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1.
Oncol Rep ; 46(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34036396

RESUMO

Our previous study has shown that CD9 knockdown could suppress cell proliferation, adhesion, migration and invasion, and promote apoptosis and the cytotoxicity of chemotherapeutic drugs in the B­lineage acute lymphoblastic leukemia (B­ALL) cell line SUP­B15. In this study, we further investigated the molecular mechanism underlying the effects of CD9 on leukemic cell progression and the efficacy of chemotherapeutic agents in B­ALL cells. Using the CD9­knockdown SUP­B15 cells, we demonstrated that the silencing of the CD9 gene significantly reduced the expression of phosphorylated­phosphatidylinositol­3 kinase (p­PI3K), phosphorylated­protein kinase B (p­AKT), P­glycoprotein (P­gp), multidrug resistance­associated protein 1 (MRP1), breast cancer resistance protein (BCRP), matrix metalloproteinase 2 (MMP2) and phosphorylated­focal adhesion kinase (p­FAK). In addition, glutathione S­transferase (GST) pull­down assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vitro, while co­immunoprecipitation assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vivo. Furthermore, the PI3K/AKT inhibitor LY294002 mirrored the effects of CD9 knockdown in SUP­B15 cells. Taken together, these findings demonstrated that CD9 activates the PI3K/AKT signaling pathway through direct interaction with PI3K­p85 in B­ALL cells. Our data provide evidence for the inhibition of the PI3K/AKT pathway as a novel therapeutic option in CD9 antigen­positive B­ALL.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tetraspanina 29/genética , Tetraspanina 29/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Morfolinas/farmacologia , Fosforilação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transdução de Sinais/efeitos dos fármacos
2.
Med. clín (Ed. impr.) ; 155(6): 235-241, sept. 2020. graf, tab
Artigo em Inglês | IBECS | ID: ibc-195867

RESUMO

OBJECTIVES: The aim of this study was to evaluate the efficacy and toxicity of high-dose rituximab (HD-R) in combination with autologous stem cell transplantation (auto-SCT) in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). METHODS: There were 22 patients in the HD-R group, to whom rituximab was administered during stem cell mobilization (375mg/m2 1 day before and 7 days after chemotherapy) and after transplantation (1000mg/m2 on days +1 and +8). In the control group, the procedure was the same as that in the HD-R group but without rituximab. We observed the safety, tolerability, adverse effects and immune reconstitution of HD-R therapy. The log-rank test, univariate analysis and multivariate Cox regression analysis were used to evaluate the effect of HD-R on survival. RESULTS: In total, 22 relapsed or refractory DLBCL patients were treated with HD-R. No dose-limiting toxicities were observed except for CD19+ B cell reconstruction in the first 6 months after SCT. There were 20 relapsed or refractory DLBCL patients in the control group. The 3-year progression-free survival (PFS) and overall survival (OS) greatly improved in the HD-R group compared to that in the control group (63.8% vs. 35.0%, P=0.028 and 80.1% vs. 50.0%, P=0.035, respectively). The univariate and multivariate analyses demonstrated that HD-R and the time to relapse were independent prognostic factors for OS and PFS. CONCLUSION: HD-R in combination with auto-SCT is a feasible and promising treatment for patients with relapsed or refractory DLBCL


OBJETIVOS: El objetivo de este estudio fue evaluar la eficacia y la toxicidad de la combinación de altas dosis de rituximab (HD-R) y el trasplante de células madre autólogas (auto-SCT) en pacientes con linfoma B difuso de células grandes (LBDCG) en recaída o refractario. MÉTODOS: El grupo HD-R incluyó 22 pacientes a quienes se les administró rituximab durante la movilización de células madre (375mg/m2 un día antes y 7 días después de la quimioterapia) y tras el trasplante (1000mg/m2 los días +1 y +8). En el grupo control, el procedimiento fue el mismo que en el grupo HD-R, aunque sin rituximab. Observamos la seguridad, la tolerabilidad, los efectos adversos y la reconstitución inmune de la terapia HD-R. Utilizamos la prueba log-rank, el análisis univariante y el análisis de regresión de Cox multivariante para evaluar el efecto de HD-R en la supervivencia. RESULTADOS: En total, 22 pacientes de LBDCG en recaída o refractario fueron tratados con HD-R. No se observaron toxicidades limitantes de dosis excepto para la reconstrucción de células CD19+ B en los primeros 6 meses tras SCT. El grupo control incluyó 20 pacientes de LBDCG en recaída o refractario. La supervivencia libre de progresión (SLP) a 3 años y la supervivencia general (SG) mejoró significativamente en el grupo HD-R en comparación con el grupo control (63,8 vs. 35%; p = 0,028 y el 80,1 vs. 50%; p = 0,035, respectivamente). Los análisis univariante y multivariante demostraron que HD-R y tiempo de recaída eran factores pronósticos independientes para SG y SLP. CONCLUSIÓN: La combinación de HD-R y auto-SCT es un tratamiento factible y prometedor para pacientes con LBDCG en recaída o refractario


