RESUMO
OBJECTIVES: Lymphomas represent around 10% of head and neck neoplasms, among which the diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype. In the present study, we characterized demographic parameters, anatomical sites, and survival rates of patients in a Brazilian cancer center. MATERIALS AND METHODS: Single-center retrospective epidemiological study of 243 head and neck DLBCL patients. Demographic characteristics, tumor localization, HIV status, lactate dehydrogenase (LDH) activity, and treatment modality were obtained from electronic medical records. RESULTS: The most common primary head and neck tumor location in patients with DLBCL was Waldeyer's ring. Interestingly, age above 80 years, male gender, high LDH levels, and HIV positivity were significantly associated with shorter overall survival (OS) rates and increased risk of death. We further demonstrated that treatment had a protective effect, improving OS, and reducing risk of death. Notably, we found no benefit of combination of chemotherapy and radiotherapy versus isolated treatment modalities. CONCLUSION: The study showed that primary head and neck DLBCL is more incident in middle age and elderly patients with a small male patients' majority in a Brazilian population. Moreover, we observed a 3-year OS rate of almost 60% and multivariate analysis showed that treatment was the only protective factor.
Assuntos
Soropositividade para HIV , Neoplasias de Cabeça e Pescoço , Linfoma Difuso de Grandes Células B , Pessoa de Meia-Idade , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Prognóstico , Estudos Retrospectivos , Brasil/epidemiologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/terapiaRESUMO
Replicative immortality is a key feature of cancer cells and it is maintained by the expression of telomerase, a promising target of novel therapies. Long-term telomerase inhibition can induce resistance, but the mechanisms underlying this process remain unclear. The Sonic hedgehog pathway (SHH) is an embryogenic pathway involved in tumorigenesis and modulates the transcription of telomerase. We evaluated the effects of long-term treatment of the telomerase inhibitor MST-312 in morphology, proliferation, resistance, and in the SHH pathway molecules expression levels in lung cancer cells. Cells treated for 12 weeks with MST-312 showed changes in morphology, such as spindle-shaped cells, and a shift in the distribution of F-ACTIN from cortical to diffuse. Treatment also significantly reduced cells' efficiency to form spheroids and their clonogenic potential, independently of the cell cycle and telomeric DNA content. Moreover, GLI-1 expression levels were significantly reduced after 12 weeks of MST-312 treatment, indicating a possible inhibition of this signaling axis in the SHH pathway, without hindering NANOG and OCT4 expression. Here, we described a novel implication of long-term treatment with MST-312 functionally and molecularly, shedding new light on the molecular mechanisms of this drug in vitro.
Assuntos
Neoplasias Pulmonares , Telomerase , Benzamidas , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Hedgehog/metabolismo , Humanos , Telomerase/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
Chronic myeloid leukemia (CML) is a rare disease in children. Different from that in adults, childhood CML involves transformative events occurring over a short time period. CML transformation to lymphoid blast phase (BP) is associated with copy number abnormalities, characteristic of BCR-ABL1 positive acute lymphoblastic leukemia, but not of CML in the chronic phase. Here, we present an unusual case of CML progressing to BP in a 1.6-year-old child, harboring IKZF1, PAX5, CDKN2A, and ETV6 deletions at diagnosis. It remains to be addressed whether distinct mechanisms might account for CML pathogenesis in early childhood.
