5. INIBITORI DELLE VIE DI SEGNALE.
5.4. Inibitori della via di segnale Wnt/β-Catenina.
Il segnale Wnt svolge un ruolo importante nello sviluppo dei melanociti, e la β-catenina è il controllore chiave. Il ligando Wnt si lega al recettore Frizzled e innesca lo spiazzamento della glicogeno sintasi chinasi-3 β (GSK3β), che fosforila la β-catenina e, quindi, la degrada attraverso un meccanismo ubiquitina-dipendente. Inoltre, il segnale Wnt regola negativamente il GSK3β e porta all'accumulo di β- catenina. La β-catenina stabilizzata è trasferita nel nucleo e promuove l'espressione del gene MITF e la melanogenesi (rif.Art.principale). La cardamonina (136, Fig. 19), un calcone isolato dalla Aplinia katsumadai, e il fingolimod (FTY720, 137, Fig. 19)
73 (rif.Art.principale) sono riportati come inibitori della melanogenesi che hanno come target il segnale Wnt. Alcuni studi hanno chiarito che il composto 136 induce la degradazione intracellulare di β-catenina, la downregulation di MITF e l'espressione di TYR; al contrario, 137 (FTY720) inibisce la sintesi di melanina attraverso la downregulation dell'espressione di β-catenina in cellule Mel-Ab.
Bellei e coll. hanno descritto i derivati piridinilimidazolici quali inibitori della melanogenesi in cellule B16-F0, attraverso l'inibizione della classica attività della Wnt/β-catenina. (127) In particolare, i composti 138, 139 e 140 iniscono la sintesi di melanina con valori di IC50, rispettivamente, di 30, 34 e 89 nM.
Recentemente, il labdano, un diterpene andrografolide (141, Fig. 19), ha mostrato potenti attività inibitorie del contenuto di melanina e dell'attività intracellulare della TYR, in cellule B16 (rif.Art.principale).
In un modello in vivo di cavia di colorazione bruna indotta dagli UVB, il composto 141 ha ridotto la melanina e il contenuto di TYR. Ulteriori studi hanno rivelato che l'andrografolide riduce la degradazione della β-catenina attraverso il meccanismo ubiquitina- dipendente.
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6. CONCLUSIONI
Negli ultimi anni sono stati descritti molti inibitori della melanogenesi. Nella maggior parte dei casi, questi composti bersagliano direttamente l'attività catalitica della TYR o la sua espressione attraverso diverse vie di segnale. La TYR è risultato il target molecolare più importante in quanto interviene nella sintesi della melanina, limitandone la velocità. Molto importante è anche il fatto che la TYR è espressa solo dai melanociti, pertanto bersagliando selettivamente la TYR si può inibire la melanogenesi nelle cellule senza alcun effetto collaterale.
Sono stati identificati numerosi inibitori della TYR fungina di origine sintetica, semisintetica o naturale, ma solo alcuni di essi hanno raggiunto applicazioni cliniche come agenti sbiancanti per la pelle, a causa di problemi di sicurezza e effetti sbiancanti troppo lievi. Soprattutto negli ultimi anni, i prodotti naturali hanno attratto molto l'attenzione a causa dei minori effetti collaterali e delle loro efficienti proprietà sbiancanti della pelle. Tuttavia, queste proprietà devono essere ancora studiate sugli animali o in modelli adatti, in vivo.
D'altra parte, l'identificazione di inibitori della TYR umana è di grande importanza. Sulla base dei dati riportati in letteratura è stato visto che c'è un'enorme differenza nell'attività inibitoria tra mTYR e hTYR. Infatti, molti inibitori della mTYR, alla fine, sono risultati circa 10 volte meno potenti o addirittura inattivi nei confronti della hTYR. Ad esempio, il ben noto acido kojico ha una più alta affinità di legame per mTYR (Ki = 4,3 µM) rispetto a hTYR (Ki = 350 µM),
75 mentre l'esculetina, identificata come un potente inibitore di mTYR, non ha mostrato attività inibitoria rilevabile nei confronti di hTYR. Sebbene sia ben chiaro che mTYR è economico e commercialmente disponibile per lo screening di agenti sbiancanti della pelle, deve essere convalidata l'efficienza di questi composti nei confronti della hTYR, prima di effettuare studi in vivo o su animali. Recentemente, Lai et coll. sono riusciti a sovraprodurre hTYR attiva in alta resa ed in forma pura, utilizzando il sistema di espressione del vettore baculovirus in cellule High Five; questo potrebbe risultare sicuramente utile, in futuro, sia per lo screening di cristallizzazione che per lo screening ad alto rendimento di nuovi potenziali agenti sbiancanti della pelle.
In generale, è importante progettare prodotti cosmetici con un efficace attività antiossidante, importante per ridurre gli effetti dell'invecchiamento. Recentemente, vi è stato un numero crescente di inibitori della melanogenesi la cui attività è stata associata alle proprietà antiossidanti. Tuttavia, sono necessari altri studi avanzati su questi inibitori, dal punto di vista clinico umano.
Nel programma di scoperta di farmaci, l'uso di farmaci esistenti è uno dei metodi più sicuri ed efficaci, poiché presenta numerosi vantaggi, che includono risparmio di tempo, disponibilità di farmaci, sicurezza/tollerabilità e buon rapporto costo-efficacia. Molti farmaci antitubercolari e antitiroidei si sono dimostrati potenti inibitori della tirosinasi, senza causare citotossicità significativa alle cellule. Pertanto, in futuro, dovranno essere fatti ulteriori studi per poterli usare come agenti sbiancanti.
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