1,720,996 research outputs found
Identify multiple myeloma stem cells: Utopia?
Full text linkMultiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs
Inhibition of Notch mediated communication in endothelial and plasma cells reduces angiogenesis in multiple myeloma patients.
No full textNON DISPONIBIL
Pharmacological therapy of non-dystrophic myotonias
Full text linkObjectives. Non-dystrophic myotonias (NDM) are rare diseases due to mutations in the voltage-gated sodium (Nav1.4) and chloride (ClC-1) channels expressed in skeletal muscle fibers. We provide an up-to-date review of pharmacological treatments available for NDM patients and experimental studies aimed at identifying alternative treatments and at better understanding the mechanisms of actions. Methods. Literature research was performed using PubMed and ClinicalTrial.gov. Results. Today, the sodium channel blocker mexiletine is the drug of choice for treatment of NDM. Alternative drugs include other sodium channel blockers and the carbonic anhydrase inhibitor acetazolamide. Preclinical studies suggest that activators of ClC-1 channels or voltage-gated potassium channels may have antimyotonic potential. Conclusions. An increasing number of antimyotonic drugs would help to design a precision therapy to address personalized treatment of myotonic individuals
Notch cross-talk between endothelial cells and plasma cells in bone marrow of multiple myeloma patients
No full textInvolvement of NOTCH signaling in multiple myeloma angiogenesis and progression
No full textBackground: Multiple Myeloma (MM) is a hematopoietic malignancy characterized by proliferation of malignant plasmacells (PCs) within the bone marrow (BM) usually preceded by a premalignant
phase called Monoclonal Gammopathies of Undetermined Significance (MGUS). Interactions between myeloma PCs and BM stromal cells facilitate tumor progression and angiogenesis. Notch family is composed of a group of proteins which act as transmembrane receptors and as regulators of gene transcription after their cleavage by -secretase. Mammals express four Notch receptors (Notch1-2-3-4) which bind five ligands (DLL1-3-4 and Jagged1-2). Aim of our study is to investigate the role of Notch pathway in MM angiogenesis and progression.
Materials and Methods: Real-time RT PCR, Western blotting and immunofluorescence were performed to assess Notch and its ligands expression in MM endothelial cells (MMECs) and MGECs (ECs of patients with MGUS). Functional in vitro assay (Matrigel assay, adhesion, chemotaxis, wound-healing, cell proliferation, apoptosis, and ELISA) were conducted in MMECs and RPMI-8226 to study Notch inhibition effects after Notch2 silencing and -secretase treatment.
Results: MMECs showed an higher expression and activation of Notch2 compared to MGECs and this higher activation in MMECs correlates whit an increased angiogenesis. Notch2 knock-down, through siRNA, reduced MMECs abilities and also their proliferation. Furthermore myeloma PCs line RPMI-8226 showed an over-expression of Notch ligands Jagged1, Jagged2 and DLL1 allowing mutual interactions between MMECs and RPMI- 8226 and Notch pathway activation, as demonstrated by co-colture experiments with or without transwell. Inhibition of Notch signaling using the -secretase inhibitor MK-0752, which prevents Notch cleavage, affected MMECs abilities in co-culture and alone. The block of Notch cleavage reduced ECs chemotaxis, migration, adhesion and furthermore the ability to form capillary structure on Matrigel. Moreover the treatment decreased the production of pro-angiogenic cytokines and of cell-cycle regulators in MMECs and in RPMI-8226 respectively. Conclusion: Our results show that Notch pathway is involved in MM progression supporting BM angiogenesis through an active interaction between myeloma PCs and MMECs. The inhibition of Notch signaling affected MMECs angiogenic abilities, highlighting the idea that this pathway could became a new target in MM therapy to counteract BM angiogenesis
Drug repurposing in skeletal muscle ion channelopathies
No full textSkeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we reviewed the available therapeutic options in non-dystrophic myotonias (NDM) and periodic paralyses (PP), which consists essentially in drug repositioning to address stiffness or weakness attacks. Empirical use followed by successful randomized clinical trials eventually led to the orphan drug designation and marketing authorization granting of mexiletine for NDM and dichlorphenamide for PP. Yet, these treatments neither consider the genetic cause of the diseases nor address the individual variability in drug response. Thus, ongoing research aims at the identification of repurposed drugs alternative to mexiletine and dichlorphenamide to allow personalization of treatment. This review highlights how drug repurposing may represent an efficient strategy in rare diseases, allowing reduction of drug development time and costs in a context in which the return on investment may be particularly challenging