Assuntos
Crise Blástica/genética , Deleção de Genes , Fator de Transcrição Ikaros/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Neoplasias/genética , Crise Blástica/patologia , Feminino , Humanos , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologiaRESUMO
Drug resistance represents a major issue in treating breast cancer, despite the identification of novel therapeutic strategies, biomarkers, and subgroups. We have previously identified the LQB-223, 11a-N-Tosyl-5-deoxi-pterocarpan, as a promising compound in sensitizing doxorubicin-resistant breast cancer cells, with little toxicity to non-neoplastic cells. Here, we investigated the mechanisms underlying LQB-223 antitumor effects in 2D and 3D models of breast cancer. MCF-7 and MDA-MB-231 cells had migration and motility profile assessed by wound-healing and phagokinetic track motility assays, respectively. Cytotoxicity in 3D conformation was evaluated by measuring spheroid size and performing acid phosphatase and gelatin migration assays. Protein expression was analyzed by immunoblotting. Our results show that LQB-223, but not doxorubicin treatment, suppressed the migratory and motility capacity of breast cancer cells. In 3D conformation, LQB-223 remarkably decreased cell viability, as well as reduced 3D culture size and migration. Mechanistically, LQB-223-mediated anticancer effects involved decreased proteins levels of XIAP, c-IAP1, and Mcl-1 chemoresistance-related proteins, but not survivin. Survivin knockdown partially potentiated LQB-223-induced cytotoxicity. Additionally, cell treatment with LQB-223 resulted in changes in the mRNA levels of epithelial-mesenchymal transition markers, suggesting that it might modulate cell plasticity. Our data demonstrate that LQB-223 impairs 3D culture growth and migration in 2D and 3D models of breast cancer exhibiting different phenotypes.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Pterocarpanos/farmacologia , Antineoplásicos/toxicidade , Movimento Celular , Proliferação de Células , Feminino , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Células MCF-7 , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Pterocarpanos/toxicidade , Esferoides Celulares/efeitos dos fármacos , Survivina/genética , Survivina/metabolismo , Células Tumorais Cultivadas , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismoRESUMO
We report an extremely rare case of a female child who presented the onset of primary myelofibrosis (PMF) harboring JAK2 (Janus Kinase 2 gene) mutation (JAK2V617F) when she was 15 months old. She was monitored over 25 years, a period in which she was treated with spleen radiotherapy and recombinant interferon α. She also underwent splenectomy when she was 13 years old, due to massive splenomegaly, anemia and various infection disease episodes. The longstanding evolution of the patient enabled us to verify that there were no complications related to post-splenectomy events and/or blast transformation. To the best of our knowledge, this is the first reported case of severe PMF with JAK2 mutation in a child. We provide evidence that a better quality of life and long survival in pediatric PMF may be provided by splenectomy.
Assuntos
Janus Quinase 2/genética , Mutação , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Feminino , Seguimentos , Humanos , Lactente , FenótipoRESUMO
Primary colorectal diffuse large B-cell lymphoma (DLBCL) is very rare colon malignancy. It is important to know the main demographic and clinical characteristics of these patients. We conducted a retrospective analysis of 18 patients diagnosed with primary colorectal DLBCL during a 17-year period at the National Cancer Institute of Brazil (INCA) between 2000 and 2018. Demographic characteristics, tumor localization, HIV status, lactate dehydrogenase (LDH) levels, treatment modality and follow-up status were obtained from medical records. Survival was estimated from the date of diagnosis until death. There were 11 male and seven female patients in our cohort, the median age at diagnosis was 59.5 years and four patients were HIV positive. Tumor was mainly localized in the right colon. Patients were treated with chemotherapy (CT) and/or surgical resection. Eleven patients died during a median follow-up of 59 months and the median survival time was 10 months. Six or more cycles of CT (HR=0.19; CI 95% 0.054-0.660, p = 0.009), LDH levels below 350 U/L (HR=0.229; CI 95% 0.060-0.876, p = 0.031) and surgical resection (HR=0.23; CI 95% 0.065-0.828, p = 0.030) were associated with reduced risk of death in univariate analysis. Patient's age and DLBCL right colon localization should be considered at diagnosis to distinguish between DLBCL and other diseases for differential diagnosis. Six cycles of CT, LDH levels below 350 U/L and surgical resection were associated with better survival. Our results are consistent with previous publications and address the importance of correct colorectal DLBCL diagnosis and treatment.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Linfoma Difuso de Grandes Células B , Humanos , Masculino , Feminino , Prognóstico , Estudos Retrospectivos , Centros de Atenção Terciária , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapiaRESUMO
Multidrug resistance (MDR) is considered a multifactorial phenotype which prevents a successful clinical cancer treatment. This phenomenon is mainly associated with mechanisms that include drug extrusion by P-glycoprotein (Pgp) overexpression and resistance to apoptosis derived by members of the inhibitor of apoptosis proteins (IAPs), such as XIAP. Studies have proposed the use of compounds that are able to inhibit or modulate Pgp function, with no changes in the physiological expression of this protein. Based on that, the present study aimed to evaluate the reversal of MDR phenotype through modulation of Pgp efflux pump activity in leukemia multidrug-resistant cells, using a low dose of cyclosporine A (CsA). We showed that modulation of Pgp activity by using CsA did not induce cytotoxic effects in leukemia cells, independently of Pgp expression. However, during the modulation condition, we could observe that vincristine-induced apoptosis was significant in resistant cells, which was also coupled with decreasing expression of the inhibitor of apoptosis protein XIAP. In summary, our data suggest that CsA is able to reversing MDR phenotype in vitro, inducing sensibility in multidrug-resistant cells with no alterations in Pgp expression. These findings contribute to our knowledge for the circumvention of MDR in cancer cells and could be helpful for new treatment approaches.
