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Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation.
- Source :
-
The Journal of surgical research [J Surg Res] 2009 Jan; Vol. 151 (1), pp. 115-20. Date of Electronic Publication: 2008 Feb 29. - Publication Year :
- 2009
-
Abstract
- Background: Zoledronic acid (ZOL) is clinically available for the treatment of skeletal complications. In preclinical studies, strong anti-cancer activities against breast cancer, prostate cancer, and leukemia were reported. It also inhibited the proliferation of cultured human endothelial cells, suggestive of an anti-angiogenic activity. Since ZOL has the tendency to accumulate in bone, we investigated the effect of ZOL on endothelial progenitor cells (EPCs), which originate from the bone marrow, and play important roles in angiogenesis.<br />Materials and Methods: Human peripheral blood mononuclear cells were cultured for 7 d to differentiate into EPCs. Cells were treated without/with ZOL or with geranylgeraniol (GGOH). Their endothelial phenotype was confirmed by the expression of CD144 and vascular endothelial growth factor receptor 2 and the tube-like formation ability on Matrigel (Becton Dickinson, Bedford, MA). Annexin V/propidium iodide staining was used to analyze apoptosis.<br />Results: ZOL treatment, even at low doses, from d 2 to 7 of culture resulted in impaired EPC differentiation and could be restored by co-treatment with GGOH. On the other hand, treatment of putative EPCs with ZOL at concentrations higher than 10 mum resulted in induction of apoptosis.<br />Conclusion: ZOL dose-dependently inhibited the differentiation of EPCs, the effect being observed even at low drug levels. At high concentrations, ZOL also induced the apoptotic death of putative EPCs. Since GGOH restored the inhibitory effect of ZOL on EPCs differentiation, the effect of ZOL appears to be dependent on the inhibition of prenylation of small-G-proteins. From these findings, we conclude that ZOL could be a potential anticancer agent by inhibiting angiogenesis.
- Subjects :
- Antigens, CD metabolism
Apoptosis drug effects
Cadherins metabolism
Cells, Cultured
Dose-Response Relationship, Drug
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Humans
Mesenchymal Stem Cells drug effects
Mesenchymal Stem Cells metabolism
Vascular Endothelial Growth Factor Receptor-2 metabolism
Zoledronic Acid
Bone Density Conservation Agents pharmacology
Cell Differentiation drug effects
Diphosphonates pharmacology
Endothelium, Vascular cytology
Imidazoles pharmacology
Mesenchymal Stem Cells cytology
Neovascularization, Physiologic drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1095-8673
- Volume :
- 151
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of surgical research
- Publication Type :
- Academic Journal
- Accession number :
- 18619615
- Full Text :
- https://doi.org/10.1016/j.jss.2008.01.031