Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue
| Autor: | James N. Ingle, Marat Ya. Karpeisky, Emily S. Sanders, Nelly Sh. Padyukova, Barbara Getz, Sergey N. Mikhailov, Thomas C. Spelsberg, Gregory G. Reinholz |
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| Rok vydání: | 2002 |
| Předmět: |
Cancer Research
Cell type medicine.medical_specialty medicine.medical_treatment Cell Mevalonic Acid Breast Neoplasms Biology Zoledronic Acid Bone and Bones Structure-Activity Relationship Mevastatin Pregnancy Internal medicine Tumor Cells Cultured medicine Humans Lovastatin Osteoblasts Diphosphonates Dose-Response Relationship Drug Cell growth Imidazoles Cell Differentiation Etidronic Acid Osteoblast Bisphosphonate medicine.anatomical_structure Endocrinology Oncology Cancer cell Cancer research Female Mevalonate pathway medicine.drug |
| Zdroj: | Breast Cancer Research and Treatment. 71:257-268 |
| ISSN: | 1573-7217 0167-6806 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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