NSAIDS AS MODULATORS OF CATION CHANNELS: FENAMATES REPURPOSING IN CHANNELOPATHIES
No full text: Cationic ion channels are transmembrane proteins that regulate the flux of cations (potassium, sodium, and calcium) across cell membrane, playing a pivotal role in many cellular functions. Disruptions of their activity can lead to the so-called genetic or acquired channelopathies, a heterogeneous group of diseases that affect multiple human systems. Fenamates, a class of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), has recently emerged as modulators of cationic ion channels highlighting the possibility of their repurposing for the treatment ion channel-related disorders, such as channelopathies, chronic pain, epilepsy, cardiac arrhythmias and cancers. In this review, we describe the ability of fenamates (i.e. niflumic, flufenamic, mefenamic, meclofenamic and tolfenamic acids) to differentially modulate the activity of cationic ion channels. Overall, preclinical and clinical studies suggest that fenamates represent a promising class of compounds for drug repurposing and for the development of new molecules, offering novel therapeutic opportunities for patients affected by ion channel-related disorders
Pleiotropic Effects of the NSAID Fenamates on Chloride Channels: Opportunity for Ion Channelopathies?
Full text linkChloride channels are involved in many cellular processes, including cell volume regulation, modulation of cell excitability, and electrolyte and water secretion. Mutations of these proteins are associated with heterogeneous diseases such as myotonia, cystic fibrosis, epilepsy, deafness, lysosomal storage disease, and various kinds of renal and ophthalmic dysfunctions, also known as channelopathies. Thus, drugs targeting chloride channels may have important therapeutic applications. In this context, fenamates, commonly used for their anti-inflammatory properties, have been explored for drug repurposing in chloride channelopathies thanks to their ability to modulate multiple chloride channels. This narrative review resumes the effects of niflumic acid (NFA), flufenamic acid (FFA), mefenamic acid (MFA), meclofenamic acid (MCFA), and tolfenamic acid (TFA) on different types of chloride channel. It emerges that fenamates have a wide spectrum of activities on these channels that vary depending on multiple factors like channel isoforms, extracellular and intracellular conditions, and cell and tissue types. They may also exhibit both activating and inhibitory effects depending on their concentration. Therefore, thanks to their variegated modulatory activity on chloride channels, fenamates might be considered promising lead compounds for the development of new drug candidates that can target these altered channels involved in channelopathies. Trial Registration: EudraCT number: 2021-000708-39; ClinicalTrials.gov identifier: NCT029930005 and NCT02429570
Functional and biological role of endothelial precursor cells in tumour progression: A new potential therapeutic target in haematological malignancies
Full text linkIt was believed that vasculogenesis occurred only during embryo life and that postnatal formation of vessels arose from angiogenesis. Recent findings demonstrate the existence of Endothelial Precursor Cells (EPCs), which take partin postnatal vasculogenesis. EPCs are recruited from the bone marrow under the stimulation of growth factors and cytokines and reach the sites of neovascularization in both physiological and pathological conditions such as malignancies where they contribute to the "angiogenic switch" and tumor progression. An implementation of circulating EPCs in the bloodstream of patients with haematological malignancies has been demonstrated. This increase is strictly related to the bone marrow microvessel density and correlated with a poor prognosis. The EPCs characterization is a very complex process and still under investigation. This literature review aims to provide an overview of the functional and biological role of EPCs in haematological malignancies and to investigate their potential as a new cancer therapeutic target
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