Assuntos
Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Rituximab/administração & dosagem , Transplante Autólogo , Linfoma Difuso de Grandes Células B/terapia , Resultado do Tratamento , Transplante de Células-Tronco/métodos , Rituximab/efeitos adversos , Rituximab/toxicidade , Análise de Regressão , Intervalo Livre de Progressão , Recidiva , Estudos Prospectivos
3.
Cancer Manag Res ; 12: 7097-7105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848464

RESUMO

BACKGROUND: Peripheral monocytes, a key cell type for innate immunity, have been shown to be associated with survival in various types of hematological malignancies. However, no previous studies regarding the prognostic impact of peripheral absolute monocyte count (AMC) in early relapsed B-lineage acute lymphoblastic leukemia (B-ALL) have been reported. METHODS: Forty-nine cases of early relapsed adult B-ALL were reviewed. The upper (0.80 × 109/L) and lower limits (0.12 × 109/L) of the normal value for AMC were used as cut-off points. Kaplan-Meier curves and Log rank test were used for comparison of overall survival (OS). The univariate and multivariate Cox proportional hazards models were used for investigating the factors associated with OS. RESULTS: More than half (59.2%) of all patients showed a normal AMC (0.12-0.80 × 109/L). The median follow-up was 5.3 months from the start of first salvage therapy. Univariate analysis revealed that normal AMC (versus low/high AMC) at the time of relapse was a prognostic factor for improved OS (P = 0.021). On multivariate analysis, normal AMC (versus low/high AMC) at the time of relapse remained an independent prognostic factor for improved OS (hazard ratio = 0.43, P = 0.030). CONCLUSION: AMC at the time of relapse, which can be easily derived from routine clinical laboratory testing of complete blood count, might be used as a prognostic marker for survival outcomes in adult patients with early relapsed B-ALL.

4.
Med Clin (Barc) ; 155(6): 235-241, 2020 09 25.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32173075

RESUMO

OBJECTIVES: The aim of this study was to evaluate the efficacy and toxicity of high-dose rituximab (HD-R) in combination with autologous stem cell transplantation (auto-SCT) in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). METHODS: There were 22 patients in the HD-R group, to whom rituximab was administered during stem cell mobilization (375mg/m2 1 day before and 7 days after chemotherapy) and after transplantation (1000mg/m2 on days +1 and +8). In the control group, the procedure was the same as that in the HD-R group but without rituximab. We observed the safety, tolerability, adverse effects and immune reconstitution of HD-R therapy. The log-rank test, univariate analysis and multivariate Cox regression analysis were used to evaluate the effect of HD-R on survival. RESULTS: In total, 22 relapsed or refractory DLBCL patients were treated with HD-R. No dose-limiting toxicities were observed except for CD19+ B cell reconstruction in the first 6 months after SCT. There were 20 relapsed or refractory DLBCL patients in the control group. The 3-year progression-free survival (PFS) and overall survival (OS) greatly improved in the HD-R group compared to that in the control group (63.8% vs. 35.0%, P=0.028 and 80.1% vs. 50.0%, P=0.035, respectively). The univariate and multivariate analyses demonstrated that HD-R and the time to relapse were independent prognostic factors for OS and PFS. CONCLUSION: HD-R in combination with auto-SCT is a feasible and promising treatment for patients with relapsed or refractory DLBCL.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva Local de Neoplasia , Recidiva , Rituximab/uso terapêutico , Transplante Autólogo , Resultado do Tratamento
5.
Am J Transl Res ; 8(5): 2011-21, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27347310

RESUMO

Angiopoietin-1 (Ang-1) plays a critical role in the regulation of endothelial cell survival and vascular maturation and stability. However, its role in hematopoiesis is not clear. Here, we determined effect of Ang-1 on the recovery of hematopoiesis in radiated mice. By injecting an Ang-1 plasmid, we found that Ang-1 was preferentially expressed in bone marrow (BM) of femur from radiated mice. This injection resulted in elevated blood counts and serum VEGF level. The blockade in S phase of cell cycle in mouse BM stromal cells following radiation was attenuated by injection of Ang-1 plasmid. In addition, injection of Ang-1 plasmid attenuated the radiation-mediated inhibition of Tie2 expression. Furthermore, through analyzing Notch1 expression, we found that injection of Ang-1 plasmid increased Notch mRNA expression in radiated mice. In conclusion, these findings suggest that Ang-1 facilitates the recovery of hematopoiesis in radiated mice with the involvement of Notch signaling pathway.

