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1.
Anticancer Res ; 39(7): 3745-3755, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262901

RESUMO

BACKGROUND/AIM: The study is directed to the effect of resveratrol on the redox-status and viability of leukemic and normal lymphocytes, as well as its ability to sensitize leukemic lymphocytes to anticancer drugs. MATERIALS AND METHODS: Cytotoxicity was analyzed by trypan blue staining, apoptosis - by Annexin V test, and oxidative stress - by the intracellular levels of reactive oxygen species (ROS) and protein-carbonyl products. RESULTS: Incubation of resveratrol in combination with the majority of anticancer drugs resulted in higher toxicity than resveratrol or drug alone. In the case of leukemic lymphocytes treated with barasertib and everolimus in the presence of resveratrol, synergistic cytotoxicity was accompanied by strong induction of apoptosis, increased levels of hydroperoxides and insignificant changes in protein-carbonyl products. None of these parameters changed in normal lymphocytes. CONCLUSION: Resveratrol is a promising supplementary compound for anticancer therapy, that may allow reduction of the therapeutic doses of barasertib and everolimus, minimizing their side-effects.


Assuntos
Antineoplásicos/farmacologia , Leucemia/metabolismo , Linfócitos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Leucemia/tratamento farmacológico , Linfócitos/metabolismo , Oxirredução
2.
Gan To Kagaku Ryoho ; 46(4): 713-716, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164513

RESUMO

An 83-year-old woman received 8 courses of chemotherapy(mogamulizumab)for adult T cell leukemia in the hematolo- gy department of our hospital, after which she achieved complete remission and was followed up with chemotherapy(VP/ MST: sobuzoxane/etoposide)as an outpatient. Later, diarrheal symptoms appeared, and detailed examinations led to a diagnosis of cancer of the ascending colon. Although no distal metastasis was found, breast cancer was also revealed in the C area of the right breast. The general status of the patient was favorable; thus, right pectoral muscle-conserving mastectomy and concomitant sentinel lymph node biopsy were performed through laparoscope-assisted extended right hemicolectomy. The postoperative course was favorable, and she was discharged on hospital day 7. The excised tumors were pathologically diagnosed as stageⅠ breast cancer and stage Ⅲa colorectal cancer. Chemotherapy(VP/MST)was administered without adjuvant chemotherapy. Presently, 18 months after surgery, complete remission of adult T cell leukemia has been maintained, without metastasis and recurrence of cancer of the ascending colon and breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias do Colo , Laparoscopia , Leucemia , Neoplasias Primárias Múltiplas , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Colo Ascendente , Neoplasias do Colo/diagnóstico , Feminino , Humanos , Leucemia/tratamento farmacológico , Mastectomia , Neoplasias Primárias Múltiplas/diagnóstico
3.
Chem Biol Interact ; 306: 29-38, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954463

RESUMO

Resveratrol, found in variety of plants, is a natural stilbene structure polyphenol. It has various pharmacological effects, such as antioxidation, anti-aging, anti-inflammation, anti-cancer, antiobesity, anti-diabetes, cardioprotection, neuroprotection. Recently, anti-leukemia activities of resveratrol has been studied extensively via its effects on a variety of biological processes involving cell proliferation, apoptosis, autophagy. Current treatments of leukemia mainly rely on intensive chemotherapy or hematopoietic stem cell transplantation, however, these treatments are still with poor survival and high treatment-related mortality. Therefore, it is extremely needed to find relatively non-toxic medicines with minimal side effects but sufficient therapeutic efficacy. Resveratrol is one such potential candidate owing to its reported anti-leukemia effect. In this review, we summarized resveratrol's discovery, sources and isolation methods, administration methods, effects in different types of leukemia, pharmacokinetics and toxicities, aiming to exploit resveratrol as a potential drug candidate for anti-leukemia.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas , Leucemia/tratamento farmacológico , Resveratrol/farmacologia , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia/patologia , Resveratrol/efeitos adversos , Resveratrol/química
4.
Biomed Res Int ; 2019: 4860268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31032347

