Multidrug resistance phenotype and its relation to stem cell characteristics in chronic myeloid leukemia.

The present work aimed to evaluate the expression profile of genes related to stem cells (SC) characteristics during the acquisition of the multidrug resistance (MDR) phenotype in the chronic myeloid leukemia (CML). For this, the K562 (non MDR) and FEPS (MDR) cell lines were used. K562 cells had resistance induced by exposure to daunorubicin (DNR), and induction was confirmed by flow cytometry with an increase in ABCB1 expression in K562 cells treated at the highest concentration.

Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells.

Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mechanisms relies on the high expression of efflux transporters, such as the ABC proteins, whose activity depends on the hydrolysis of ATP to reduce intracellular drug accumulation.

Tumor-Released Products Promote Bone Marrow-Derived Macrophage Survival and Proliferation.

Macrophages play a central role within the tumor microenvironment, with relevant implications for tumor progression. The modulation of their phenotype is one of the mechanisms used by tumors to escape from effective immune responses. This study was designed to analyze the influence of soluble products released by tumors, here represented by the tumor-conditioned media of two tumor cell lines (3LL from Lewis lung carcinoma and MN/MCA from fibrosarcoma), on murine macrophage differentiation and polarization in vitro.

Relation between ABCB1 overexpression and COX2 and ALOX5 genes in human erythroleukemia cell lines.

This study aimed to characterize the relationship between the COX2 and ALOX5 genes, as well as their link with the multidrug resistance (MDR) phenotype in sensitive (K562) and MDR (K562-Lucena and FEPS) erythroleukemia cells. For this, the inhibitors of 5-LOX (zileuton) and COX-2 (acetylsalicylic acid-ASA) and cells with the silenced ABCB1 gene were used. The treatment with ASA caused an increase in the gene expression of COX2 and ABCB1 in both MDR cell lines, and a decrease in the expression of ALOX5 in the FEPS cells.

In vitro antitumoral effects of the steroid ouabain on human thyroid papillary carcinoma cell lines.

Ouabain is a steroid described as a compound extracted from plants that is capable of binding to Na , K -ATPase, inhibiting ion transport and triggering cell signaling pathways. Due to its positive ionotropic effect, ouabain was used for more than 200 years for the treatment of cardiac dysfunctions. Numerous antitumor effects of ouabain have been described so far; however, its role on thyroid cancer is still poorly understood.

Synthesis of new α-Aryl-α-tetralones and α-Fluoro-α-aryl-α-tetralones, preliminary antiproliferative evaluation on drug resistant cell lines and in silico prediction of ADMETox properties.

α-aryl-α-tetralones and α-fluoro-α-aryl-α-tetralones derivatives were synthesized by palladium catalyzed α-arylation reaction of α-tetralones and α-fluoro-α-tetralones, with bromoarenes in moderate to good yields. These compounds were evaluated for their in vitro anti-proliferative effects against human breast cancer and leukemia cell lines with diverse profiles of drug resistance. The most promising compounds, 3b, 3c, 8a and 8c, were effective on both neoplastic models.

Selective Cytotoxicity of Piperine Over Multidrug Resistance Leukemic Cells.

Multidrug resistance (MDR) is the main challenge in the treatment of chronic myeloid leukemia (CML), and P-glycoprotein (P-gp) overexpression is an important mechanism involved in this resistance process. However, some compounds can selectively affect MDR cells, inducing collateral sensitivity (CS), which may be dependent on P-gp. The aim of this study was to investigate the effect of piperine, a phytochemical from black pepper, on CS induction in CML MDR cells, and the mechanisms involved.

Modulation of cytokine production by monocytes and developing-dendritic cells under the influence of leukemia and lymphoma cell products.

Cytokines and other soluble factors released by tumor cells play an important role in modulating immune cells to favor tumor development. Monocyte differentiation into macrophages or dendritic cells (DCs) with specific phenotypes is deeply affected by tumor signals and understanding this context is paramount to prevent and propose new therapeutic possibilities. Hence, we developed a study to better describe the modulatory effects of leukemia and lymphoma cell products on human monocytes and monocyte-derived DCs secretion of cytokines such as interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6, and IL-12.

Glucocorticoid susceptibility and in vivo ABCB1 activity differ in murine B cell subsets.

Glucocorticoids are produced and released by the adrenal gland and become elevated in response to stress. Although glucocorticoids are well known for their immunosuppressive effects, less is known about their effects on B cells. ABCB1 is an efflux pump expressed in both cancer and normal cells, modulating the gradient of various metabolites, including hydrocortisone.

Insights into the Biological Evaluation of Pterocarpanquinones and Carbapterocarpans with Anti-tumor Activity against MDR Leukemias.

In an attempt to find anticancer agents that could overcome multidrug resistance (MDR), two new classes of modified isoflavonoids were designed and synthesized, and their effectiveness evaluated against a vast array of tumor cell lines. Pterocarpanquinone (LQB-118) and 11a-aza-5-carbapterocarpan (LQB-223) were the most promising. LQB-118 induced cell death, , in the µM range, to a number of human cancer cell lines as well as to fresh tumor cells obtained from patients with acute or chronic myeloid leukemia, independent on whether they exhibit the MDR phenotype or not.

Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia.

: The introduction of imatinib (IM), a tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs-dasatinib, nilotinib, and bosutinib-and the third-generation TKI-ponatinib.

Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice.

Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS).

In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118.

Cancer is a malignancy of worldwide prevalence, and although new therapeutic strategies are under investigation, patients still resort to reductive or palliative chemotherapy. Side effects are a great concern, since treatment can render patients susceptible to infections or secondary cancers. Thus, design of safer chemotherapeutic drugs must consider the risk of immunotoxicity.

Sensitivity of Dendritic Cells to Microenvironment Signals.

Dendritic cells are antigen-presenting cells capable of either activating the immune response or inducing and maintaining immune tolerance. They do this by integrating stimuli from the environment and changing their functional status as a result of plasticity. The modifications suffered by these cells have consequences in the way the organism may respond.

Dynamics of murine B lymphocytes is modulated by in vivo treatment with steroid ouabain.

Ouabain (OUA) is a steroid hormone capable of inhibiting the protein Na+K+ATPase present in the plasma membrane of cells. Ouabain was initially extracted from the roots of African trees such as Acocanthera ouabaio and Strophantus gratus seeds and later described as an endogenous component found in higher mammals. The adrenal gland is the main site of synthesis of ouabain and it is released in stressful situations, conditions similar to those where there is secretion of corticosteroids.

Ouabain Modulates Zymosan-Induced Peritonitis in Mice.

Ouabain, a potent inhibitor of the Na(+), K(+)-ATPase, was identified as an endogenous substance. Recently, ouabain was shown to affect various immunological processes. We have previously demonstrated the ability of ouabain to modulate inflammation, but little is known about the mechanisms involved.

Changes in gene expression profile in two multidrug resistant cell lines derived from a same drug sensitive cell line.

Resistance to chemotherapy is one of the most relevant aspects of treatment failure in cancer. Cell lines are used as models to study resistance. We analyzed the transcriptional profile of two multidrug resistant (MDR) cell lines (Lucena 1 and FEPS) derived from the same drug-sensitive cell K562.

Ouabain affects the expression of activation markers, cytokine production, and endocytosis of human monocytes.

Ouabain is a steroid capable of binding to and inhibiting Na(+),-K(+)-ATPase. Studies have demonstrated some actions of ouabain on immune cells, which indicated both pro- and anti-inflammatory properties of this molecule. Nevertheless, its effects on human monocytes are still poorly understood.

Induction of suppressive phenotype in monocyte-derived dendritic cells by leukemic cell products and IL-1β.

Professional antigen-presenting cells, dendritic cells (DCs) play an important role in controlling tumors. It is known that solid tumor cell products inhibit DC differentiation. Recently a similar effect produced by leukemic cell products has been demonstrated.

Heparanase expression and localization in different types of human lung cancer.

Background: Heparanase is the only known mammalian glycosidase capable of cleaving heparan sulfate chains. The expression of this enzyme has been associated with tumor development because of its ability to degrade extracellular matrix and promote cell invasion.

Methods: We analyzed heparanase expression in lung cancer samples to understand lung tumor progression and malignancy.

Immune status of Fanconi anemia patients: decrease in T CD8 and CD56dim CD16+ NK lymphocytes.

Fanconi anemia (FA), a rare genetic disease in which patients' life is compromised mainly by hematological abnormalities and cancer prone, seems to be affected by subtle immune cell irregularities. Knowing that FA presents developmental abnormalities and, based on recent reports, suggesting that natural killer (NK) CD56(dim) and NK CD56(bright) correspond to sequential differentiation pathways, we investigated if there were changes on the total number of NK cells and subsets as well as on T CD4 and T CD8 lymphocytes and their ratio. A large sample of FA patients (n = 42) was used in this work, and the results were correlated to clinical hematological status of these patients.

Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR-CML cell lines?

The hallmark of CML (chronic myeloid leukaemia) is the BCR (breakpoint cluster region)-ABL fusion gene. CML evolves through three phases, based on both clinical and pathological features: a chronic phase, an accelerated phase and blast crisis. TKI (tyrosine kinase inhibitors) are the treatment modality for patients with chronic phase CML.

Increased IL10 plasmatic levels in Fanconi anemia patients.

Fanconi anemia (FA) is a rare disease, autosomal recessive and X linked, which is clinically prone to development of hematological abnormalities and neoplasms, especially acute myeloid leukemia. In this work IL-10 and TGF-β levels were measured on FA patients' plasma since they are the regulatory cytokines of TNF-α and INF-γ which had been described to be overexpressed in this genetic disease. Our results show increased IL-10 plasma levels in 25% of FA patients studied, but levels of TGF-β within the normal range.