6.
Hematology ; 21(6): 332-7, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27077765

RESUMO

BACKGROUND: Gut-derived bacteraemia is a major complication in patients with haematological malignancy after chemotherapy. OBJECTIVE: Our study aimed to investigate the role of proton pump inhibitors (PPIs) in the occurrence of gut-derived bacteraemia. METHODS: We compared data from 92 hospitalized haematological malignancy patients after chemotherapy with gut-derived bacteraemia, collected from January 2009 to July 2015, with those of 92 contemporaneous, hospitalized haematological malignancy patients without bacteraemia. We evaluated PPIs use and analysed the effects of covariates. RESULTS: Patients with gut-derived bacteraemia had a significantly higher incidence of PPIs use (69.6%) than that of controls (47.8%). Of the patients with gut-derived bacteraemia, only 44.6% had a documented indication for PPIs therapy. The antibacterial prophylaxis rate was 38.0% in the bacteraemia group and 58.7% in the non-antibacterial group. Based on multivariable logistic regression analysis, only PPIs use (P = 0.00, odds ratio (OR) = 0.546) was found to be associated with the risk of bacteraemia whereas antibacterial prophylaxis (P = 0.00, OR = 0.652) was protective. There were no significant differences in demographics, malignancy status, length of neutropenia, complications, or steroid use between the gut-derived bacteraemia and control group. CONCLUSIONS: This study suggests a potential association between PPIs use and development of gut-derived bacteraemia in haematological malignancy patients after chemotherapy.


Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/microbiologia , Neoplasias Hematológicas/tratamento farmacológico , Inibidores da Bomba de Prótons/farmacologia , Adulto , Estudos de Casos e Controles , Feminino , Neoplasias Hematológicas/complicações , Humanos , Masculino , Inibidores da Bomba de Prótons/uso terapêutico , Estudos Retrospectivos
7.
Leuk Res ; 39(4): 471-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25666256

RESUMO

Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling caused by JAK2V617F and other mutations is central to the pathogenesis of myeloproliferative neoplasm (MPN). Negative regulators such as suppressors of cytokine signaling (SOCS) inhibit activated JAK2/STAT signaling. However, whether silencing of negative regulators facilitates JAK2/STAT signaling is unclear. Here, we report that loss of miR-375 expression contributes to the constitutive activation of JAK2/STAT signaling. MiR-375 reduced JAK2 protein level and repressed the activity of a luciferase reporter by binding 3'-untranslated regions, which was abolished by the mutation of the predicted miR-375-binding site. Meanwhile, a significant inverse correlation between the expressions of miR-375 and JAK2 was found in multiple types of leukemic cell lines and bone marrow mononuclear cells from MPN patients, suggesting that JAK2 may be a miR-375 target gene. Furthermore, forced expression of miR-375 inhibited constitutive and inducible JAK2/STAT signaling, suppressed cell proliferation, and decreased colony formation in hematopoietic progenitors from MPN patients. Finally, histone deacetylation (HDAC) inhibitors restored miR-375 expression, which was much lower in patients with MPN compared with healthy volunteers. Collectively, our data suggest that the loss of miR-375 expression enhances the constitutive and persistent activation of JAK2/STAT signaling. Restoration of miR-375 expression might contribute to the clinical treatment for MPN patients.


Assuntos
Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Janus Quinase 2/metabolismo , MicroRNAs/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Fatores de Transcrição STAT/metabolismo , Apoptose , Western Blotting , Proliferação de Células , Imunoprecipitação da Cromatina , Humanos , Janus Quinase 2/genética , Mutação/genética , Transtornos Mieloproliferativos/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição STAT/genética , Transdução de Sinais , Células Tumorais Cultivadas
8.
Carcinogenesis ; 34(7): 1442-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23430957

RESUMO

Suppressors of cytokine signaling, SOCS1 and SOCS3, are important negative regulators of Janus kinase 2/signal transducers and activators of transcription signaling, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia. Curcumin has been shown to possess anticancer activity through different mechanisms. However, whether curcumin can regulate the expression of SOCS1 and SOCS3 is still unknown. Here, we found that curcumin elevated the expression of SOCS1 and SOCS3 via triggering acetylation of histone in the regions of SOCS1 and SOCS3 promoter in K562 and HEL cells. As a novel histone deacetylases (HDACs) inhibitor, curcumin inhibited HDAC enzyme activities and decreased the levels of HDAC1, 3 and 8 but not HDAC2. Knockdown of HDAC8 by small interfering RNA markedly elevated the expression of SOCS1 and SOCS3. Moreover, ectopic expression of HDAC8 decreased the levels of SOCS1 and SOCS3. Thus, HDAC8 plays an important role in the modulation of SOCS1 and SOCS3 by curcumin. Also, trichostatin A (TSA), an inhibitor of HDACs, increased the levels of SOCS1 and SOCS3. Furthermore, curcumin increased the transcript levels of SOCS1 and SOCS3 and significantly inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Finally, curcumin markedly inhibited HDAC activities and decreased HDAC8 levels in primary MPN cells. Taken together, our data uncover a regulatory mechanism of SOCS1 and SOCS3 through inhibition of HDAC activity (especially HDAC8) by curcumin. Thus, being a relative non-toxic agent, curcumin may offer a therapeutic advantage in the clinical treatment for MPNs.


