Bisphosphonates Induce Breast Cancer Cell Death In Vitro

Authors

  • Olivia Fromigue,

    1. Laboratory of Endocrinology and Bone Metabolism, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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  • Laurence Lagneaux,

    1. Laboratory of Haematology, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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  • Jean-Jacques Body M.D., Ph.D.

    Corresponding author
    1. Laboratory of Endocrinology and Bone Metabolism, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
    • Institut Jules Bordet, Department of Medicine, Rue Héger-Bordet 1, 1000 Brussels, Belgium
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  • Results presented in part at the poster plenary session of the American Society for Bone and Mineral Research meeting, St. Louis, Missouri, U.S.A., 1999.

Abstract

Breast cancer frequently spreads to bone and is almost always associated with osteolysis. This tumor-induced osteolysis is caused by increased osteoclastic bone resorption. Bisphosphonates are used successfully to inhibit bone resorption in tumor bone disease and may prevent development of new osteolytic lesions. The classical view is that bisphosphonates only act on bone cells. We investigated their effects on breast cancer cells using three human cell lines, namely, MCF-7, T47D, and MDA.MB.231, and we tested four structurally different bisphosphonates: clodronate, pamidronate, ibandronate, and zoledronate. We performed time course studies for each bisphosphonate at various concentrations and found that all four compounds induced a nonreversible growth inhibition in both MCF-7 and T47D cell lines in a time- and dose-dependent manner. The MDA.MB.231 cell line was less responsive. Bisphosphonates induced apoptosis in MCF-7 and cell necrosis in T47D cells. The inhibition of MCF-7 cell proliferation could be reverted almost completely by the benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk) inhibitor of caspases, suggesting that the apoptotic process observed in the MCF-7 cell line is mediated, at least partly, by the caspase system. Caspase activity was little changed by bisphosphonates in T47D cells and the inhibitor of caspase did not modify bisphosphonates effects. In summary, we found that bisphosphonates inhibit breast cancer cell growth by inducing cell death in vitro. Such effects could contribute to the beneficial role of bisphosphonates in the treatment and the prevention of tumor-induced osteolysis.

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