title: Investigation of inhibitory effects on EPC-mediated neovascularization by different bisphosphonates for cancer therapy.
abstract: Bisphosphonates (BPs) are potent drugs, used in metastatic cancer-like prostate or breast carcinoma. In recent studies, besides reduced bone remodeling, influences on angiogenesis and neovascularization were reported. Since BPs have the tendency to accumulate in the bones, the biological effect of various nitrogen- and non-nitrogen BPs on endothelial progenitor cells (EPCs) that originated from bone marrow and mobilized under physiological and pathophysiological conditions, such as tumor neovascularization, was investigated. EPCs subsequent to 72-h treatment with different concentrations of bisphosphonates comprised the non-nitrogen-containing BP clodronate and the nitrogen-containing BPs ibandronate, pamidronate and zoledronate. After incubation, biological activity was measured by using the migration boyden chamber assay and measurement of the colony-forming ability. Nitrogen-containing BPs inhibited the migration ability and differentiation of EPCs in a dose-dependent manner, as compared to the non-treated control groups. More specifically, the nitrogen-containing BP zoledronate significantly inhibited angiogenesis and neovascularization. Clodronate was less distinct on EPC function. To underline the importance of neovascularization in the context of tumor angiogenesis, EPC functions were significantly influenced in a dose-dependent manner by nitrogen-containing BPs. From these findings, we conclude that especially the nitrogen-containing BPs, such as zoledronate, are potential anticancer agents through the inhibition of neovascularization.
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ziebart
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz ; Department of Prosthodontics, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ziebart
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
authors.forename: Leonie
authors.initials: L
authors.lastname: Gauss
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pabst
authors.affiliation: Institute of Functional and Clinical Anatomy, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Ackermann
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Smeets
authors.affiliation: Institute of Functional and Clinical Anatomy, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
authors.forename: Moritz A
authors.initials: MA
authors.lastname: Konerding
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
authors.forename: Christian
authors.initials: C
authors.lastname: Walter
keywords: angiogenesis; bisphosphonate; cancer; endothelial progenitor cell; endothelial progenitor cells; neovascularization