Assuntos
Neoplasias da Medula Óssea/metabolismo , Curcumina/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Transtornos Mieloproliferativos/patologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Acetilação , Neoplasias da Medula Óssea/enzimologia , Neoplasias da Medula Óssea/genética , Imunoprecipitação da Cromatina , Ativação Enzimática , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Células K562 , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/genética , Cultura Primária de Células , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína 1 Supressora da Sinalização de Citocina , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética
9.
Toxicol Lett ; 203(2): 111-7, 2011 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21382456

RESUMO

Topoisomerase IIα (Topo IIα) has been implicated in the benzene-induced hemotoxicity in vitro. This study was to examine the effect of in vivo chronic benzene exposure on Topo IIα in human bone marrow mononuclear cells, and to further explore the mechanism underlying decreased Topo IIα expression in patients with chronic benzene exposure. Topo IIα activity, expression, and mRNA level assessed by DNA cleavage/relaxation assay, Western blot, and reverse transcriptase-PCR, decreased in patients with benzene exposure. These changes were accompanied by reduced histone H4 and H3 acetylation and H3K4 methylation, and increased H3K9 methylation in the Topo IIα promoter, which were evaluated by chromatin immunoprecipitation (ChIP) assay. In addition, there were alterations in mRNA levels of Topo IIα promoter regulatory factors such as SP1, ATF-2, SP3, NF-YA, NF-M, P53, C-MYB, C-JUN, and ICBP90. Our results demonstrate that Topo IIα expression was reduced in patients with chronic benzene exposure, which was accompanied by alterations in histone acetylation and methylation and regulatory factor mRNA levels of Topo IIα promoter.


Assuntos
Antígenos de Neoplasias/biossíntese , Benzeno/intoxicação , DNA Topoisomerases Tipo II/biossíntese , Proteínas de Ligação a DNA/biossíntese , Histonas/metabolismo , Acetilação , Adulto , Antígenos de Neoplasias/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Imunoprecipitação da Cromatina , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Histonas/efeitos dos fármacos , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Intoxicação/enzimologia , Intoxicação/etiologia , Intoxicação/metabolismo , Intoxicação/patologia , Regiões Promotoras Genéticas , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
10.
Artigo em Chinês | MEDLINE | ID: mdl-21126478

RESUMO

OBJECTIVE: To investigate the effects of hydroquinone (HQ) on expression of topoisomerase IIα (TOPOIIα) in human bone marrow mononuclear cells, and to explore the role and possible regulatory mechanism of TOPOIIα involved in toxicity of HQ to hematopoietic cells. METHODS: After human bone marrow mononuclear cells were exposed to 50 µmol/L HQ (used the cells which were exposed to sterile distilled water as control); the activity of TOPOII was measured by TOPOII assay kit; the expression levels of TOPOIIα mRNA and protein were detected by RT-PCR technique and Western blotting method respectively; the chromatin immunoprecipitation (ChIP) assay was carried out to study the possible mechanism of TOPOIIα expression changes. RESULTS: (1) The activity of TOPOII was inhibited obviously; the protein and mRNA expression of TOPOIIα were 0.017 ± 0.029 and 0.610 ± 0.128, significantly lower than that in the control with the significant difference (P < 0.01) after treated with HQ for 10 h; (2) The decreased content of TOPOIIα was associated with descended level of histone H4 acetylation than in the control, from 1.198 ± 0.056 to 0.324 ± 0.229, with the significant difference (P < 0.01), without accompanied descended level of histone H3 acetylation, from 1.253 ± 0.045 to 1.177 ± 0.025 (P > 0.05); (3) TOPOIIα mRNA expression decreased gradually after HQ processing, and the chemical modification (histone H4 acetylation) of TOPOIIα promoter happened prior to the mRNA expression. CONCLUSION: HQ could repress the expression of TOPOIIα in human bone marrow mononuclear cells; the change of histone chemical modification plays an important role in the benzene's hematopoietic toxicity.


Assuntos
Antígenos de Neoplasias/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hidroquinonas/toxicidade , Acetilação , Adulto , Células Cultivadas , Feminino , Histonas/metabolismo , Humanos , Masculino , Adulto Jovem
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