Assuntos
Apoptose/efeitos dos fármacos , Ciclosporina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Western Blotting , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Citometria de Fluxo , Humanos , Imunossupressores/farmacologia , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismoRESUMO
Centroblastic diffuse large B cell lymphoma (DLBCL) samples were analyzed by immunohistochemistry to evaluate the expression of p53, Bcl-2, Survivin, XIAP, and Ki-67. Survivin was the only protein which expression exhibited a trend for impact in progression-free (p = .077) and overall survival (p = .054). In the Mann-Whitney test, Survivin expression correlated with a negative overall survival (p = .045). These results appeared to be intimately related to Survivin cytoplasmic localization. Moreover, the anti-apoptotic proteins Bcl-2 and Survivin were less frequent in centroblastic DLBCL. Our results indicate that centroblastic DLBCL may be a disease with characteristic biology and clinical course and, therefore, specific prognostic factors.
Assuntos
Apoptose , Linfoma Difuso de Grandes Células B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Proteínas Inibidoras de Apoptose/análise , Antígeno Ki-67/análise , Linfoma Difuso de Grandes Células B/mortalidade , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/análise , Survivina , Proteína Supressora de Tumor p53/análise , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/análiseRESUMO
Detection of tumor necrosis factor-alpha (TNF-α) is usually performed in cell cultured medium or body fluids via measurement of its soluble extracellular form. However, depending on cellular condition, TNF-α might be transported through extracellular vesicles (EV) from donor cells to recipient cells. EV are small membrane-delimited structures (â¼50 nm to 10 µm) that are spontaneously released from multiple cell types. In cancer, EV arise as important mediators in intercellular communication, and their molecular content may support tumor progression. This chapter describes methods to identify protein content in EV released from the tumor cell cultures. Through this protocol, we show first how to purify EV from in vitro cell culture by using differential centrifugation technique and then we demonstrate how to identify both membrane and soluble TNF-α forms in EV by Western blotting.
Assuntos
Western Blotting , Vesículas Extracelulares/metabolismo , Neoplasias/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores , Western Blotting/métodos , Fracionamento Químico , Eletroforese em Gel de Poliacrilamida , HumanosRESUMO
Acute myeloid leukemia (AML) is one of the most common hematological neoplasia causing death worldwide. The long-term overall survival is unsatisfactory due to many factors including older age, genetic heterogeneity and molecular characteristics comprising additional mutations, and resistance to chemotherapeutic drugs. The expression of ABCB1/P-glycoprotein, ABCC1/MRP1, ABCG2/BCRP and LRP transporter proteins is considered the major reason for multidrug resistance (MDR) in AML, however conflicting data have been reported. Here, we review the main issues about drug transporter proteins in AML clinical scenario, and highlight the clinicopathological significance of MDR phenotype associated with ABCB1 polymorphisms and FLT3 mutation.
