MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer

• Autor(a) principal: Passadouro, Marta
• Data de Publicação: 2014
• Outros Autores: Lima, Maria C. Pedroso de, Faneca, Henrique
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/109459; https://doi.org/10.2147/IJN.S64456
• topic: pancreatic cancer gene therapy; anti-microRNAs oligonucleotides; delivery nanosystems; albumin-associated lipoplexes; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Survival; Drug Synergism; Gene Expression Regulation, Neoplastic; Genetic Therapy; Humans; Indoles; MicroRNAs; Oligonucleotides, Antisense; Pancreatic Neoplasms; Phosphatidylcholines; Pyrroles; Sunitinib; Transfection

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.