Non-viral gene delivery of the oncotoxic protein NS1 for treatment of hepatocellular carcinoma
| Autor: | Bernhard Englinger, Salvatore Piscuoglio, Jean Rommelaere, Dominik Witzigmann, Sushilla van Schoonhoven, Walter Berger, David Grünig, Xue-Ting Tran, Patrick Hauswirth, Susanne H. Schenk, Stephan Krähenbühl, Jörg Huwyler, Luigi Terracciano, Manuela Lanzafame, Philip Grossen, Cristina Quintavalle, Jürg P. F. Nüesch, Luca Quagliata |
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| Rok vydání: | 2021 |
| Předmět: |
Carcinoma
Hepatocellular viruses Genetic enhancement Pharmaceutical Science 02 engineering and technology Viral gene Mice 03 medical and health sciences Therapeutic approach Animals Medicine 030304 developmental biology 0303 health sciences Expression vector biology Parvovirus Kinase business.industry Liver Neoplasms In vitro toxicology Proteins Genetic Therapy 021001 nanoscience & nanotechnology biology.organism_classification medicine.disease Hepatocellular carcinoma Cancer research 0210 nano-technology business Plasmids |
| Zdroj: | Journal of Controlled Release. 334:138-152 |
| ISSN: | 0168-3659 |
| Popis: | Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling the expression of the parvovirus-derived oncotoxic protein NS1 in HCC. This anticancer protein interacts with different cellular kinases mediating a multimodal host-cell death. Lipoplexes (LPX) designed to deliver a DNA expression plasmid encoding NS1 are characterized using a comprehensive set of in vitro assays. The mechanisms of cell death induction are assessed and phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential predictive biomarker for a NS1-LPX-based gene therapy. In an HCC xenograft mouse model, NS1-LPX therapeutic approach results in a significant reduction in tumor growth and extended survival. Data provide convincing evidence for future studies using a targeted NS1 gene therapy for PDK1 overexpressing HCC. |
| Databáze: | OpenAIRE |
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