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

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). In this report...

Full description

Saved in:
Bibliographic Details
Published in:Breast cancer research and treatment 2002-02, Vol.71 (3), p.257-268
Main Authors: REINHOLZ, Gregory G, GETZ, Barbara, SANDERS, Emily S, KARPEISKY, Marat Ya, PADYUKOVA, Nelly Sh, MIKHAILOV, Sergey N, INGLE, James N, SPELSBERG, Thomas C
Format: Article
Language:rus ; eng
Subjects:
Bone and Bones - cytology
Bone and Bones - embryology
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer research
Cancer therapies
Cell Differentiation - drug effects
Diphosphonates - chemistry
Diphosphonates - pharmacology
Dose-Response Relationship, Drug
Etidronic Acid - chemistry
Female
Humans
Imidazoles - chemistry
Lovastatin - analogs & derivatives
Lovastatin - chemistry
Mevalonic Acid - chemistry
Mevalonic Acid - metabolism
Osteoblasts - cytology
Osteoblasts - drug effects
Osteoblasts - physiology
Pregnancy
Structure-Activity Relationship
Tumor Cells, Cultured - drug effects
Tumor Cells, Cultured - physiology
Zoledronic Acid
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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). 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.
ISSN:0167-6806
1573-7217
DOI:10.1023/A:1014418017382