Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation.
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.


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.


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.


CONCLUSIONS
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.
Yamada
Jun
J
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan. jymda-tky@umin.ac.jp
Tsuno
Nelson H
NH
Kitayama
Joji
J
Tsuchiya
Takeshi
T
Yoneyama
Satomi
S
Asakage
Masahiro
M
Okaji
Yurai
Y
Shuno
Yasutaka
Y
Nishikawa
Takeshi
T
Tanaka
Junichiro
J
Takahashi
Koki
K
Nagawa
Hirokazu
H
D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000077211:Zoledronic Acid; D000099152:Cadherin 5
D015703:Antigens, CD; D050071:Bone Density Conservation Agents; D015820:Cadherins; D004164:Diphosphonates; D007093:Imidazoles; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077211:Zoledronic Acid; D000099152:Cadherin 5