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1.
Expert Opin Drug Metab Toxicol ; 19(9): 617-633, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37714711

RESUMO

INTRODUCTION: Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. AREAS COVERED: This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English. RESULTS/CONCLUSION: PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies, including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. EXPERT OPINION: The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.


Assuntos
Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Inibidores de Fosfoinositídeo-3 Quinase , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/uso terapêutico , Antineoplásicos/efeitos adversos , Fosfatidilinositol 3-Quinase/uso terapêutico
2.
J Pers Med ; 13(9)2023 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-37763082

RESUMO

Melatonin (MLT), a pineal gland hormone, not only regulates circadian and seasonal rhythms, but also plays an important role in many aspects of human physiology and pathophysiology. MLT is of great interest as a natural substance with anti-cancer activities. The aim of this study was to assess the cytotoxicity and apoptosis of MLT, used alone or in combination with one of the most active anti-cancer drugs, doxorubicin (DOX), and a well-known anti-inflammatory drug, dexamethasone (DEX), on a diffuse large B-cell lymphoma (DLBCL)-derived cell line. The cytotoxicity and cell cycle distribution were measured using propidium iodide staining, while apoptosis was assessed using the annexin-V binding method. Additionally, to elucidate the mechanisms of action, caspase-3, -8, and -9 and a decline in the mitochondrial potential were determined using flow cytometry. MLT inhibited cell viability as well as induced apoptosis and cell cycle arrest at the G0/G1 phase. The pro-apoptotic effect was exerted through both the mitochondrial and caspase-dependent pathways. Furthermore, we observed increased cytotoxic and pro-apoptotic activity as well as the modulation of the cell cycle after the combination of MLT with DOX, DEX, or a combination of DOX + DEX, compared with both drugs or MLT used alone. Our findings confirm that MLT is a promising in vitro anti-tumour agent that requires further evaluation when used with other drugs active against DLBCL.

3.
Blood ; 138(26): 2753-2767, 2021 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-34724563

RESUMO

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Europa (Continente) , Citometria de Fluxo/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leucemia Mieloide Aguda/genética , Neoplasia Residual/genética , Prognóstico
4.
Arch Med Sci ; 17(3): 700-707, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025840

RESUMO

INTRODUCTION: The misbalance between a family of inhibitor of apoptosis proteins (IAP), regulated by the nuclear factor kappa B (NF-κB) and their natural antagonist second mitochondrial-derived activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO) are important to biology of acute myeloid leukemia (AML). MATERIAL AND METHODS: The aim of the study was to assess NF-κB and Smac/DIABLO proteins expression in blasts of 109 newly diagnosed AML patients using the multicolor flow cytometry and evaluate their influence on AML patients outcome. RESULTS: Expression of NF-κB and of Smac/DIABLO proteins were found in 95% and 98% of the patients, respectively. A negative correlation between Smac/DIABLO and NF-κB was observed. Age < 60 years old as well as higher Smac/DIABLO expression were associated with a higher probability of complete response achievement in the multivariate analysis. Longer overall survival (OS) in the univariate and multivariate analyses was influenced by age < 60 years old, a favorable or intermediate-risk karyotype and high Smac/DIABLO expression. Additionally, in the survival analysis of the subgroups, the patients aged < 60 years old, with high Smac/DIABLO expression, lower NF-κB expression and < 50% of bone marrow blasts who were treated with standard treatment had better OS. CONCLUSIONS: Lower NF-κB and higher Smac/DIABLO expression may influence AML patients outcome.