Assuntos
Leucemia Mieloide Aguda , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP , Idoso , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoRESUMO
Osteopontin (OPN) is upregulated in several types of tumor and has been associated with chemoresistance. However, the contribution of OPN splicing isoforms (OPNSIs) to chemoresistance requires further investigation. The present study aimed to evaluate the expression patterns of each tested OPNSI in cisplatin (CDDP)resistant ovarian carcinoma cell lines, focusing on the role of the OPNc isoform (OPNc) in drug resistance. ACRP ovarian cancer cells resistant to CDDP, as well as their parental cell line A2780, were used. Analyses of the transcriptional expression of OPNSIs, epithelialmesenchymal transition (EMT) markers and EMTrelated cytokines were performed using reverse transcriptionquantitative PCR. OPNc was silenced in ACRP cells using antiOPNc DNA oligomers and stably overexpressed by transfecting A2780 cells with a mammalian expression vector containing the full length OPNc cDNA. Functional assays were performed to determine cell proliferation, viability and colony formation. The results demonstrated that among the three tested OPNSIs, OPNc was the most upregulated transcript in the ACRP cells compared with the parental A2780 cells. In addition, the expression levels of Pglycoprotein multidrug transporter were upregulated in CDDPresistant ACRP cells compared with those in A2780 cells. OPNc knockdown sensitized ACRP cells to CDDP treatment and downregulated Pgp expression levels compared with those in the negative control group. Additionally, silencing of OPNc impaired cell proliferative and colony formation abilities, as well as reversed the expression levels of EMT markers and EMTrelated cytokines compared with those in the negative control cells. Notably, although stable OPNc overexpression resulted in increased A2780 cell proliferation, it notably increased CDDP sensitivity compared with that in the cells transfected with a control vector. These results suggested that OPNc silencing may represent a putative approach to sensitize resistant ovarian cancer cells to chemotherapeutic agents.
Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Osteopontina/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Processamento Alternativo , Linhagem Celular Tumoral , Plasticidade Celular/efeitos dos fármacos , Plasticidade Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cisplatino/uso terapêutico , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Osteopontina/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Acute myeloid leukemia (AML) is a complex hematological disorder characterized by blockage of differentiation and high proliferation rates of myeloid progenitors. Anthracycline and cytarabinebased therapy has remained the standard treatment for AML over the last four decades. Although this treatment strategy has increased survival rates, patients often develop resistance to these drugs. Despite efforts to understand the mechanisms underlying cytarabine resistance, there have been few advances in the field. The present study developed an in vitro AML cell line model resistant to cytarabine (HL60R), and identified chromosomal aberrations by karyotype evaluation and potential molecular mechanisms underlying chemoresistance. Cytarabine decreased cell viability, as determined by MTT assay, and induced cell death and cell cycle arrest in the parental HL60 cell line, as revealed by Annexin V/propidium iodide (PI) staining and PI DNA incorporation, respectively, whereas no change was observed in the HL60R cell line. In addition, the HL60R cell line exhibited a higher tumorigenic capacity in vivo compared with the parental cell line. Notably, no reduction in tumor volume was detected in mice treated with cytarabine and inoculated with HL60R cells. In addition, western blotting revealed that the protein expression levels of Bcl2, Xlinked inhibitor of apoptosis protein (XIAP) and cMyc were upregulated in HL60R cells compared with those in HL60 cells, along with predominant nuclear localization of the p50 and p65 subunits of NFκB in HL60R cells. Furthermore, the antitumor effect of LQB118 pterocarpanquinone was investigated; this compound induced apoptosis, a reduction in cell viability and a decrease in XIAP expression in cytarabineresistant cells. Taken together, these data indicated that acquired cytarabine resistance in AML was a multifactorial process, involving chromosomal aberrations, and differential expression of apoptosis and cell proliferation signaling pathways. Furthermore, LQB118 could be a potential alternative therapeutic approach to treat cytarabineresistant leukemia cells.
