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Porcù, Elena/EP (2014) MICROTUBULE DEPOLYMERIZING COMPOUNDS AS NOVEL POTENTIAL ANTIVASCULAR AGENTS IN CANCER THERAPY. [Tesi di dottorato]

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Abstract (inglese)

In the last years, biomedical research was focused on cancer, since it is a leading cause of death in the developed countries. However several molecular targets were identified thus making necessary to find new strategies to improve the traditional chemotherapy.
Aberrant tumors grow and spread, and they require their own blood supply. Some approaches of anticancer therapy utilize antiangiogenic drugs, including tubulin binding agents (TBAs). Here we focused our studies on several combretastatin-like molecules (TR-644, TR-764, 3b) which bind to tubulin with high affinity. We report the activity of our TBAs on endothelial cell cytoskeleton, cell motility, permeability, and other processes involved in angiogenesis. Our compounds strongly induce microtubules derangement, and alter the actin microfilaments organization. These effects result in focal adhesions and adherens junctions impairment, by affecting FAK/Src and VE-cadherin/β-catenin molecular pathways. We also evaluated the antivascular activity in vivo both in the chick embryo chorioallantoic membrane (CAM) and in an allograft mouse tumor model. These compounds induce a significant decrease in microvascular density, and strongly inhibit the tumor growth. Additionally, compound TR-764 is endowed with the ability to counteract in vitro hypoxic stimuli on endothelial cells, which usually give rise to resistance mechanisms. Thus we propose our molecules as potential single agents against highly vascularized tumors.
A subtype of non-toxic TBAs is represented by noscapines. Some derivatives were synthesized and we investigated their antimitotic effect, on cancer cell lines. They induce cell cycle arrest in G2/M phase and consequently they stimulate apoptosis, following the mitochondrial way. Radial organization of microtubules is altered and multipolar spindles occur after treatment. These modifications trigger DNA damage, and caspase-9/PARP activation. Here we report a new effective method for chemical synthesis (Suzuki cross-coupling), even though the biological activity of our compounds is comparable to other known noscapine derivatives.
Another part of the study concern the pharmacological evaluation of a series of small molecules as potential inhibitors of the Wnt/β-catenin pathway. The most potent compounds induce Wnt repression, in a colon cancer cell line (HT-29). They impair β-catenin activity as transcription factor, by downregulating its target genes cyclin D1 and c-myc and altering TCF-1/4 co-factors. Therefore the treatment leads to a reduction of cell proliferation in vitro. Finally we confirmed the inhibitory effects on β-catenin transcriptional activity in vivo, in Wnt-reporter zebrafish models.
All these pharmacological studies could be helpful to improve potential approaches for an effective anticancer therapy.

Abstract (italiano)

Negli ultimi anni la ricerca biomedica si è interessata principalmente di patologie oncologiche, le quali causano un’elevata incidenza di morte nei Paesi sviluppati. Sebbene siano stati identificati numerosi target molecolari, risulta ancora necessario trovare nuove strategie per migliorare la chemioterapia tradizionale.
I tumori crescono in maniera aberrante, e la loro espansione necessita dell’apporto di nuovi vasi sanguigni. Alcuni approcci terapeutici nella lotta contro i tumori prevedono l’utilizzo di farmaci antiangiogenici, tra i quali sono comprese le molecole che legano la tubulina (TBA). Questo studio riguarda la valutazione farmacologica di molecole con struttura simile alla combretastatina (TR-644, TR-764, 3b) che sono in grado di legarsi alla tubulina con alta affinità. E’ stata studiata l’attività di questi composti sul citoscheletro di cellule endoteliali, e su processi legati all’angiogenesi, quali la motilità cellulare o la permeabilità. Essi alterano la struttura dei microtubuli e inducono un’elevata disorganizzazione dei microfilamenti di actina. Tali effetti danneggiano le proteine che costituiscono le adesioni focali o le giunzioni aderenti, compromettendo le vie di segnale di FAK/Src e VE-caderina/β-catenina.
È stata valutata l’attività antivascolare anche in modelli in vivo, sulla membrana corioallantoidea di pollo (CAM) e in modelli di allotrapianto tumorale nel topo. I composti testati agiscono in maniera significativa sia riducendo la densità microvascolare, sia inibendo la crescita tumorale. Inoltre, in cellule endoteliali, il composto TR-764 è in grado di contrastare stimoli ipossici, che sono stati descritti come possibili responsabili dell’insorgenza di meccanismi di resistenza del tumore.
Questi nuovi TBA vengono quindi proposti come potenziali agenti terapeutici per la monoterapia di tumori altamente vascolarizzati.
Oltre a derivati della combretastatina è stato studiato un altro sottotipo di TBA non tossici, le noscapine. Una serie di derivati della noscapina è stata sintetizzata ed è stato analizzato il l’effetto antimitotico su linee cellulari tumorali. Questi composti bloccano il ciclo cellulare in fase G2/M, e di conseguenza inducono l’apoptosi, attivando la via mitocondriale. Essi agiscono riorganizzando la struttura radiale dei microtubuli e portano alla formazione di fusi mitotici multipolari. Queste modificazioni stimolano l’insorgenza di danni al DNA, e l’attivazione di caspasi-9 e PARP, effetti già dimostrati per altri derivati della noscapina.
Tuttavia in questo studio viene proposto un nuovo metodo molto efficace per la sintesi chimica dei composti (Suzuki cross-coupling).
Infine, è stata svolta una valutazione farmacologica di una serie di piccole molecole, con potenziale attività inibitoria della via di segnale di Wnt/β-catenina in una linea cellulare di cancro al colon (HT-29). I composti più attivi inibiscono questa via di segnale, compromettendo l’attività del fattore di trascrizione β-catenina, inibendo i suoi geni target, quali la ciclina D1 e c-myc, e alterando l’attività dei suoi cofattori TCF-1/4. Il trattamento quindi comporta la riduzione della proliferazione cellulare in vitro. Gli effetti di inibizione dell’attività trascrizionale della β-catenina sono stati confermati anche in vivo, tramite saggi reporter di Wnt, in modelli di zebrafish.
Gli studi farmacologici riportati in questa tesi possono essere utili per migliorare gli approcci terapeutici per il trattamento di alcuni tumori.

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Tipo di EPrint:Tesi di dottorato
Relatore:Basso, Giuseppe/GB
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > EMATOONCOLOGIA, IMMUNOLOGIA E GENETICA
Data di deposito della tesi:30 Gennaio 2014
Anno di Pubblicazione:30 Gennaio 2014
Parole chiave (italiano / inglese):angiogenesi, HUVEC, tubulina, antimitotici, Wnt β-catenina / angiogenesis, HUVEC, tubulin, antimitotics, Wnt β-catenin
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:6678
Depositato il:24 Apr 2015 17:25
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