5.
Tumour Biol ; 39(3): 1010428317694551, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28349818

RESUMO

The SMAD proteins are responsible for transducing signals from activated transforming growth factor-beta. This is the first study assessing the expression of SMAD-1/8, SMAD-2/3, SMAD-4, and SMAD-7 in chronic lymphocytic leukemia cells with regard to their clinical significance and potential prognostic value. Overexpression of SMAD-1/8 was observed in 160 chronic lymphocytic leukemia patients compared to 42 healthy volunteers (p = 0.023) and was associated with a more progressive course of the disease (p = 0.016). Moreover, the high expression of SMAD-1/8 correlated with other, well-established prognostic factors, including clinical stage (p = 0.010) and lymphocyte doubling time (p = 0.021). The expression of SMAD-4 was lower in chronic lymphocytic leukemia patients compared with the control group (p = 0.003). Importantly, lower SMAD-4 levels correlated with longer progression-free survival (p = 0.009), progressive course of the disease (p = 0.002), advanced clinical stage (p = 0.0004), elevated beta-2-microglobulin and lactate dehydrogenase levels (p < 0.05), shorter lymphocyte doubling time (p = 0.009), and CD38 antigen expression (p = 0.039). In addition, lower SMAD-4 expression correlated with lower apoptotic index (p = 0.0007) and lower expression of receptors for vascular endothelial growth factors VEGFR-1 and VEGFR-2. A significant association was found between the low expression of inhibitory protein SMAD-7 and both zeta-chain-associated protein kinase 70-negative cells (p = 0.04) and lower apoptotic index (p = 0.004). No differences were observed in SMAD-2/3 expression. In conclusion, our results demonstrate a significant correlation between greater SMAD-1/8 and lower SMAD-4 expression in chronic lymphocytic leukemia cells, as well as more progressive outcome and poor prognosis. These data provide supporting evidence that the expression of SMAD proteins plays an important role in disease development and may be considered as a novel, biologic prognostic factor in this disease.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Proteína Smad1/biossíntese , Proteína Smad2/biossíntese , Proteína Smad4/biossíntese , Proteína Smad7/biossíntese , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Intervalo Livre de Doença , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteína Smad1/genética , Proteína Smad2/genética , Proteína Smad4/genética , Proteína Smad7/genética , Fator de Crescimento Transformador beta/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Proteína-Tirosina Quinase ZAP-70/biossíntese
6.
Molecules ; 21(8)2016 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-27483232

RESUMO

Honokiol and triphenylmethanes are small molecules with anti-tumor properties. Recently, we synthesized new honokiol analogues (HAs) that possess common features of both groups. We assessed the anti-tumor effectiveness of HAs in B-cell leukemia/lymphoma cells, namely in chronic lymphocytic leukemia (CLL) cells ex vivo and in pre-B-cell acute lymphoblastic leukemia (Nalm-6), Burkitt lymphoma (BL; Raji), diffuse large B-cell lymphoma (DLBCL; Toledo) and multiple myeloma (MM; RPMI 8226) cell lines. Four of these compounds appeared to be significantly active against the majority of cells examined, with no significant impact on healthy lymphocytes. These active HAs induced caspase-dependent apoptosis, causing significant deregulation of several apoptosis-regulating proteins. Overall, these compounds downregulated Bcl-2 and XIAP and upregulated Bax, Bak and survivin proteins. In conclusion, some of the HAs are potent tumor-selective inducers of apoptosis in ex vivo CLL and in BL, DLBCL and MM cells in vitro. Further preclinical studies of these agents are recommended.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Leucemia/metabolismo , Lignanas/farmacologia , Linfoma/metabolismo , Mieloma Múltiplo/metabolismo , Compostos de Tritil/farmacologia , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico
7.
Expert Opin Drug Discov ; 11(11): 1033-1045, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27569454

RESUMO

INTRODUCTION: A new generation of anticancer agents called target drugs has been recently developed for the treatment of non-Hodgkin lymphomas. Current recovery rates in these diseases are up to 70% with immunotherapy based on the anti-CD20 monoclonal antibody combined with standard chemotherapeutics. However, there are still refractory or relapsed patients. Recently, several novel anti-lymphoma agents have been developed. Choosing the most effective personalized therapy still remains a crucial challenge in hematology. Areas covered: New drugs can specifically target malignant cells and inhibit cancer cell growth, proliferation and survival by specific interactions with one or more target proteins. Recent clinical studies have illustrated promising outcomes for novel drugs used as single agents and in combination with traditional therapeutics. In this article, the authors discuss novel targeted therapies with a promising outcome in NHL patients that are becoming integrated into treatment paradigms. Expert opinion: The development of new treatment options may help to avoid cytotoxic chemotherapy entirely in some clinical settings. Multicenter studies should be continued to investigate small agents and pathways inhibitors as this will enable us to enhance not only the duration of the treatment response but also the quality of the extended survival.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Linfoma não Hodgkin/tratamento farmacológico , Antineoplásicos/administração & dosagem , Descoberta de Drogas/métodos , Humanos , Imunoterapia/métodos , Linfoma não Hodgkin/patologia , Terapia de Alvo Molecular , Medicina de Precisão , Taxa de Sobrevida , Fatores de Tempo
8.
Adv Clin Exp Med ; 24(2): 195-202, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25931349