Assuntos
Aberrações Cromossômicas , Leucemia Mieloide Aguda/tratamento farmacológico , Naftoquinonas/farmacologia , Pterocarpanos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Citarabina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Naftoquinonas/uso terapêutico , Pterocarpanos/uso terapêutico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The ABCB1/MDR-1 gene, which encodes P-glycoprotein, is highly polymorphic. We analyzed 278 healthy Brazilian individuals through PCR-RFLP to identify ABCB1 variants and determine the genotypic and allelic frequencies. Genotypic frequencies for C1236T (rs1128503) were 0.31 for CC, 0.60 for CT and 0.09 for TT and allelic frequencies were 0.61 and 0.39 for C and T, respectively. Genotypic frequencies for C3435T (rs1045642) were 0.24 for CC, 0.61 for CT and 0.15 for TT, and allelic frequencies were 0.55 and 0.45 for C and T, respectively. Both variants showed significant differences in genotypic frequencies for both studied regions. Gender comparisons did not show significant differences between genotypes at both sites. Significant differences were observed between C1236C and C3435T and also C1236C and C3435C. Comparisons between ABCB1 polymorphisms in Brazilians and other populations show significant differences. The understanding of the effects of several drugs associated to these variants may help an individualized treatment in clinical practice.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adolescente , Adulto , Sequência de Bases , Brasil , Análise Mutacional de DNA , Etnicidade/genética , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Caracteres Sexuais , Adulto JovemRESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL oncoprotein, known to drive leukemogenesis by orchestrating multiple signaling pathways ultimately involved in cell survival. Despite successful response rates of CML patients to tyrosine kinase inhibitors (TKIs), resistance eventually arises due to BCR-ABL-dependent and independent mechanisms. Survivin is an inhibitor of apoptosis protein acting in the interface between apoptosis deregulation and cell cycle progression. In CML, high levels of survivin have been associated with late stages of disease and therapy resistance. In this review, we provide an overview of important aspects concerning survivin subcellular localization and expression pattern in CML patients and cell lines. Moreover, we highlight the relevance of molecular networks involving survivin for disease progression and treatment resistance. Finally, we discuss the mechanisms accounting for survivin overexpression, as well as novel therapeutic interventions that have been designed to counteract survivin-associated malignancy in CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Survivina/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Survivina/análise , Regulação para Cima/efeitos dos fármacosRESUMO
p53 protein induces cell cycle arrest, DNA repair, or apoptosis of damaged cells. Loss of wild-type p53 (wt-p53) function was shown to be associated with upregulation of survivin and resistance to therapy. Here we investigated the effects of DNA-damage agents in inducing apoptosis and cell cycle arrest, and modulation of survivin levels in two Burkitt's lymphoma (BL) cell lines with different p53 mutations. Our results showed that BL cell lines have variable response to DNA-damaging agents that cannot be correlated exclusively with p53 mutation or survivin expression suggesting that p53-independent transactivation may play a role in apoptosis induced by DNA-damaging agents.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Linfoma de Burkitt/patologia , Ciclo Celular , Dano ao DNA , Raios gama , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Cisplatino/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Doxorrubicina/farmacologia , Etoposídeo/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , Survivina , Fatores de Tempo , Proteína Supressora de Tumor p53/genéticaRESUMO
Forkhead box (FOX) transcription factors compose a large family of regulators of key biological processes within a cell. FOXK2 is a member of FOX family, whose biological functions remain relatively unexplored, despite its description in the early nineties. More recently, growing evidence has been pointing towards a role of FOXK2 in cancer, which is likely to be context-dependent and tumour-specific. Here, we provide an overview of important aspects concerning the mechanisms of regulation of FOXK2 expression and function, as well as its complex interactions at the chromatin level, which orchestrate how it differentially regulates the expression of gene targets in pathophysiology. Particularly, we explore the emerging functions of FOXK2 as a regulator of a broad range of cancer features, such as cell proliferation and survival, DNA damage, metabolism, migration, invasion and metastasis. Finally, we discuss the prognostic value of assessing FOXK2 expression in cancer patients and how it can be potentially targeted for future anticancer interventions.
