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MRP5 nitration by NO-releasing gemcitabine encapsulated in liposomes confers sensitivity in chemoresistant pancreatic adenocarcinoma cells.
- Source :
-
Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2020 Dec; Vol. 1867 (12), pp. 118824. Date of Electronic Publication: 2020 Aug 21. - Publication Year :
- 2020
-
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.<br />Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Adenocarcinoma genetics
Adenocarcinoma pathology
Apoptosis drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Deoxycytidine chemistry
Deoxycytidine pharmacology
Drug Resistance, Neoplasm drug effects
Humans
Liposomes chemistry
Liposomes pharmacology
Nitric Oxide metabolism
Pancreatic Neoplasms genetics
Pancreatic Neoplasms pathology
Gemcitabine
Adenocarcinoma drug therapy
Deoxycytidine analogs & derivatives
Multidrug Resistance-Associated Proteins genetics
Pancreatic Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1879-2596
- Volume :
- 1867
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular cell research
- Publication Type :
- Academic Journal
- Accession number :
- 32828758
- Full Text :
- https://doi.org/10.1016/j.bbamcr.2020.118824