Moriceau, G., Ory, B., Mitrofan, L. et al. (11 more authors) (2010) Zoledronic Acid Potentiates mTOR Inhibition and Abolishes the Resistance of Osteosarcoma Cells to RAD001 (Everolimus): Pivotal Role of the Prenylation Process. Cancer Research, 70 (24). pp. 10329-10339. ISSN 0008-5472
Abstract
Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated vivo the effects of RAD001 (Everolimus®), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone and in combination with zoledronate (ZOL), an osteoporesis drug which is used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared to single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly to an increase of non-isoprenylated cytosolic Ras in sensitive- and resistant-osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2010 American Association for Cancer Research |
Keywords: | osteosarcoma; mTOR; rapamycin; bisphosphonate; drug resistance |
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: | 18 May 2016 15:34 |
Last Modified: | 11 Apr 2017 04:43 |
Published Version: | http://dx.doi.org/10.1158/0008-5472.CAN-10-0578 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Identification Number: | 10.1158/0008-5472.CAN-10-0578 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:98193 |