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, 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.
Reinholz
Gregory G
GG
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. reinholz.gregory@mayo.edu
Getz
Barbara
B
Sanders
Emily S
ES
Karpeisky
Marat Ya
MY
Padyukova
Nelly Sh
NSh
Mikhailov
Sergey N
SN
Ingle
James N
JN
Spelsberg
Thomas C
TC
D001842:Bone and Bones / Q000166:cytology / Q000196:embryology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D012968:Etidronic Acid / Q000737:chemistry; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000737:chemistry; D008798:Mevalonic Acid / Q000737:chemistry / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; C012258:mevastatin; D000077211:Zoledronic Acid; D008148:Lovastatin; D012968:Etidronic Acid; D008798:Mevalonic Acid