RESUMO

BACKGROUND: The JAK2V617F mutation plays a crucial role in the pathogenesis of myeloproliferative neoplasms (MPNs). Inhibition of JAK2 activity by ruxolitinib (RX) results in growth inhibition and apoptosis of cells carrying the JAK2V617F mutation however the exact mechanisms regulating apoptosis have not been fully elucidated. OBJECTIVES: This study assessed the potential cytotoxicity of RX against JAK2-positive human cell lines (SET-2 and HEL), either alone or in combination with hydroxyurea, busulphan, rapamycin or LY294002. MATERIAL AND METHODS: Cell viability, the apoptosis rate (annexin-V staining), drop of mitochondrial transmembrane potential (Δψm) and caspase activation, were measured using flow cytometry. Additionally, the expression of several apoptosis-regulating proteins was evaluated. RESULTS: RX showed cytotoxicity against both SET-2 and HEL cell lines. The main mechanism of this action was apoptosis, with significant drop of Δψm, caspase-3 and -9 activation, and moderate activation of caspase-8 (only for SET-2 cells). Corresponding to enhanced apoptosis, the expression levels of some apoptosis-regulating proteins were changed, the most pronounced in both cell lines being up-regulation of Bax and down-regulation of Bcl-2 proteins. Additionally, up-regulation of Bak and Bad (SET-2) and down-regulation of Mcl-1 (HEL) were observed. Of the studied compounds, a combination of RX + LY294002 induced the greatest cytotoxicity in both SET-2 and HEL cell lines, and rapamycin the least. CONCLUSIONS: This study shows that the combination of RX and a PI3K kinase inhibitor provokes a significant pro-apoptotic effect in JAK2V617F mutated cells, which may justify the beginning of clinical trials based on the combination of these drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Neoplasias/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Bussulfano/farmacologia , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Ativação Enzimática , Humanos , Hidroxiureia/farmacologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Terapia de Alvo Molecular , Morfolinas/farmacologia , Mutação , Neoplasias/patologia , Nitrilas , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo
9.
Biomed Res Int ; 2015: 485071, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25705661

RESUMO

Currently, Hodgkin's lymphoma (HL) has an excellent clinical outcome, with overall survival of approximately 90% in early stages of the disease. Based on young age of the majority of patients at the time of diagnosis and their long survival time, increased attention has been focused on long-term toxicity of therapy. While novel, directly targeting antitumor agents, with an excellent safety profile, have been developed for HL treatment, the role of radiotherapy is still debated. Radiotherapy may induce cardiovascular disease and impairment of thyroid or pulmonary function and, most importantly, may lead to development of secondary cancers. As a consequence, the current radiation therapy planning paradigm is mainly focused on a reduction of field size. As it was investigated in clinical trials regional therapy is as effective as extended field radiotherapy, but less toxic. Although chemotherapy is the mainstay of HL treatment, consolidative involved field radiation therapy is still considered to be the standard of care in both early and advanced stages. Recently, further field reduction has been investigated to further decrease the late radiation-induced toxicity. In this paper we describe the role and safety profile of radiotherapy in the past and present and hope for the novel techniques in the future.


Assuntos
Doença de Hodgkin/radioterapia , Radioterapia/efeitos adversos , Antineoplásicos/uso terapêutico , Terapia Combinada , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Prognóstico
10.
Molecules ; 19(9): 14304-15, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25215588

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is one of the most common non-Hodgkin lymphomas in adults. The disease is very heterogeneous in its presentation, that is DLBCL patients may differ from each other not only in regard to histology of tissue infiltration, clinical course or response to treatment, but also in respect to diversity in gene expression profiling. A growing body of knowledge on the biology of DLBCL, including abnormalities in intracellular signaling, has allowed the development of new treatment strategies, specifically directed against lymphoma cells. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in controlling proliferation and survival of tumor cells in various types of malignancies, including DLBCL, and therefore it may be a promising target for therapeutic intervention. Currently, novel anticancer drugs are undergoing assessment in different phases of clinical trials in aggressive lymphomas, with promising outcomes. In this review we present a state of art review on various classes of small molecule inhibitors selectively involving PI3K/Akt/mTOR pathway and their clinical potential in this disease.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética
11.
Eur J Cancer ; 50(15): 2677-84, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25154027

