance is a major obstacle to effective breast cancer chemotherapy. However, the underlying molecular mechanisms remain unclear. In this study, nuclear receptor coactivator 3 (NCOA3) was found to be significantly increased in taxol-resistant breast cancer tissues and cells. Moreover, overexpression of NCOA3 enhanced breast cancer cell resistance to taxol, whereas depletion of NCOA3 decreased taxol resistance. Subsequently, we investigated whether NCOA3 expression was regulated by miRNAs in breast cancer. By bioinformatics prediction in combination with the data of previous report, miR-17 and miR-20b were selected as the potential miRNAs targeting NCOA3. By real-time PCR analysis, we found that miR-17 and miR-20b were significantly reduced in taxol-resistant breast cancer tissues and cells. In addition, we provided some experimental evidences that miR-17 and miR-20b attenuated breast cancer resistance to taxol in vitro and in vivo models. Furthermore, by luciferase reporter assays, we further validated that both miR-17 and miR-20b directly binded the 3'-untranslated region of NCOA3 mRNA and inhibited its expression in breast cancer cells. Finally, both miR-17 and miR-20b levels were found to be significantly negatively correlated with NCOA3 mRNA levels in breast cancer tissues. Together, our results indicated that loss of miR-17 and miR-20b enhanced breast cancer resistance to taxol by upregulating NCOA3 levels. Our study suggested miR-17, miR-20b and NCOA3 may serve as some predictive biomarkers and potential therapeutic targets in taxol-resistant breast cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MicroRNAs/genética , Coativador 3 de Receptor Nuclear/genética , Paclitaxel/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Nus , MicroRNAs/metabolismo , Coativador 3 de Receptor Nuclear/metabolismo , Paclitaxel/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tamoxifeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Biochem Biophys Res Commun ; 478(1): 227-233, 2016 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-27425252

RESUMO

SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuating AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Coativador 3 de Receptor Nuclear/genética , Coativador 3 de Receptor Nuclear/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Depsipeptídeos/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Inativação Gênica , Humanos , Neoplasias Experimentais/patologia , Coativador 3 de Receptor Nuclear/antagonistas & inibidores
6.
Oncotarget ; 7(18): 26480-95, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-27034162

RESUMO

In this study, to investigate whether endoplastic reticulum (ER) stress correlated with FOXM1 in colorectal cancer, we analysed the mRNA levels of FOXM1 and ER stress markers HSPA5 and spliced XBP1 by qRT-PCR. FOXM1 mRNA levels were found to positively correlate with HSPA5 in colorectal cancer. However, no significant correlation between FOXM1 and spliced XBP1 mRNA levels was found. Theses results suggested the positive correlation between FOXM1 and HSPA5 in colorectal cancer was not associated with ER stress. Next, we provided evidences that FOXM1 promoted HSPA5 transcription by directly binding to and stimulating HSPA5 promoter. Moreover, a FOXM1-binding site mapped between -1019 and -1012 bp of the proximal HSPA5 promoter was identified. In addition, we found that enhancement of cell migration and invasion by FOXM1 was significantly attenuated by depletion of HSPA5 in colorectal cancer cell. Furthermore, FOXM1 triggered colorectal cancer cell migration and invasion was involved in activities of cell-surface HSPA5. Lastly, our results suggested FOXM1 facilitated the activities and expressions of MMP2 and 9 associated with cell-surface HSPA5 in colorectal cancer cells. Moreover, statistically significant positive correlations between FOXM1 and MMP2 mRNA expression, between HSPA5 and MMP2 were found in colorectal cancer tissue specimens. Together, our results suggested that FOXM1-HSPA5 signaling might be considered as a novel molecular target for designing novel therapeutic regimen to control colorectal cancer metastasis and progression.


