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1.
J Biol Chem ; 294(25): 10006-10017, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31101655

RESUMO

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.

2.
Oncol Lett ; 9(4): 1549-1556, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25788999

RESUMO

Radiofrequency ablation (RFA) causes coagulative necrosis of tumor tissue and the production of local tumor protein debris. These fragments of tumor protein debris contain a large number of various antigens, which can stimulate a specific cellular immune response. In the present study, dendritic cells (DCs) were loaded with tumor protein lysate antigens that were produced in situ by RFA, and were used to treat murine colon carcinoma in combination with cytokine-induced killer (CIK) cells. Subsequent to the treatment of murine colon carcinoma by RFA, the in situ supernatant of tumor lysis was collected and the DCs were loaded with the lysate antigen to generate Ag-DCs. CIK cells induced from the spleen cells of mice were co-cultured with Ag-DCs to generate Ag-DC-CIK cells. The results revealed that the Ag-DC-CIK cells exhibited strong antitumor activity in vitro and in vivo. The morphology and immunophenotypes of these cells were determined using microscopy and flow cytometry, respectively. The cytotoxic activity of Ag-DC-CIK cells was determined using a CCK-8 assay. To establish a mouse model, mice were randomized into Ag-DC-CIK, DC-CIK, CIK and PBS control groups and monitored for tumor growth and survival time. ANOVA was used to compare the trends in the three groups for implanted tumor volumes. The log-rank test was used to compare the survival time. The present findings indicated that DCs loaded with the protein lysate antigens of tumors, produced in situ by RFA, combined with CIK cells may be a novel strategy for cancer treatment.

3.
Zhonghua Wei Chang Wai Ke Za Zhi ; 10(5): 458-62, 2007 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-17851789

RESUMO

OBJECTIVE: To study the expression of B7-H3 mRNA and B7-H3 protein in gastric carcinoma and their clinical significance. METHODS: The expression of B7-H3 mRNA and B7-H3 protein in gastric carcinoma and the nearby normal tissue of 38 patients was detected by real-time RT-PCR and immunohistochemical assay respectively. RESULTS: B7-H3 mRNA was expressed both in gastric carcinoma and nearby normal tissue, but the expression level in gastric carcinoma was much lower than that in nearby normal tissue. There were no significant differences of B7-H3 mRNA expression among gender, age, histological type, tumor size, lymph node metastasis and invasive depth (all P >0.05). The positive rate of B7-H3 protein expressed in gastric carcinoma was 39.5%. There were no significant differences of B7-H3 protein expression among gender, age, histological type, tumor size, lymph node metastasis and invasive depth (all P >0.05), but there were significant differences among groups of clinical stage (P=0.022) and pathological grade (P=0.039). Kaplan-Meier analysis revealed that disease-free survival or overall survival of the patients with positive B7-H3 expression were significantly longer than those with negative B7-H3 expression (P=0.009 and P=0.010 respectively). CONCLUSION: Detection of B7-H3 expression in gastric carcinoma will be beneficial to the judgment of the prognosis of gastric carcinoma and the choice of individualized treatment.


Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Receptores Imunológicos/metabolismo , Neoplasias Gástricas/metabolismo , Antígenos CD/genética , Antígenos B7 , Biomarcadores Tumorais/genética , Citotoxicidade Imunológica , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/genética , Receptores Imunológicos/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
4.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 27(8): 736-8, 2007 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-17879541

RESUMO

OBJECTIVE: To investigate the effects of Shenqi Fuzheng injection (SQFZI) combined with docetaxcl, flurouracil and calcium folinate in treating advanced gastric carcinoma, and to evaluate the action of SQFZI for enhancing therapeutic effect and alleviating adverse reaction of chemotherapy. METHODS: Sixty advanced gastric cancer patients were assigned to two groups randomly, the control group treated with chemotherapy alone and the treated group treated with SQFZI combined chemotherapy. Chemotherapy regimens (TFC) was given to all patients consisting of docetaxel 75 mg/m2 intravenous dripping on the 1st day, flurouracil (5-FU) 350 mg/m2 and calcium folinate (CF) 120 mg/m2 intravenous dripping with micro-pump continuously from day 1 to 5, for 21-28 days as a cycle. To patients in the treated group, starting from 3 days before chemotherapy, SQFZI 250 mL was dripped every day for 14 successive days. The clinic effects were evaluated after two-cycle treatment. RESULTS: The short-term effective rate was 40.0% in the treated group and 33.3% in the control group. As compared with those in the control group, patients in the treated group after treatment had a higher Karnofsky score (chi2 = 7.21, P < 0.05) and body weight (chi2 = 11.47, P < 0.05), lesser adverse reactions in decreasing of peripheral blood leucocyte, damage of peripheral nerve, adverse reaction of gastrointestinal tract, as well as better immune function. CONCLUSION: SQFZI could effectively improve the clinical symptoms induced by chemotherapy regimen TFC, alleviate the adverse reaction, raise patients' quality of life and their immune function.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Injeções , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fitoterapia , Neoplasias Gástricas/patologia , Taxoides/administração & dosagem , Resultado do Tratamento
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