title: MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and mortal cancer, characterized by a set of known mutations, invasive features, and aberrant microRNA expression that have been associated with hallmark malignant properties of PDAC. The lack of effective PDAC treatment options prompted us to investigate whether microRNAs would constitute promising therapeutic targets toward the generation of a gene therapy approach with clinical significance for this disease. In this work, we show that the developed human serum albumin-1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine:cholesterol/anti-microRNA oligonucleotides (+/-) (4/1) nanosystem exhibits the ability to efficiently deliver anti-microRNA oligonucleotides targeting the overexpressed microRNAs miR-21, miR-221, miR-222, and miR-10 in PDCA cells, promoting an almost complete abolishment of microRNA expression. Silencing of these microRNAs resulted in a significant increase in the levels of their targets. Moreover, the combination of microRNA silencing, namely miR-21, with low amounts of the chemotherapeutic drug sunitinib resulted in a strong and synergistic antitumor effect, showing that this combined strategy could be of great importance for therapeutic application in PDAC.
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal ; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal.
authors: Marta
authors: M
authors: Passadouro
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal ; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal.
authors: Maria C
authors: MC
authors: Pedroso de Lima
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: Henrique
authors: H
authors: Faneca
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D010713:Phosphatidylcholines; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D014162:Transfection / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D010713:Phosphatidylcholines; D011758:Pyrroles; D000077210:Sunitinib
keywords: albumin-associated lipoplexes; anti-microRNAs oligonucleotides; delivery nanosystems; pancreatic cancer gene therapy