RESUMO

Hematological malignancies including leukemia and lymphoma can severely impact human health. With the current therapies combined with chemotherapy, stem cell transplantation, radiotherapy, and immunotherapy, the prognosis of hematologic malignancies improved significantly. However, most hematological malignancies are still incurable. Therefore, research for novel treatment options was continuing with the natural product as one source. Icaritin is a compound extracted from a traditional Chinese herb, Epimedium Genus, and demonstrated an antitumor effect in various neoplasms including hematological malignancies such as leukemia, lymphoma, and multiple myeloma. In hematological malignancies, icaritin showed multiple cytotoxic effects to induce apoptosis, arrest the cell cycle, inhibit proliferation, promote differentiation, restrict metastasis and infiltration, and suppress the oncogenic virus. The proved underlying mechanisms of the cytotoxic effects of icaritin are different in various cell types of hematological malignancies but associated with the critical cell signal pathway, including PI3K/Akt, JAK/STAT3, and MAPK/ERK/JNK. Although the primary target of icaritin is still unspecified, the existing evidence indicates that icaritin is a potential novel therapeutic agent for neoplasms as with hematological malignancies. Here, in the field of hematology, we reviewed the reported activity of icaritin in hematologic malignancies and the underlying mechanisms and recognized icaritin as a candidate for therapy of hematological malignancies.


Assuntos
Produtos Biológicos/uso terapêutico , Epimedium/química , Flavonoides/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Flavonoides/química , Humanos , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Medicina Tradicional Chinesa , Mieloma Múltiplo/tratamento farmacológico
5.
Cancer Commun (Lond) ; 39(1): 17, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947742

RESUMO

BACKGROUND: Internal tandem duplications (ITD) within the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3) represent a poor prognostic indicator in acute myeloid leukemia (AML). Therapeutic benefits of tyrosine kinase inhibitors, such as sorafenib, are limited due to the emergence of drug resistance. While investigations have been conducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor, a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created. This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor. METHODS: We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations, namely the murine BaF3/ITD-R and the human MV4-11-R cell lines. We performed a global untargeted metabolomics and stable isotope-labeling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance. RESULTS: The resistant cells displayed fundamentally rewired metabolic profiles, characterized by a higher demand for glucose, accompanied by a reduction in glucose flux into the pentose phosphate pathway (PPP); and by an increase in oxidative stress, accompanied by an enhanced glutathione synthesis. We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation. A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells. Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency (G6PD) in the oxidative arm and transketolase (TKT) in the non-oxidative arm. In addition, we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leukemia cells, which was accompanied by decreased cell proliferation and an enhanced antioxidant response. CONCLUSIONS: Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Leucemia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Apoptose/efeitos dos fármacos , Isótopos de Carbono , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glucose/metabolismo , Glutationa/metabolismo , Humanos , Leucemia/tratamento farmacológico , Leucemia/genética , Espectrometria de Massas , Metabolômica , Camundongos , NADP/metabolismo , Oxirredução , Via de Pentose Fosfato/efeitos dos fármacos
6.
ACS Appl Mater Interfaces ; 11(17): 16065-16074, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30990996

RESUMO

In this work, a nanohybrid-based imprinted polymer consisting of N-doped hollow carbon nanospheres and palladium is reported for the electroanalysis of ultratrace level of anticancer drug, 6-mercaptopurine, used in the treatment of leukemia. For this, N-doped carbon nanospheres decorated with palladium were first developed, and subsequently, a molecular imprinted polymer layer was grown onto their surfaces. The so-produced silica-embedded nanocomposite was made hollow by etching silica moieties with hydrofluoric acid. Finally, the whole system was doped on an ionic-liquid-modified pencil graphite electrode. The underlying synergistic effect of hollow carbon nanosphere-supported palladium nanoparticles inculcated electrocatalytic action. Notably, all rebinding sites in solid core-shells were confined within the shell, which hampers the effective diffusion of template. However, in this work, an effective diffusion of template across the hollow structure of inner and outer surfaces was observed. Consequently, this rendered approximately 2-fold heterogeneous rate constant as compared to the solid core-shell-based sensor. Differential pulse voltammetric transduction was used for ultratrace detection of 6-mercaptopurine through anodic stripping method. The hollow imprinted sensor revealed a linear dependence of current with concentration range 0.80-70.748 ng mL-1. The limits of detection 0.11-0.22 ng mL-1 were realized in water, human blood plasma, urine, and pharmaceuticals. Thus, the proposed sensor demonstrated an attractive sensitivity reproducibility, as well as endurance requisite for the treatment of leukemia patients.


