Zoledronate inhibits alphavbeta3 and alphavbeta5 integrin cell surface expression in endothelial cells.
Zoledronate exhibits antiangiogenic properties in vitro and in vivo. Integrins alphavbeta3 and alphavbeta5 are involved in angiogenesis. Because zoledronate inhibits endothelial cell adhesion, the authors explored the hypothesis that it could alter these integrins recruitment to focal adhesion sites. Human umbilical vein endothelial cells (HUVECs) were treated with zoledronate or with mevalonate pathway intermediates geranylgeraniol (GGOH) and farnesol (FOH). Zoledronate generated a significant decrease in alphavbeta3 and alphavbeta5 expression at HUVEC cell surface using flow cytometry and immunofluorescence. This inhibition was reversed by GGOH but not by FOH. Cells cotreated with zoledronate and GGOH were able to attach to vitronectin through alphavbeta3 and alphavbeta5, as confirmed by the use of specific function-blocking antibodies. The authors showed that zoledronate alters endothelial cell integrin-mediated adhesion. This effect is likely to contribute to the previously demonstrated antiangiogenic effect of zoledronate. Whether this mechanism of action also applies to metastatic tumor cells is under investigation.
Bellahcène
A
A
Metastasis Research Laboratory, Center of Experimental Cancer Research, University of Liège, 4000 Liège, Belgium. a.bellahcene@ulg.ac.be
Chaplet
M
M
Bonjean
K
K
Castronovo
V
V
D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005204:Farnesol / Q000494:pharmacology; D022001:Focal Adhesions / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D051419:Paxillin / Q000172:deficiency; D019030:Receptors, Vitronectin / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004224:Diterpenes; D007093:Imidazoles; D039302:Integrin alphaVbeta3; D016023:Integrins; D051419:Paxillin; D019030:Receptors, Vitronectin; D019096:Vitronectin; C064660:integrin alphaVbeta5; D005204:Farnesol; D000077211:Zoledronic Acid; C017338:geranylgeraniol; D008798:Mevalonic Acid