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1.
Mol Clin Oncol ; 20(1): 7, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38125742

RESUMO

Lenalidomide is a second-generation new immunomodulatory medication used to treat multiple myeloma (MM). Its mechanism of action involves affecting the expression of vascular endothelial growth factor, interleukin-6, cytochrome c, caspase-8, as well as other factors including immunological modulation and the direct killing of cells, among others, rendering it a fundamental medication, useful for the treatment of MM. Combining lenalidomide with other medications such dexamethasone, bortezomib, ixazomib, carfilzomib and daratumumab can markedly alleviate MM. When autologous-hematopoietic stem cell transplantation (ASCT) cannot be utilized to treat newly diagnosed individuals with MM (NDMM), monotherapy maintenance following lenalidomide and dexamethasone may be employed. Following ASCT, single-agent maintenance with lenalidomide can be performed as an additional treatment. The combination of bortezomib and lenalidomide has been demonstrated to be associated with favorable response rates, tolerable toxicity, and therapeutic benefits although caution is warranted to prevent the onset of peripheral neuropathy with its use. A new-generation oral drug with an excellent safety profile, ixazomib, is more practical and therapeutically applicable in relapsed refractory MM. However, the frequent occurrence of cardiovascular events, hematocrit, and infections with it require flexible adjustment in its clinical application. Carfilzomib produces a rapid and profound response in patients with NDMM eligible for transplantation, but its cardiovascular side effects need to be closely monitored. The primary aim of the present review was to examine the pharmacological properties and pharmacokinetics of lenalidomide, as well as the efficacy and safety of lenalidomide-based treatments with reference to data from clinical trials and real-world studies.

2.
Biochem Biophys Res Commun ; 464(1): 292-8, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26116769

RESUMO

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t (11; 14) (q13; q32). Drug resistance remains a formidable obstacle to treatment and the median survival for MCL patients is between 3 and 5 years. Thus, there is an urgent need to discover novel approaches to MCL therapy. The signal transducer and activation of transcription 3 (STAT3) has been found to be constitutively activated in several subtypes of MCL cell lines and MCL tumors. WP1066, a small-molecule inhibitor of STAT3, exerted antitumor activity in hematological and solid malignancies by inhibiting key survival and growth signaling pathways. In the present study, we evaluated the antiproliferative and proapoptotic activity of WP1066 combined with pan-histone deacetylase (HDAC) inhibitor vorinostat (SAHA) in a panel of MCL cell lines. In addition, potential mechanisms involved were also explored. The outcome showed that combination of WP1066 with SAHA resulted in synergistic growth inhibition and apoptosis induction in MCL cell lines in vitro. Furthermore, combination of WP1066 with SAHA inhibited the constitutive STAT3 activation and modulated mRNA expressions of anti- and pro-apoptotic genes. Our findings suggest that agents targeting the STAT3 pathway such as WP1066 may be useful therapeutic drugs for MCL when combined with SAHA.


Assuntos
Antineoplásicos/farmacologia , Linfócitos B/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Ácidos Hidroxâmicos/farmacologia , Piridinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Tirfostinas/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Histona Desacetilases/metabolismo , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Vorinostat
3.
Med Oncol ; 32(2): 479, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25575438

RESUMO

Metadherin (MTDH) is involved in aberrant proliferation, migration, and chemoresistance of tumor cells. It has been demonstrated that it can promote tumor growth by modulation multiple oncogenic signaling pathways. However, MTDH expression, significance, and related mechanism in chronic lymphocytic leukemia (CLL) are still unclear. The objective of this study was to investigate the expression of MTDH in CLL and the involvement of Wnt/ß-catenin signaling pathway in MTDH effects. Overexpression of MTDH mRNAs was seen in CLL samples. MTDH expression was associated with Rai stage classification of CLL, and altered levels of ß2-MG and lactate dehydrogenase in serum samples from patients. Overexpression of MTDH protein was seen in 87 % of CLL samples. Specific siRNAs inhibited MEC-1 cell growth and enhanced cell apoptosis (P < 0.05). Inhibition of MTDH expression resulted in decreased expression levels of lymphoid enhancer-binding factor 1 (LEF-1), and its downstream target genes c-myc and cyclin D1. And there was a strong correlation between MTDH and LEF-1 protein expression in 14 patients with CLL. The results demonstrate that MTDH is specifically expressed in B cell of CLL and exert a preservative role through activation of Wnt signaling pathway. Our findings indicated that MTDH may be a potential therapeutic target of CLL.