RESUMO

SMIP-016, a new anti-tumour agent, is a mouse/human chimeric fusion protein built on the ADAPTIR™ (modular protein therapeutic) platform targeting human CD37. In this study, for the first time, we examined pro-apoptotic activity of SMIP-016 in combination with monoclonal anti-CD20 antibody, ofatumumab (HuMax-CD20) in de novo chronic lymphocytic leukaemia (CLL) cells and in different B-cell neoplasm-derived lines. In CLL cells SMIP-016 exerted significant cytotoxicity (versus control - p=0.01). In the in vitro models, SMIP-016 was also distinctly active against Raji line (Burkitt lymphoma; BL) (versus control - p=0.007), Riva-1 line (diffuse large B-cell lymphoma; DLBCL) (versus control - p=0.002) and RPMI 8226 line (multiple myeloma cells; MM) (versus control - p=0.03). In studies combining SMIP-016 and ofatumumab, the cytotoxicity against CLL cells was significantly higher than the agents used alone (p<0.03). Remarkably enhanced cytotoxic activity of SMIP-016 and ofatumumab in combination was also observed in Raji and Riva-1 cell lines (p<0.01 and p<0.003, respectively). Importantly, both agents induced cytotoxicity at very low concentrations which suggests that potential side-effects may be decreased in clinical practice. The mechanism responsible for cytotoxicity of SMIP-016 in all the examined models was connected with caspase-dependent apoptosis. In majority of cell types SMIP-016 induced overexpression of Bax protein, as well as downregulation of Bcl-2, cIAP1 (p<0.03) and Smac/DIABLO (p<0.003) apoptosis-regulating proteins. In conclusion, our study demonstrated high pro-apoptotic activity of SMIP-016, especially in combination with ofatumumab, against ex vivo CLL cells, and BL or DLBCL in vitro cell lines. Thus, further preclinical studies in in vivo models are warranted, as this combination may be a promising therapeutic concept for treatment of those malignancies.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Antígenos de Neoplasias/imunologia , Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Integrina beta1/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Tetraspaninas/imunologia
12.
Int J Oncol ; 45(1): 419-25, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24789756

RESUMO

Although major advancements in antitumor treatment have been observed, several B cell-derived malignancies still remain incurable. A promising approach that involves targeting RNA either by the use of specific antisense oligonucleotides or cytostatic/cytotoxic ribonucleases (RNases) is being promoted. Two amphibian RNases, onconase (ONC; ranpirnase) and, more recently, r-amphinase (r-Amph), have already been tested, but thus far, mostly on solid tumors. In this study, for the first time we provide comprehensive data on ex vivo and in vivo cytotoxic activity of ONC or r-Amph against cancer cells from different B cell lymphoid malignancies, together with their detailed mode of antitumor action. Our data revealed strong pro-apoptotic activity of ONC and r-Amph in both chronic lymphocytic leukemia and aggressive B cell lymphomas, with less impact on acute lymphoblastic leukemia or multiple myeloma cells. Moreover, the antitumor action of ONC and r-Amph was markedly selective against neoplastic cells sparing normal, healthy control­derived lymphocytes.


Assuntos
Antineoplásicos/administração & dosagem , Linfócitos B/patologia , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transtornos Linfoproliferativos/patologia , Ribonucleases/administração & dosagem , Adulto , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Ribonucleases/farmacologia , Adulto Jovem
13.
Cytometry B Clin Cytom ; 86(6): 410-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24515875

RESUMO

Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) still remains an incurable disease. Major advances have been recently made to understand the molecular pathogenesis underlying CLL, but defects in apoptosis are considered to be the most important factors. Although neoplastic cells are resistant to apoptosis in vivo, they show decreased level of spontaneous in vitro apoptosis, with significant differences among CLL patients. This work compares the level of spontaneous CLL cell apoptosis with prognostic factors and clinical course of the disease. In vitro spontaneous apoptosis of peripheral blood lymphocytes was analyzed using Annexin-V assay (confirmed by TUNEL method) in 135 treatment naïve patients with CLL. Levels of apoptosis after 48 h culture in patients with stable disease were found to be significantly higher than in the group with progressive course of the disease (P = 0.015). Moreover, the level of spontaneous apoptosis after 24 and 48 h of incubation correlated inversely with the progression free survival (P = 0.026 and 0.009, respectively). These results suggest that in vitro spontaneous apoptosis of CLL cells may be a simple and cheap prognostic test which is relatively quick to use, and can predict the course of the disease and response to treatment.


