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Investigation of inhibitory effects on EPC-mediated neovascularization by different bisphosphonates for cancer
Thomas Ziebart1, Johanna Ziebart2, Leonie Gauss1
1Department of Maxillofacial Surgery, University Medical Center of Johannes Gutenberg University Mainz, D-55131 Mainz.
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.
Insights
Nitrogen-containing bisphosphonates, like zoledronate, inhibit endothelial progenitor cell function and neovascularization. These findings suggest nitrogen-containing bisphosphonates may act as anticancer agents by blocking tumor blood vessel formation.
Area of Science:
- Pharmacology
- Oncology
- Cell Biology
Background:
- Bisphosphonates (BPs) are used for metastatic cancers and may affect angiogenesis.
- Endothelial progenitor cells (EPCs) are crucial for neovascularization, especially in tumor growth.
- BPs accumulate in bone, necessitating investigation into their effects on bone-marrow-derived EPCs.
Purpose of the Study:
- To investigate the impact of nitrogen-containing and non-nitrogen-containing bisphosphonates on endothelial progenitor cell (EPC) function.
- To determine the dose-dependent effects of bisphosphonates on EPC migration and differentiation.
- To assess the potential of bisphosphonates as anticancer agents via inhibition of neovascularization.
Main Methods:
- Treatment of EPCs with various concentrations of clodronate (non-nitrogen BP) and ibandronate, pamidronate, zoledronate (nitrogen BPs) for 72 hours.
- Assessment of EPC biological activity using migration boyden chamber assay.
- Measurement of EPC colony-forming ability to evaluate differentiation capacity.
Main Results:
- Nitrogen-containing bisphosphonates significantly inhibited EPC migration and differentiation in a dose-dependent manner.
- Zoledronate demonstrated a marked inhibition of angiogenesis and neovascularization.
- Clodronate exhibited less pronounced effects on EPC function compared to nitrogen-containing BPs.
Conclusions:
- Nitrogen-containing bisphosphonates, particularly zoledronate, effectively inhibit EPC function and neovascularization.
- The anti-angiogenic properties of nitrogen-containing bisphosphonates suggest their potential as anticancer agents.
- Targeting neovascularization through bisphosphonates offers a promising strategy in cancer therapy.
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