Assuntos
Moléculas de Adesão Celular/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismo , Linfócitos B/patologia , Western Blotting , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Interferência de RNA , Proteínas de Ligação a RNA , Reação em Cadeia da Polimerase em Tempo Real
4.
Int J Clin Exp Med ; 7(8): 2081-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25232390

RESUMO

Metadherin (MTDH) is highly expressed in many tumors and is involved in the proliferation, metastasis and drug resistance of tumor cells by regulating multiple signaling pathways. Our previous studies demonstrated that MTDH is overexpressed in diffuse large B cell lymphoma (DLBCL) and involved in apoptosis resistance, in part, via Wnt signaling. Here, we investigated the role of MTDH in the chemo-sensitivity of DLBCL. The study was performed in the DLBCL cell line LY8 to investigate the relationship between MTDH expression and doxorubicin (DOX) sensitivity in DLBCL. A MTDH interference model was developed in LY8 cells by transfected with lentivirus which is carrying MTDH interference sequence. Western blot was used to detect the protein expression. A CCK-8 assay was used to evaluate cell proliferation. The results showed that DOX treatment had no effect on the intracellular MTDH expression of LY8 cells. The proliferation of LY8 cells was inhibited after MTDH interference. MTDH interference increased the DOX sensitivity in the LY8 cell lines. The results suggested that MTDH is a potential therapeutic target in DLBCL, and it cooperates with DOX in treatment of DLBCL.

5.
Int J Clin Exp Pathol ; 7(4): 1588-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24817955

RESUMO

We have reported Metadherin (MTDH) was proven to be overexpression and involved in malignance of chronic lymphocytic leukemia (CLL) via Wnt signaling pathway. In this study, we further investigate the role of MTDH in regulation of BCR signaling pathway in CLL. Six CLL samples whose cells were proliferation after BCR activation were chosen from patients with unmutated IgVH. CCK-8 method used to evaluate the proliferation rate. MTDH expression was measured by quantitative PCR and Western blot. After BCR activation, there exist upregulation of MTDH expression in mRNA and protein level in all six CLL patients (P<0.05). In cell line MEC-1, we observed the same pro-proliferation effect accompanying with elevated MTDH expression. The proliferation effects of BCR activation to MEC-1 can be inhibited by MTDH interference. The results of this study indicate that MTDH involved in the pro-proliferation effect of BCR activation in CLL. And the results imply that MTDH can be a potential therapy target of CLL.


Assuntos
Moléculas de Adesão Celular/fisiologia , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Proteínas Proto-Oncogênicas c-bcr/fisiologia , Transdução de Sinais/fisiologia , Biomarcadores Tumorais/fisiologia , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Proteínas de Membrana , Proteínas de Ligação a RNA , Regulação para Cima/fisiologia
6.
Leuk Lymphoma ; 55(2): 405-14, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23682557

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1), which is a key enzyme in tryptophan metabolism expressed in some subsets of normal and neoplastic cells, participates in tumor-induced tolerance. However, the mechanisms involved are not clearly understood. A hypothesis suggests that IDO1 may be involved in proliferation and conversion of regulatory T cells (Tregs). In this study, we evaluated the levels of IDO1 and forkhead box P3 (FoxP3) in non-Hodgkin lymphoma (NHL) tissues and performed ex vivo experiments to investigate the role of IDO1 on T-cell tolerance in NHL. The results showed that expressions of IDO1 mRNA and protein were coincidentally higher in NHL tissues than in reactive hyperplasia of lymph node tissues. Up-regulation of IDO1 was correlated with later clinical phases, larger tumors and higher serum lactate dehydrogenase (LDH), and indicated a worse prognosis. FoxP3 mRNA and protein levels were markedly increased alongside elevated IDO1 levels. Co-culture of murine CD4 + CD25- T cells with A20 cells could initiate the conversion of CD4 + CD25+ T cells, which showed a suppressive function in the mixed lymphocyte reaction. Moreover, the potent inhibitor of IDO1, 1-methyl-l-tryptophan, attenuated the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells. The results suggested that up-regulation of IDO1 in NHL tissues could induce local immune tolerance by favoring development and infiltration of FoxP3 + Tregs through the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells in the tumor microenvironment. This could be a novel mechanism of NHL escape from immune control.