Assuntos
Apoptose/fisiologia , Leucemia Linfocítica Crônica de Células B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anexina A5/metabolismo , Progressão da Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Risco
14.
Artigo em Inglês | MEDLINE | ID: mdl-24470252

RESUMO

Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) still remains an incurable disease. Major advances have been recently made to understand the molecular pathogenesis underlying CLL, but defects in apoptosis are considered to be the most important factors. Although neoplastic cells are resistant to apoptosis in vivo, they show decreased level of spontaneous in vitro apoptosis, with significant differences among CLL patients. This work compares the level of spontaneous CLL cell apoptosis with prognostic factors and clinical course of the disease. In vitro spontaneous apoptosis of peripheral blood lymphocytes was analyzed using Annexin-V assay (confirmed by TUNEL method) in 135 treatment naïve patients with CLL. Levels of apoptosis after 48h culture in patients with stable disease were found to be significantly higher than in the group with progressive course of the disease (p=0.015). Moreover, the level of spontaneous apoptosis after 24h and 48h of incubation correlated inversely with the progression free survival (p=0.026 and 0.009, respectively). These results suggest that in vitro spontaneous apoptosis of CLL cells may be a simple and cheap prognostic test which is relatively quick to use, and can predict the course of the disease and response to treatment. © 2014 Clinical Cytometry Society.

15.
Postepy Hig Med Dosw (Online) ; 67: 107-18, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23475487

RESUMO

INTRODUCTION: Chronic lymphocytic leukemia (CLL) remains incurable; therefore searching for new therapeutic strategies in this disease is necessary. An important mechanism of tumor development is neoangiogenesis. A potent antiangiogenic factor, bevacizumab (Avastin, AVA), has been poorly explored in CLL so far. In the current study we assessed cytotoxic activity of AVA alone or in combinations with drugs routinely used in this disease. MATERIALS AND METHODS: Cells isolated from 60 CLL patients were treated with AVA alone or in combination with anti-CD20 monoclonal antibody (MoAb), rituximab (RIT), anti-CD52 MoAb, alemtuzumab (ALT), 2-CdA (2-chlorodeoxyadenosine), FA (fludarabine), MAF (mafosfamide) or RAPA (rapamycin). Cytotoxicity was assessed by propidium iodide staining. Apoptosis was evaluated using annexin-V and TUNEL assays. Additionally, a drop of mitochondrial potential (DYm) as well as expression of apoptosis-regulating proteins Bax, Bak, Bid, Bad, Bcl-2, Mcl-2, XIAP, FLIP, Akt and Bcl-2-A1 were determined by flow cytometry. RESULTS: At the dose of 40 µg/ml, after 48 hours of incubation, AVA induced significant cytotoxicity against CLL cells. The drug triggered apoptosis, with activation of caspase-3 and -9, but not caspase-8, along with a drop of DYm. Incubation with AVA induced significant overexpression of proapoptotic Bak and Bad as well as downregulation of antiapoptotic Mcl-2 and Akt proteins. Combination of AVA with RIT, ALT or RAPA significantly increased cytotoxicity when compared with the effects of single drugs. DISCUSSION: In conclusion, this is the first report showing proapoptotic activity of AVA against CLL cells. Combination of AVA with RIT, ALT or RAPA may be a promising therapeutic strategy, which requires confirmation in further studies.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Alemtuzumab , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Bevacizumab , Caspase 3/efeitos dos fármacos , Caspase 9/efeitos dos fármacos , Cladribina/administração & dosagem , Ciclofosfamida/administração & dosagem , Ciclofosfamida/análogos & derivados , Regulação para Baixo , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Rituximab , Sirolimo/administração & dosagem , Células Tumorais Cultivadas , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
16.
Postepy Hig Med Dosw (Online) ; 67: 1166-72, 2013 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-24379257

RESUMO

Ranpirnase (onconase; ONC) is an endoribonuclease obtained from the frog Rana pipiens. This enzyme exhibits anticancer properties mediated by degradation of cellular RNA and induction of apoptosis. In this study we assessed cytotoxicity of ONC in combination with currently used anticancer drugs on a human diffuse large B-cell lymphoma (DLBCL)-derived cell line (Toledo). Cytotoxic activity was measured by the exclusion of propidium iodide assay while apoptosis was assessed using the annexin-V binding method. Additionally, flow cytometry was used to assess the decline of mitochondrial potential and to determine activation of caspases 3, 8 and 9. It was observed that in vitro treatment with ONC in combination with rituximab, mafosfamide, vincristine, doxorubicin, and dexamethasone (drugs corresponding with elements of R-CHOP regimen) resulted in increased cytotoxicity. As a result ONC showed marked cytotoxicity against Toledo cells. Importantly, in combination of ONC with drugs imitating the R-CHOP regimen, this effect was significantly intensified. The main mechanism responsible for this event was induction of apoptosis along a mitochondrial dependent pathway. In conclusion, these data indicate that further preclinical and eventually clinical studies assessing activity of ONC+R-CHOP treatment are warranted.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Ribonucleases/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Prednisona/administração & dosagem , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem
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