Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and drug chemoresistance. In this study, we synthesize a library of seven novel nitric oxide-releasing gemcitabine pro-drugs (NO-GEMs) in order to improve the effectiveness of GEM by exploiting the therapeutic effects of NO. Among these NO-GEM pro-drugs we select 5b as the most effective compound in GEM-resistant PDAC cells. After its encapsulation in liposomes for drug delivery the intracellular NO level increases and nitration associated to activity inhibition of the multidrug resistance associated protein 5 (MRP5; ABCC5) occurs. This results in GEM intracellular accumulation and enhanced apoptotic cell death in GEM-resistant PDAC cells, which express MRP5 at higher levels than GEM-sensitive cells. Our results support the development of a new anti-tumoral strategy to efficiently affect GEM-resistant PDAC cells based on the usage of NO-GEM pro-drugs.
MRP5 nitration by NO-releasing gemcitabine encapsulated in liposomes confers sensitivity in chemoresistant pancreatic adenocarcinoma cells
Chegaev K.;Gazzano E.;Rolando B.;Arpicco S.
;Fruttero R.
;Riganti C.
;Donadelli M.
2020-01-01
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and drug chemoresistance. In this study, we synthesize a library of seven novel nitric oxide-releasing gemcitabine pro-drugs (NO-GEMs) in order to improve the effectiveness of GEM by exploiting the therapeutic effects of NO. Among these NO-GEM pro-drugs we select 5b as the most effective compound in GEM-resistant PDAC cells. After its encapsulation in liposomes for drug delivery the intracellular NO level increases and nitration associated to activity inhibition of the multidrug resistance associated protein 5 (MRP5; ABCC5) occurs. This results in GEM intracellular accumulation and enhanced apoptotic cell death in GEM-resistant PDAC cells, which express MRP5 at higher levels than GEM-sensitive cells. Our results support the development of a new anti-tumoral strategy to efficiently affect GEM-resistant PDAC cells based on the usage of NO-GEM pro-drugs.File | Dimensione | Formato | |
---|---|---|---|
Masetto, BBA manuscript 2020.pdf
Accesso riservato
Descrizione: Masetto, BBA 2020
Tipo di file:
PDF EDITORIALE
Dimensione
4.97 MB
Formato
Adobe PDF
|
4.97 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Masetto et al.docx
Accesso riservato
Descrizione: Masetto, pre-print, Open access, BBA 2020
Tipo di file:
PREPRINT (PRIMA BOZZA)
Dimensione
2.03 MB
Formato
Microsoft Word XML
|
2.03 MB | Microsoft Word XML | Visualizza/Apri Richiedi una copia |
Masetto et al.pdf
Accesso aperto
Descrizione: Masetto, pre-print, Open access, BBA 2020
Tipo di file:
PREPRINT (PRIMA BOZZA)
Dimensione
2.63 MB
Formato
Adobe PDF
|
2.63 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.