Ory, B., Moriceau, G.D., Trichet, V. et al. (5 more authors) (2008) Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells. J Cell Mol Med, 12 (3). pp. 928-941. ISSN 1582-1838
Abstract
We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2008 The Authors Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article. Reuse permissible under the following terms and conditions: http://olabout.wiley.com/WileyCDA/Section/id-828080.html |
Keywords: | Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diphosphonates; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Geranyltranstransferase; Humans; Imidazoles; Male; Middle Aged; Osteosarcoma; RNA, Small Interfering; Time Factors; Transfection |
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: | 20 Apr 2016 13:10 |
Last Modified: | 20 Apr 2016 13:10 |
Published Version: | http://dx.doi.org/10.1111/j.1582-4934.2008.00141.x |
Status: | Published |
Publisher: | Journal of Cellular and Molecular Medicine |
Refereed: | Yes |
Identification Number: | 10.1111/j.1582-4934.2008.00141.x |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:97881 |