Assuntos
Antineoplásicos/análise , Técnicas Eletroquímicas/métodos , Mercaptopurina/análise , Impressão Molecular , Nanocompostos/química , Nanosferas , Polímeros/química , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Antineoplásicos/urina , Carbono/química , Eletrodos , Humanos , Leucemia/tratamento farmacológico , Limite de Detecção , Mercaptopurina/sangue , Mercaptopurina/uso terapêutico , Nitrogênio/química , Paládio/química , Preparações Farmacêuticas/análise , Reprodutibilidade dos Testes
7.
Crit Rev Oncol Hematol ; 136: 56-63, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30878129

RESUMO

Bruton tyrosine kinase signaling (BTK) is critical step for B-cell development and immunoglobulin synthesis. Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib has been approved by FDA for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, marginal zone lymphoma and chronic graft-versus-host disease in allogeneic stem cell transplantation. Ibrutinib is generally well tolerated drug with rapid and durable responses but has some side events. The most common side effects are diarrhea, upper respiratory tract infection, bleeding, fatigue and cardiac side effects. These events are generally mild (grade I-II). However atrial fibrillation (AF) and bleeding are important and may be grade III or higher side effects require strict monitoring. Here side effects of ibrutinib have been summarized and important considerations in the management of these adverse events have been reviewed.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/terapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/terapia , Humanos , Incidência , Leucemia/tratamento farmacológico , Leucemia/epidemiologia , Linfoma/tratamento farmacológico , Linfoma/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
8.
Chem Biol Interact ; 304: 131-138, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30890322

RESUMO

Non-apoptotic cell-death induction is a potential strategy for cancer treatment. Cytoplasmic vacuolation-associated cell death represents a novel type of non-apoptotic cell-death. Here, we showed that isobavachalcone (IBC), a naturally occurring chalcone compound, selectively induced cell death with massive cytoplasmic vacuolation in some leukemic cells but not in normal peripheral blood cells. Although the IBC-induced cell death displayed certain apoptotic changes, the caspase inhibitor Z-VAD-FMK did not significantly suppress IBC-induced cell death. IBC-induced vacuoles are acidic in nature, as revealed by neutral red staining. However, these vacuoles could not be labeled by lysosome or mitochondrial trackers. Moreover, the knockdown of several autophagy-related genes, such as LC3, Beclin-1, and ATG7, did not inhibit IBC-induced vacuolation. Transmission electron microscope examination revealed that these vacuoles mainly derived from the endosome. Surprisingly, Vacuolar-type H + -ATPase inhibitors, weak bases, such as chloroquine and AKT inhibitors, markedly abrogated vacuolization but enhance IBC-induced cell death, suggesting that IBC-induced vacuolation and cell death go into different direction and the vacuolization is a protective action rather than a part of the death mechanism. In conclusion, by using IBC as a chemical probe, we provide new characteristics of methuosis-like cell death. Inducing methuosis-like cell death may represent a novel strategy to combat leukemia.