Assuntos
Neoplasias Colorretais/patologia , Proteína Forkhead Box M1/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Choque Térmico/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteína Forkhead Box M1/genética , Proteínas de Choque Térmico/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Ativação Transcricional
7.
PLoS One ; 10(7): e0132880, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26176608

RESUMO

Cancer metabolism has greatly interested researchers. Mammalian target of rapamycin (mTOR) is dysregulated in a variety of cancers and considered to be an appealing therapeutic target. It has been proven that growth factor signal, mediated by mTOR complex 1 (mTORC1), drives cancer metabolism by regulating key enzymes in metabolic pathways. However, the role of mTORC2 in cancer metabolism has not been thoroughly investigated. In this study, by employing automated spectrophotometry, we found the level of glucose uptake was decreased in non-small-cell lung carcinoma (NSCLC) A549, PC-9 and SK-MES-1 cells treated with rapamycin or siRNA against Raptor, indicating that the inhibition of mTORC1 attenuated glycolytic metabolism in NSCLC cells. Moreover, the inhibition of AKT reduced glucose uptake in the cells as well, suggesting the involvement of AKT pathway in mTORC1 mediated glycolytic metabolism. Furthermore, our results showed a significant decrease in glucose uptake in rictor down-regulated NSCLC cells, implying a critical role of mTORC2 in NSCLC cell glycolysis. In addition, the experiments for MTT, ATP, and clonogenic assays demonstrated a reduction in cell proliferation, cell viability, and colony forming ability in mTOR inhibiting NSCLC cells. Interestingly, the combined application of mTORC1/2 inhibitors and glycolysis inhibitor not only suppressed the cell proliferation and colony formation, but also induced cell apoptosis, and such an effect of the combined application was stronger than that caused by mTORC1/2 inhibitors alone. In conclusion, this study reports a novel effect of mTORC2 on NSCLC cell metabolism, and reveals the synergistic effects between mTOR complex 1/2 and glycolysis inhibitors, suggesting that the combined application of mTORC1/2 and glycolysis inhibitors may be a new promising approach to treat NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Glicólise , Neoplasias Pulmonares/metabolismo , Complexos Multiproteicos/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Benzamidas , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose/farmacologia , Regulação para Baixo/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glicólise/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Morfolinas/farmacologia , Complexos Multiproteicos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas , Proteína Companheira de mTOR Insensível à Rapamicina , Proteína Regulatória Associada a mTOR , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Ensaio Tumoral de Célula-Tronco
8.
Cell Physiol Biochem ; 35(6): 2255-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25895606

RESUMO

BACKGROUND/AIM: Treatment of human non-small-cell lung cancer (NSCLC) often involves uses of multiple therapeutic strategies with different mechanisms of action. Here we found that resveratrol (RV) enhanced the anti-tumor effects of epidermal growth factor receptor (EGFR) inhibitor erlotinib in NSCLC cells. METHODS: Cell viability was measured by MTT assay and clonogenicity assay. Western blot was applied to assess the protein expression levels of target genes. Cell apoptosis was monitored by AnnexinV-FITC assay and sub-G1 population assay. Intracellular ROS were measured by flow cytometric analysis. Cell caspase activities were carried out by fluorometric assays. RESULTS: Exposure of H460, A549, PC-9 and H1975 cells to minimal or non-toxic concentrations of RV and erlotinib synergistically reduced cell viability, colony formation and induced cell apoptosis. Furthermore, RV synergistically enhanced erlotinib-induced apoptosis was involved in ROS production. Additionally, co-treatment with RV and erlotinib repressed the expressions of anti-apoptosis proteins, such as survivin and Mcl-1, whereas promoted p53 and PUMA expression and caspase 3 activity. Moreover, the combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. Subsequently, small interfering RNA (siRNA) depletion of PUMA and overexpression of survivin significantly attenuated NSCLC cells apoptosis induced by the combination of the two drugs. CONCLUSION: Our findings suggested that RV synergistically enhanced the anti-tumor effects of erlotinib in NSCLC cells were involved in decrease of survivin expression and induction of PUMA expression. In conclusion, based on the observations from our study, we indicated that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating NSCLC.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/farmacologia , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Estilbenos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Resveratrol , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Survivina , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53 , Regulação para Cima/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA