Canthin-6-one presents an interesting cytotoxic activity against leukemic cells and represents a promising scaffold for the development of molecules for anti-leukemic applications, especially by its anti-leukemic stem cell activity.
Hematopoiesis is the main function of bone marrow. Human hematopoietic stem and progenitor cells reside in the bone marrow microenvironment, making it a hotspot for the development of hematopoietic diseases. Numerous alterations that correspond to disease progression have been identified in the bone marrow stem cell niche. Complex interactions between the bone marrow microenvironment and hematopoietic stem cells determine the balance between the proliferation, differentiation and homeostasis of the stem cell compartment. Changes in this tightly regulated network can provoke malignant transformation. However, our understanding of human hematopoiesis and the associated niche biology remains limited due to accessibility to human material and the limits of in vitro culture models. Traditional culture systems for human hematopoietic studies lack microenvironment niches, spatial marrow gradients, and dense cellularity, rendering them incapable of effectively translating marrow physiology ex vivo. This review will discuss the importance of 2D and 3D culture as a physiologically relevant system for understanding normal and abnormal hematopoiesis.
BackgroundAll hematopoietic cells express P2 receptors, however pharmacological characteristics such as expression and affinity in granulocytes are unknown.MethodsPharmacological characteristics of P2 receptors were evaluated by Ca2+ measurements using Fura-2 fluorophore. P2 receptors expression were analyzed by flow cytometry and RT-PCR. P2 interaction were shown by coimmunoprecipitation, western blotting and FRET.ResultsGranulocytes were responsive to P2Y agonists, whereas P2X agonists were ineffective. Ca2+ increase, elicited by ADP and UTP was dependent on intracellular stocks and sensitive to G-coupled receptor inhibition. Moreover, MRS2179, a specific antagonist of the P2Y1 receptor, abolished ADP response. Interestingly, ADP and UTP exhibited full heterologous desensitization, suggesting that these agonists interact with the same receptor. The heteromeric association between P2Y1 receptor and the P2Y2 and P2Y4 receptors was shown by immunoprecipitation and FRET analysis.ConclusionClear evidence of heteromeric association of P2Y receptors was found during the evaluation of P2 receptors present in mice granulocytes, which could impact in the classical pharmacology of P2Y receptors in granulocytes.
Due to the cytotoxic effect of antimicrobial peptides (AMP) against several microorganism and tumor cells has been proposed their association with the immune system. However, just a few reports have shown this relationship. In this study, mice were treated with gomesin, a β-hairpin AMP that exhibit high cytotoxicity against bacterial and tumor cells. Different effects in the immune system were observed, such as, decrease of CD3 in T lymphocytes (Control: 17.7±1.4%; Gomesin: 7.67±1.2%) and in hematopoietic progenitors and increase of hematopoietic stem cell (Control: 0.046±0.004%; Gomesin: 0.067±0.003%), B220 B lymphocytes (Control: 38.63±1.5%; Gomesin: 47.83±0.48%), and Mac-1F4/80 macrophages (Control: 11.76±3.4%; Gomesin: 27.13±4.0%). Additionally, macrophage increase was accompanied by an increase of macrophage phagocytosis (Control 20.85±1.53; Gomesin 31.32±1 Geometric mean), interleukin 6 (Control: 47.24±1.9ng/mL; Gomesin: 138.68±33.68ng/mL) and monocyte chemoattractant protein-1 (Control: 0.872±0.093ng/mL; Gomesin: 1.83±0.067ng/mL). Thus, this report showed immunomodulatory activity of gomesin in the immune system of mice.
Leukemia is a disease that affects the proliferation and differentiation of bone marrow cells. News therapies against leukemia stem cells (LSC) are under investigation. We have previously shown the ability of ATP (which activates P2 receptors) and antimicrobial peptides (AMPs: magainin, protegrin, polyphemusin and gomesin) to affect hematopoietic stem cells. Thus, herein explore the antitumor capability of ATP and AMPs against LSC using concentrations that do not induce cell death. Human Leukemia lineages K562 and KG1 cells were used. Immunophenotyping and cell viability were performed by flow cytometry and clonogenic assay was performed in methylcellulose. ATP promotes an increase in the percentage of LSC (CD34+CD38− Linlow/−) after three days of treatment in a concentration‐dependent manner. However, ATP leads to a decrease in the clonogenic capacity and also in the total number of K562 and KG1 cells. Similar results were obtained with the AMPs. Viability assay showed that ATP and the AMPs did not induce cell death in LSC but they were able to induce an increase of LSC population, although the clonogenic capability of this population decreased.
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