RESUMO
Subsequent to the publication of the above article, the authors have realized that there were errors associated with Figs. 1c and 2b. In Fig. 1c, the authors noted that the same data were incorrectly presented for the 'Untreated cells" and 'DMSO' dotblot experiments. After having reexamined their source data, the authors were able to confirm that the data correctly shown for the 'Untreated cells' experiment had inadvertently been included in the Figure as the data for the 'DMSO' experiment. Additionally, in Fig. 2b, the authors noticed that the percentage of untreated cells with active caspase3 was missing (the label for the 'No antibody' experiment). Corrected versions of Figs. 1 (including the correct data for the 'DMSO' dot blot) and 2 (with the label now incorporated) are shown opposite. Note that these changes do not affect the results or the conclusions reported in this paper, and all the authors agree to this correction. The authors apologize to the Editor and to the readership of the Journal for any inconvenience caused. [the original article was published in International Journal of Oncology 45: 19491958, 2014; DOI: 10.3892/ijo.2014.2615].
RESUMO
Multidrug resistance in gliomas is the major challenges in the clinical setting. We investigated the expression of P-glycoprotein (Pgp) and multidrug resistance-related protein 1 (MRP1) in 50 gliomas using immunohistochemistry. Compared to Pgp, MRP1 positivity was observed in highest percentage of gliomas grade IV samples (p = 0.008). Unlike MRP1 expression observed in high-grade, gliomas grade II exhibited a greater number of Pgp positive samples as compared to grades III and IV (p = 0.026). Our results suggest that the difference between the histological grade gliomas regarding MRP1 and Pgp expression must have implications in the choice of chemotherapeutic protocols.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Glioma/patologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Adulto JovemRESUMO
PURPOSE: The anti-tumoral activity of bisphosphonates (BPs) has been reported in leukemia. In this study, we attempted to evaluate the apoptotic effects of the BPs pamidronate (PAM) and zoledronic acid (ZOL) in chronic lymphocytic leukemia (CLL) samples, and to correlate it with clinical parameters and multidrug resistance (MDR) phenotype (P-glycoprotein and multidrug resistance-related protein expression and/or their functional activity). RESULTS: Both BPs were able to induce apoptosis significantly. No correlation was observed between BP-induced apoptosis and clinical parameters or MDR phenotype. CONCLUSION: Our data suggest that concurrent or sequential administration of BPs with conventional chemotherapeutic drugs may have significant therapeutic potential for CLL patients.
Assuntos
Apoptose/efeitos dos fármacos , Difosfonatos/farmacologia , Genes MDR/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Citometria de Fluxo , Humanos , Imidazóis/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Pamidronato , Fenótipo , Ácido ZoledrônicoRESUMO
PURPOSE: Diffuse astrocytic tumors are the most frequently occurring primary central nervous system (CNS) tumors. Their histological sub-classification into diffuse astrocytoma (DA), anaplastic astrocytoma (AA) and glioblastoma (GB) is challenging and the available prognostic factors are limited to age and tumor subtype. Biomarkers that may improve the histological sub-classification and/or serve as prognostic factors are, therefore, urgently needed. The relationship between survivin and p53 in diffuse astrocytic tumor progression and survival is currently unclear. Here, we aimed to assess the relevance of these proteins in the accuracy of the histological sub-classification of these tumors and their respective treatment responses. METHODS: One hundred and thirty-three formalin-fixed paraffin-embedded diffuse astrocytic tumor samples were included. The tumor samples were histologically reviewed and subsequently assessed for p53 and survivin expression and the presence of the IDH R132H mutation by immunohistochemistry. p53 expression levels and survivin subcellular localization patterns were correlated with histological classification and clinical outcome. RESULTS: We found that age and histological subtype were the only features with a prognostic impact. In addition, we found that high p53 expression levels and a nuclear survivin localization correlated with the AA subtype, whereas cytoplasmic survivin localization correlated with the GB subtype. We also found that patients carrying tumors with a high cytoplasmic survivin expression, a high nuclear survivin expression or a high p53 expression, and who did not receive radiotherapy, exhibited poorer short-term and long-term overall survival rates. CONCLUSIONS: Our data suggest that subcellular survivin localization and p53 expression may be employed as valuable tools to improve the accuracy of the histological sub-classification of diffuse astrocytic tumors. Patients whose tumors overexpress these proteins may benefit from radiotherapy, irrespective age and/or histological classification.