• Open Access

Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells

Authors

  • B. Ory,

    1. Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France
    2. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
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  • G. Moriceau,

    1. Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France
    2. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
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  • V. Trichet,

    1. Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France
    2. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
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  • F. Blanchard,

    1. Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France
    2. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
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  • M. Berreur,

    1. Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France
    2. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
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  • F. Rédini,

    1. Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France
    2. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
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  • M. Rogers,

    1. Bone & Musculoskeletal Research Program, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
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  • D. Heymann

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale, ERI 7, Nantes, France
    2. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
    3. Hospital, Nantes, France
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*Correspondence to: DOMINIQUE HEYMANN,
Laboratoire de Physiopathologie de la Résorption
Osseuse et Thérapie des Tumeurs Osseuses Primitives,
EA3822 – INSERM ERI 7, Faculté de Médecine, 1 rue
Gaston Veil, 44035 Nantes cedex 1, France.
Tel.:33 240 412 845
Fax:33 240 412 860
E-mail: dominique.heymann@univ-nantes.fr

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 μm Zol, the effects of high doses of Zol (10–100 μm) 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 μm 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.

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