Assuntos
Antineoplásicos/farmacologia , Chalconas/farmacologia , Leucemia/tratamento farmacológico , Leucemia/patologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos
9.
Pharmacol Rep ; 71(2): 248-256, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30822618

RESUMO

BACKGROUND: Sodium dichloroacetate (DCA) is an agent with anticancer properties against solid tumors. DCA also seems to have antileukemic activity. In order to affirm it we investigate the effect of DCA on cell viability and apoptotic gene expression profiles in leukemia cell lines: CEM/C1, CCRF/CEM, HL-60, HL-60/MX2. METHODS: Cell viability was assessed by trypan blue staining. The expression of 93 genes involved in the process of apoptosis was determined by real-time PCR method using Taqman Low Density Array (TLDA). RESULTS: CEM/C1, CCRF/CEM, HL-60, HL-60/MX2 cells were exposed to DCA for 24 h. The sensitivity of each cell line to DCA is different and depends on the concentration. CEM/C1 was the most sensitive with an half-maximal inhibitory concentration (IC50) value of 30 mM, while HL-60/MX2 was the most resistant with an IC50 value of 75 mM. Exposure of leukemia cells to DCA causes differences in gene expression profiles which cannot indicate that any particular pathway of apoptosis is initiated. However, the presence of 388 statistically significant correlations between expression pattern of gens was determined. CONCLUSION: We showed that DCA causes a decrease in viability of leukemia cells. The decline depends on DCA concentration. The induction of any particular apoptosis pathway is not shown in cells after DCA treatment. For that reason, studies on the molecular mechanism of cell death after exposure to DCA should be continued.


Assuntos
Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácido Dicloroacético/farmacologia , Leucemia/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ácido Dicloroacético/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Concentração Inibidora 50 , Leucemia/patologia , Reação em Cadeia da Polimerase em Tempo Real
11.
Ann Hematol ; 98(5): 1209-1216, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30824955

RESUMO

Febrile neutropenia is often observed in patients with hematologic malignancies, especially in those with acute leukemia. Meropenem has potent and broad antibacterial activity against gram-positive and gram-negative bacteria, and is recommended as first-line empiric therapy for febrile neutropenia. In contrast, the safety and efficacy of doripenem in patients with febrile neutropenia and hematologic malignancies is limited. In this randomized, prospective, cooperative, open-label trial, we compared doripenem (1.0 g every 8 h) to meropenem (1.0 g every 8 h) as first-line empiric antibacterial treatment of febrile neutropenia. To evaluate efficacy and safety, 133 hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed febrile neutropenia during or after chemotherapy, were randomized to each drug. Resolution of fever within 3 to 5 days without treatment modification (i.e., the primary endpoint) did not significantly differ between the doripenem and meropenem groups (60.0% vs. 45.6%, respectively; P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the doripenem group than in the meropenem group (78.4% vs. 60.2%, respectively; P = 0.037). Similar rates of adverse events (grades 1-2) were observed in both groups. Thus, we conclude that both drugs are safe and well-tolerated for the treatment of febrile neutropenia in patients with acute leukemia or high-risk myelodysplastic syndrome, and that the clinical efficacy of doripenem is noninferior to that of meropenem. UMIN Clinical Trial Registry number: 000006124.


Assuntos
Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Doripenem/administração & dosagem , Leucemia/tratamento farmacológico , Meropeném/administração & dosagem , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doripenem/efeitos adversos , Feminino , Febre/tratamento farmacológico , Humanos , Masculino , Meropeném/efeitos adversos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Estudos Prospectivos
12.
Hematology ; 24(1): 362-368, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30880638

RESUMO

OBJECTIVES: The incidence of febrile neutropenia (FN) in acute leukemia patients following induction or consolidation chemotherapy is high. Several clinical practice guidelines recommend the use of a fluoroquinolone prophylaxis to prevent bacterial infection in patients being prone to prolonged profound neutropenia. METHODS: This systematic review and meta-analysis aimed to investigate the efficacy and complications of levofloxacin as a prophylaxis for FN patients following chemotherapy for acute leukemia. Two databases from MEDLINE and EMBASE were searched for published studies indexed before 10 July 2018. RESULTS: A total of 862 acute leukemia patients were included, with 356 in the levofloxacin prophylaxis arm and 506 in the no-prophylaxis arm. Patients receiving levofloxacin had a significantly lower FN rate than patients who did not receive the antibiotic prophylaxis (odds ratio [OR]: 0.43, 95% confidence interval [CI]: 0.32-0.58, p < .00001, I2 = 0%). The rate of microbiologically documented infection in the no-prophylaxis group was higher than that for the levofloxacin prophylaxis group (OR: 0.45, 95% CI: 0.34-0.60, p < .00001, I2 = 0%). The bacteremia rate in the levofloxacin prophylaxis group was significantly lower than that for the no-prophylaxis group (OR: 0.45, 95% CI: 0.31-0.66, p < .00001, I2 = 0%). However, the mortality rates of the two groups were quite similar between the two groups (OR: 0.67, 95% CI: 0.34-1.33, p = .26, I2 = 0%). CONCLUSIONS: Although the levofloxacin prophylaxis for the acute leukemia patients receiving intensive chemotherapy showed advantages for infectious complications, it did not affect mortality.


