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Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue

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Abstract

While the effects of bisphosphonates on bone-resorbing osteoclasts have been well documented, the effects of bisphosphonates on other cell types are not as well studied. Recently, we reported that bisphosphonates have direct effects on bone-forming human fetal osteoblast cells (hFOB) [1]. In this report, the role of the mevalonate pathway in the actions of bisphosphonates on hFOB, and MDA-MB-231 human breast cancer cells was examined. These studies included a novel bisphosphonate analog, the anhydride formed between arabinocytidine 5′ phosphate and etidronate (Ara-CBP). Ara-CBP was the most potent inhibitor of hFOB and MDA-MB-231 cell proliferation, and stimulator of hFOB cell mineralization compared to etidronate, the anhydride formed between AMP and etidronate (ABP), pamidronate, and zoledronate. Inhibition of hFOB cell proliferation by Ara-CBP and zoledronate was partially reversed by mevalonate pathway intermediates, and stimulation of hFOB cell mineralization was completely reversed by mevalonate pathway intermediates. These results suggest that zoledronate and Ara-CBP act, at least in part, via inhibition of the mevalonate pathway in hFOB cells. In contrast, none of the mevalonate pathway intermediates reversed the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates, or the effects of pamidronate on hFOB cells. As a positive control, the effects of mevastatin on hFOB and MDA-MB-231 cells were completely reversed by mevalonate. In summary, these data suggest that zoledronate and Ara-CBP induce human osteoblast differentiation via inhibition of the mevalonate pathway. In contrast, the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates appears to be through mechanisms other than inhibition of the mevalonate pathway.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Russia

    Gregory G. Reinholz, Barbara Getz & Emily S. Sanders

  2. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia

    Marat Ya. Karpeisky, Nelly Sh. Padyukova & Sergey N. Mikhailov

  3. MBC Research, Inc., Boulder, CO, 80301

    Marat Ya. Karpeisky

  4. Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA

    James N. Ingle & Thomas C. Spelsberg

Authors
  1. Gregory G. Reinholz
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  2. Barbara Getz
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  3. Emily S. Sanders
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  4. Marat Ya. Karpeisky
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  5. Nelly Sh. Padyukova
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  6. Sergey N. Mikhailov
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  7. James N. Ingle
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  8. Thomas C. Spelsberg
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Reinholz, G.G., Getz, B., Sanders, E.S. et al. Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue. Breast Cancer Res Treat 71, 257–268 (2002). https://doi.org/10.1023/A:1014418017382

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