Assuntos
Regulação Neoplásica da Expressão Gênica , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Linfoma não Hodgkin/genética , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/patologia , Triptofano/análogos & derivados , Triptofano/farmacologia , Adulto Jovem
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 19(5): 1129-33, 2011 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-22040957

RESUMO

This study was aimed to investigate the expression and clinicopathologic significance of Gli1 and Gli2, 2 factors of Hedgehog(Hh) signaling pathway, in non-Hodgkin's lymphoma (NHL). Gli1 and Gli2 mRNA and protein in 18 cases of NHL and 10 cases of reactive lymphadenitis were amplified and identified by real-time PCR, and were assayed by immunohistochemical staining respectively. The results showed that (1) Gli1 and Gli2 mRNA in NHL group (RQ 2.05, 2.31) were expressed higher than that in reactive lymphadenitis group (RQ 0.82, 0.89). Gli1 mRNA activated level was positively related with Gli2 (r = 0.63, p < 0.01). In addition, Gli2 also positively correlated to clinical stages of NHL (p = 0.03), but the expressions of Gli1 and Gli2 mRNA had no significant correlation to B symptoms, blood ß(2)-microglobulin, age and sex. (2) The positive expression rate of Gli1 and Gli2 protein in NHL group were 80% and 68% respectively, which were extremely higher than that in reactive lymphadenitis group. Gli1 protein level was positively related with Gli2 (r = 0.62, p < 0.05). Both Gli1 and Gli2 protein expression positively correlated to clinical staging of NHL (p = 0.05, p = 0.01). It is concluded that the Gli1 and Gli2 of Hh signaling pathway have been found to higher express in patients with NHL, and have significance for clinical staging and predicting prognosis of NHL. To further investigate the role of Hh signaling pathway in NHL will contribute to elucidate the occurrence and development of NHL, and provide a favorable method for therapy of NHL.


Assuntos
Proteínas Hedgehog/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Transdução de Sinais , Proteína GLI1 em Dedos de Zinco , Proteína Gli2 com Dedos de Zinco
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 18(2): 385-90, 2010 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-20416174

RESUMO

This study was aimed to explore clinical significance of Livin mRNA and protein expressions in non-Hodgkin's lymphoma (NHL). The immunohistochemistry was used to determine the expression of Livin protein in lymph nodes of 30 patients with NHL and 11 patients with reactive hyperplasia of lymph node. The real-time PCR was performed to detect the expression levels of Livin mRNA in 20 patients with NHL, 10 patients with reactive hyperplasia of lymph node and 4 normal person lymph nodes. The correlation of Livin mRNA and protein expressions with NHL clinical features were analyzed. The results showed that the expression of Livin mRNA was statistically higher in NHL samples than in normal lymph nodes and reactive hyperplastic lymph nodes (12.4 vs 0.34, 12.4 vs 0.61, median) (p<0.05), while there was no statistical difference between normal and reactive hyperplastic lymph nodes (p>0.05). Livin protein expression was exhibited to be positive in 16 of 30 cases of NHL with a positive rate of 53.3% and only 1 in reactive hyperplastic lymph nodes with a positive rate of 9.1%. In addition, Livin protein almost appeared in the cytoplasm of cells, seldom in nucleus. The expressions of both Livin mRNA and protein were positively correlated with clinical stages of NHL (p=0.023; p=0.009), B symptoms (p=0.015; p=0.026), blood beta2-microglobulin (beta2-MG, p=0.031; p=0.012) and the serum level of lactate dehydrogenase (LDH, p=0.037; p=0.007), but the expressions of Livin mRNA and protein had no significant correlation with age, sex and typing. It is concluded that the Livin mRNA and protein highly express in NHL patients and correlate with many clinical features, such as stage of NHL, B symptom, beta2-MG and LDH, therefore, the Livin may play a role in the prognosis of NHL patients. The further study on inhibitory effect of Livin expression will promote the illustration of NHL pathogenesis and contribute to the treatment and prognosis of NHL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Linfoma não Hodgkin/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Feminino , Humanos , Proteínas Inibidoras de Apoptose/genética , Linfonodos/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , RNA Mensageiro/genética
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