Assuntos
Bacteriemia/prevenção & controle , Neutropenia Febril/tratamento farmacológico , Leucemia/tratamento farmacológico , Levofloxacino/uso terapêutico , Doença Aguda , Bacteriemia/induzido quimicamente , Neutropenia Febril/induzido quimicamente , Feminino , Humanos , Masculino
13.
BMJ Case Rep ; 12(1)2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30700454

RESUMO

We describe three cases of pulmonary aspergillosis (PA) in three patients without traditional risk factors for invasive aspergillosis infection, such as prolonged neutropenia or high dose systemic corticosteroid therapy. All three patients developed PA while taking tyrosine kinase inhibitors (TKI) and sustained greater clinical improvement once TKI were withdrawn. Our case series supports the theory TKI treatment can increase susceptibility to PA without causing neutropenia. Recognition that TKI treatment may predispose to invasive aspergillosis will allow for rapid recognition of affected patients and more effective management of future cases.


Assuntos
Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Tumores do Estroma Gastrointestinal/complicações , Infecções Fúngicas Invasivas/tratamento farmacológico , Leucemia/complicações , Inibidores de Proteínas Quinases/farmacologia , Idoso , Evolução Fatal , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Leucemia/tratamento farmacológico , Pulmão/diagnóstico por imagem , Pulmão/microbiologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Mol Omics ; 15(2): 117-129, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30720033

RESUMO

Protein isoforms are structurally similar proteins produced by alternative splicing of a single gene or genes from the same family. Isoforms of a protein can perform the same, similar, or even opposite biological functions. A previous study identified principal isoforms of proteins based on the extent of interactions per isoform in a functional relationship network, focusing on data from normal tissues. Additionally, the expression levels of specific isoforms of various genes associated with tumorigenesis and prognosis are frequently altered in tumors compared with those in normal tissues. In this study, we aimed to identify higher degree isoforms (HDIs) of multi-isoform genes (MIGs) in cancer by applying a meta-analytical framework to calculate co-expression between each pair of isoforms in two large datasets of RNA-seq profiles from breast cancer, lung cancer, leukemia, and colon cancer cell lines. Then, we compared HDIs with isoforms identified by proteomic data and prognostic and predictive evidence in various cancers. In addition, we separately analyzed the associations between HDIs and non-HDIs (nHDIs) of the same genes according to transcript expression and drug responses in various cancer type cell lines. Collectively, these results indicated the complex properties of HDIs per gene identified by cancer type-based isoform-isoform co-expression networks and showed the potential of HDIs as novel therapeutic targets for cancer treatment.


Assuntos
Processamento Alternativo/genética , Neoplasias da Mama/genética , Neoplasias do Colo/genética , Leucemia/genética , Neoplasias Pulmonares/genética , Isoformas de Proteínas/genética , Biomarcadores Farmacológicos/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/tratamento farmacológico , Feminino , Humanos , Leucemia/diagnóstico , Leucemia/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Neoplasias/genética , Prognóstico , Proteômica , RNA Neoplásico/genética
15.
Cell Mol Life Sci ; 76(13): 2489-2497, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30715556

