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

Gregory G. Reinholz, Barbara Getz, Emily S. Sanders, Marat Ya Karpeisky, Nelly Sh Padyukova, Sergey N. Mikhailov, James N. Ingle, Thomas C. Spelsberg

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)257-268
Number of pages12
JournalBreast Cancer Research and Treatment
Volume71
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Bisphosphonates
  • Breast neoplasms
  • Mevalonate pathway
  • Osteoblasts

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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