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Bridi, Deborah (2013) Effetto dell'inibizione del sistema adrenomedullinico in una linea promielocitica umana. [Tesi di dottorato]

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Abstract (inglese)

The outcome of acute myeloid leukemia (AML) has not undergone significant improvements despite an increasingly accurate description of the pathogenetic mechanisms underlying the malignant transformation of hematopoietic stem cell. The block maturation is distinctive of all acute leukemias and possibly the presence of a minority of cells more immature phenotype is responsible for chemoresistance and relapse. The prospect of using pharmacological strategies to overcome the differentiation block, encouraged by the success achieved in acute promyelocytic leukemia (APL) with the introduction in therapy protocols of all-trans retinoic acid (ATRA), it becomes very attractive.
Experimental evidence suggests that peptides derived from adrenomedullin (ADM) play an important role in the regulation of cellular processes, such as proliferation, differentiation and apoptosis. Synthesized and secreted by many cell types, such as epithelial cells, neurons, endothelial cells, ADM was also detected in the conditioned medium of granulocytes, lymphocytes, monocytes and macrophages. In the present study, the effect induced by ADM and its specific inhibitor Fragment Inhibitor22-52 was evaluated in vitro in different intervals of time on HL60 cells, an established human cell line of APL, by growth assays and analysis flow cytometric.
Taken together, our results suggest an involvement of ADM in the pathogenesis of leukemias and/or in the maintenance of differentiative impairment typical of these diseases. In HL60 cells, ADM system modulated itself through ADM secretion, exposure of its receptors and control of gene expression (Cul5). Furthermore, ADM expression was related to the increase in cell proliferation and the inhibition of cell differentiation. These effects were abolished or reversed by using a receptor antagonist.
On this basis, it can be hypothesized that the modulation of ADM system could represent a potential terapeutical approach for the treatment of leukemias.

Abstract (italiano)

L’outcome della leucemia mieloide acuta (AML) non ha subìto significativi miglioramenti nonostante la sempre più accurata descrizione dei meccanismi patogenetici che sottendono la trasformazione neoplastica della cellula staminale ematopoietica. Il blocco maturativo è caratteristica distintiva di tutte le leucemie acute e verosimilmente la presenza di una quota minoritaria di cellule a fenotipo più immaturo è responsabile di chemoresistenza e ricadute. La prospettiva di poter utilizzare strategie farmacologiche volte a superare il blocco differenziativo, incoraggiata dal successo ottenuto nella leucemia acuta promielocitica (APL) con l'introduzione nei protocolli di terapia dell'acido all-trans retinoico (ATRA), diventa alquanto attraente.
Evidenze sperimentali suggeriscono che i peptidi derivati da
adrenomedullina (ADM) giocano un ruolo importante nella regolazione di processi cellulari, quali la proliferazione, il differenziamento e
l’apoptosi cellulare. Sintetizzata e secreta da numerosi tipi cellulari,
quali cellule epiteliali, neuroni, cellule endoteliali, ADM è stata anche
rilevata nel terreno condizionato di granulociti, linfociti, monociti e
macrofagi.
Nel presente studio, l’effetto indotto da ADM e dal suo
inibitore Fragment Inhibitor22-52 è stato valutato in vitro a
differenti intervalli di tempo su cellule HL60, una linea cellulare umana stabilizzata di APL, mediante saggi di crescita e analisi
citofluorimetrica.
Collettivamente, i risultati raccolti in questa tesi suggeriscono un possibile coinvolgimento di ADM nella patogenesi di forme leucemiche e/o nel mantenimento del blocco differenziativo caratteristico di tali patologie. Nelle cellule HL60, il sistema adrenomedullico appariva in grado di autoregolarsi mediante un controllo della secrezione di ADM, dell’espressione dei suoi recettori e di geni, quali il Cul5. Inoltre, l'espressione di ADM era correlata ad una stimolazione della proliferazione cellulare e ad una inibizione della formazione di fenotipi maturi. Tali effetti venivano annullati o reversati in seguito al blocco del recettore. Sulla base di tali evidenze, si può ipotizzare che la modulazione del sistema adrenomedullinico possa rappresentare una possibile strategia terapeutica per il trattamento delle forme leucemiche.

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Tipo di EPrint:Tesi di dottorato
Relatore:Grandi, Claudio
Correlatore:De Angeli , Sergio
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE > INGEGNERIA DEI TESSUTI E DEI TRAPIANTI
Data di deposito della tesi:30 Gennaio 2013
Anno di Pubblicazione:30 Gennaio 2013
Parole chiave (italiano / inglese):Leucemia Mieloide Acuta, Leucemia Promielocitica Acuta, Adrenomedullina, ADM-FragmentInhibitor22-52. Acute Myeloid Leukaemia, Acute Promyelocytic Leukemia, Adrenomedullin, ADM-Fragment Inhibitor22-52.
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/16 Anatomia umana
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:5773
Depositato il:22 Ott 2013 09:33
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