RESUMO

Adipose tissue (AT) is an extramedullary reservoir of normal hematopoietic stem cells (HSCs). Adipocytes prevent the production of normal HSCs via secretion of inflammatory factors, and adipocyte-derived free fatty acids may contribute to the development and progression of leukemia via providing energy for leukemic cells. In addition, adipocytes are able to metabolize and inactivate therapeutic agents, reducing the concentrations of active drugs in adipocyte-rich microenvironments. The aim of this study was to detect the role of adipocytes in the progression and treatment of leukemia. Relevant literature was identified through a PubMed search (2000-2018) of English-language papers using the following terms: leukemia, adipocyte, leukemic stem cell, chemotherapy, and bone marrow. Findings suggest the striking interplay between leukemic cells and adipocytes to create a unique microenvironment supporting the metabolic demands and survival of leukemic cells. Based on these findings, targeting lipid metabolism of leukemic cells and adipocytes in combination with standard therapeutic agents might present novel treatment options.


Assuntos
Adipócitos/patologia , Antineoplásicos/farmacologia , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos , Leucemia/patologia , Microambiente Tumoral/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo
16.
Methods Mol Biol ; 1956: 351-362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30779044

RESUMO

Response to anticancer agents is often restricted to subsets of patients. The recognition of factors underlying this heterogeneity and the identification of biomarkers associated with response to drugs would greatly improve the efficacy of drug treatment. Platforms that can comprehensively map drug response in high-throughput ex vivo provide a unique tool to identify associated biomarkers and provide hypotheses for mechanisms underlying variable response. Such screens can be performed on cell lines and short-term cultures of primary cells to take advantage of the respective models' strength, which include, e.g., the ability to silence genes in cell lines and the "indefinite" supply of primary cells where clonal selection can be avoided. Cohorts of such samples represent the natural diversity of cancers, including rarer mutations and combinatorial patterns of mutations.We here summarize a simple and scalable method for the measurement of viability after drug exposure based on ATP measurements as a surrogate for viability, which we use to measure and understand drug response in cell lines and primary cells.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Biomarcadores Farmacológicos/análise , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/economia , Ensaios de Triagem em Larga Escala/economia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Células Tumorais Cultivadas
17.
Bratisl Lek Listy ; 120(1): 15-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30685987

RESUMO

The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". A number of therapeutic approaches are available for cancer treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes. These include methods for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchins, 1988), and bone marrow transplantation for leukemia (Thomas, 1990). Many scientists engaged in intense basic research and uncovered fundamental mechanisms regulating immunity and also showed how the immune system can recognize cancer cells. T-cells were shown to have receptors that bind to structures recognized as non-self and such interactions trigger the immune system to engage in defense. However, additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Many scientists contributed to this important basic research and identified other proteins that function as brakes on the T-cells, inhibiting immune activation. This intricate balance between the accelerators and inhibitors is essential for a tight control. New strategy was developed into a therapy for humans. Promising results soon emerged from several groups, and in 2010 an important clinical study showed striking effects in patients with advanced melanoma. In several patients, signs of remaining cancer disappeared. The results were dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer, a condition that had previously been considered essentially untreatable. Such remarkable results had never been seen in this patient group before (Fig. 2, Ref. 12). Keywords: Nobel Prize, physiology, medicine, immune system, inhibition, cancer therapy.


Assuntos
Imunoterapia , Leucemia , Melanoma , Neoplasias da Próstata , Humanos , Leucemia/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Prêmio Nobel , Neoplasias da Próstata/tratamento farmacológico
18.
Yonsei Med J ; 60(2): 182-190, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30666840

