Rousseau, J., Escriou, V., Lamoureux, F. et al. (8 more authors) (2011) Formulated siRNAs Targeting Rankl Prevent Osteolysis and Enhance Chemotherapeutic Response in Osteosarcoma Models. Journal of Bone and Mineral Research, 26 (10). pp. 2452-2462. ISSN 0884-0431
Abstract
The development of osteosarcoma, the most common malignant primary bone tumor is characterized by a vicious cycle established between tumor proliferation and paratumor osteolysis. This osteolysis is mainly regulated by the receptor activator of nuclear factor κB ligand (RANKL). Preclinical studies have demonstrated that Rankl blockade by soluble receptors is an effective strategy to prevent osteolytic lesions leading to osteosarcoma inhibition. A new therapeutic option could be to directly inhibit Rankl expression by small interfering RNAs (Rkl-siRNAs) and combine these molecules with chemotherapy to counteract the osteosarcoma development more efficiently. An efficient siRNA sequence directed against both mouse and rat mRNAs coding Rankl was first validated in vitro and tested in two models of osteosarcoma: a syngenic osteolytic POS-1 model induced in immunocompetent mice and a xenograft osteocondensant model of rat OSRGA in athymic mice. Intratumor injections of Rankl-directed siRNAs in combination with the cationic liposome RPR209120/DOPE reduced the local and systemic Rankl production and protected bone from paratumor osteolysis. Although Rkl-siRNAs alone had no effect on tumor development in both osteosarcoma models, it significantly blocked tumor progression when combined with ifosfamide compared with chemotherapy alone. Our results indicate that siRNAs could be delivered using cationic liposomes and thereby could inhibit Rankl production in a specific manner in osteosarcoma models. Moreover, the Rankl inhibition mediated by RNA interference strategy improves the therapeutic response of primary osteosarcoma to chemotherapy.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2011 American Society for Bone and Mineral Research |
Keywords: | RANKL; siRNAs; OSTEOCLASTOGENESIS INHIBITION; BITHERAPY |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 May 2016 11:50 |
Last Modified: | 09 May 2016 11:55 |
Published Version: | http://dx.doi.org/10.1002/jbmr.455 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/jbmr.455 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:98183 |