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Endonucleases induced TRAIL-insensitive apoptosis in ovarian carcinoma cells |
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| Authors: | Tessa M Geel Bernardina T van der Gun Lou F de Leij Arūnas Šilanskas Alfred Pingoud Pamela M McLaughlin Marianne G Rots |
| Institution: | a Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen, The Netherlands b Institute of Biochemistry, Justus-Liebig-University Gieβen, D-35392 Giessen, Germany c Institute of Biotechnology, Vilnius LT-02241, Lithuania d IMBB/FORTH and University of Crete/Department of Biology, GR-71409 Heraklion/Crete, Greece e Synvolux therapeutics, Groningen, The Netherlands |
| Abstract: | TRAIL induced apoptosis of tumor cells is currently entering phase II clinical settings, despite the fact that not all tumor types are sensitive to TRAIL. TRAIL resistance in ovarian carcinomas can be caused by a blockade upstream of the caspase 3 signaling cascade. We explored the ability of restriction endonucleases to directly digest DNA in vivo, thereby circumventing the caspase cascade. For this purpose, we delivered enzymatically active endonucleases via the cationic amphiphilic lipid SAINT-18®:DOPE to both TRAIL-sensitive and insensitive ovarian carcinoma cells (OVCAR and SKOV-3, respectively). Functional nuclear localization after delivery of various endonucleases (BfiI, PvuII and NucA) was indicated by confocal microscopy and genomic cleavage analysis. For PvuII, analysis of mitochondrial damage demonstrated extensive apoptosis both in SKOV-3 and OVCAR. This study clearly demonstrates that cellular delivery of restriction endonucleases holds promise to serve as a novel therapeutic tool for the treatment of resistant ovarian carcinomas. |
| Keywords: | Protein delivery TRAIL resistance Ovarian carcinoma Restriction endonucleases Apoptosis |
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