RESUMO

PURPOSE: This study aimed to investigate the effects of PIK3CA on the sensitivity of acute B lymphocytic leukemia cells (Nalm-6 cells) to chemotherapy drugs. MATERIALS AND METHODS: Children's normal B lymphocytes and Nalm-6 cells were cultured. Nalm-6 cells were transfected with PIK3CA siRNA (siPIK3CA group) or its negative control (PIK3CA-Control group). Normal Nalm-6 cells were named Mock group. Nalm-6 cells transfected by PIK3CA siRNA were treated with Akt inhibitor (siPIK3CA+Akti-1/2 group). mRNA and protein expression was detected by qRT-PCR and Western blot. Proliferation and sensitivity to chemotherapeutic drugs was detected by MTT assay. Cell cycle and apoptosis was explored by low cytometry. Transwell assay was performed to test invasion. RESULTS: PIK3CA mRNA (p=0.008) and protein (p=0.006) expression was higher in Nalm-6 cells than that in normal B lymphocytes. Compared with the Mock group and PIK3CA-Control group, Nalm-6 cells of the siPIK3CA group had lower OD495 values (all p<0.05) and invasion cell numbers (p=0.03 and p=0.025), as well as a higher proportion of G0/G1 phase cells (p=0.020 and p=0.022), percentage of apoptosis (p=0.016 and p=0.022), and inhibition rate (all p<0.05). pAkt expression in the siPIK3CA group (p=0.026 and p=0.031) and siPIK3CA+Akti-1/2 group (p=0.019 and p=0.023) was lower than that in the Mock group. CONCLUSION: PIK3CA silencing inhibited Nalm-6 cell proliferation and invasion, and promoted their apoptosis and sensitivity to chemotherapeutic drugs, potentially through regulation of the PI3K/AKT signaling pathway.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Inativação Gênica , Leucemia/tratamento farmacológico , Leucemia/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Criança , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia/genética , Leucemia/patologia , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
19.
Eur J Med Chem ; 164: 304-316, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605829

RESUMO

BTK and PI3Kδ play crucial roles in the progression of leukemia, and studies confirmed that the dual inhibition against BTK and PI3Kδ could provide superior anticancer agents to single targeted therapies. Herein, a new series of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives were optimized based on a BTK/PI3Kδ inhibitor 2 designed by our group. Biological studies clarified that compound 6f exhibited the most potent inhibitory activity (BTK: IC50 = 74 nM; PI3Kδ: IC50 = 170 nM) and better selectivity than 2. Moreover, 6f significantly inhibited the proliferation of Raji and Ramos cells with IC50 values of 2.1 µM and 2.65 µM respectively by blocking BTK and PI3K signaling pathways. In brief, 6f possessed of the potency for further optimization as an anti-leukemic drug by inhibiting BTK and PI3Kδ kinase.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/química , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Piridonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucemia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridonas/química
20.
Int J Nanomedicine ; 14: 543-556, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30666113

RESUMO

Purpose: Nanoparticle (NP)-based drug delivery approaches have tremendous potential for enhancing treatment efficacy and decreasing doses of chemotherapeutics. Idarubicin (IDA) is one of the most common chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). However, severe side effects and drug resistance markedly limit the application of IDA. Methods: In this study, we encapsulated IDA in polymeric NPs and validated their antileukemia activity in vitro and in vivo. Results: NPs with an average diameter of 84 nm was assembled from a methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) (mPEG-PLGA). After loading of IDA, IDA-loaded mPEG-PLGA NPs (IDA/mPEG-PLGA NPs) were formed. The in vitro release data showed that the IDA/mPEG-PLGA NPs have excellent sustained release property. IDA/mPEG-PLGA NPs had exhibited the lower IC50 than pure IDA. Moreover, IDA/mPEG-PLGA NPs in the same concentration substantially induced apoptosis than did pure IDA. Most importantly, IDA/MPEG-PLGA NPs significantly decreased the infiltration of leukemia blasts and improved the overall survival of MLL-AF9-induced murine leukemia compared with free IDA. However, the blank NPs were nontoxic to normal cultured cells in vitro, suggesting that NPs were the safe carrier. Conclusion: Our data suggest that IDA/mPEG-PLGA NPs might be a suitable carrier to encapsulate IDA. Low dose of IDA/mPEG-PLGA NPs can be used as a conventional dosage for antileukemia therapy to reduce side effect and improve survival.


Assuntos
Sistemas de Liberação de Medicamentos , Idarubicina/farmacologia , Leucemia/tratamento farmacológico , Nanopartículas/administração & dosagem , Poliésteres/química , Polietilenoglicóis/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Transporte Biológico , Humanos , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Leucemia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Distribuição Tecidual , Células Tumorais Cultivadas
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