Zoledronate Sensitizes Endothelial Cells to Tumor Necrosis Factor-induced Programmed Cell Death
Open accessAbstract
Bisphosphonates are potent inhibitors of osteoclast function widely used to treat conditions of excessive bone resorption, including tumor bone metastases. Recent evidence indicates that bisphosphonates have direct cytotoxic activity on tumor cells and suppress angiogenesis, but the associated molecular events have not been fully characterized. In this study we investigated the effects of zoledronate, a nitrogen-containing bisphosphonate, and clodronate, a non-nitrogen-containing bisphosphonate, on human umbilical vein endothelial cell (HUVEC) adhesion, migration, and survival, three events essential for angiogenesis. Zoledronate inhibited HUVEC adhesion mediated by integrin alphaVbeta3, but not alpha5beta1, blocked migration and disrupted established focal adhesions and actin stress fibers without modifying cell surface integrin expression level or affinity. Zoledronate treatment slightly decreased HUVEC viability and strongly enhanced tumor necrosis factor (TNF)-induced cell death. HUVEC treated with zoledronate and TNF died without evidence of enhanced annexin-V binding, chromatin condensation, or nuclear fragmentation and caspase dependence. Zoledronate inhibited sustained phosphorylation of focal adhesion kinase (FAK) and in combination with TNF, with and without interferon (IFN) gamma, of protein kinase B (PKB/Akt). Constitutive active PKB/Akt protected HUVEC from death induced by zoledronate and TNF/IFNgamma. Phosphorylation of c-Src and activation of NF-kappaB were not affected by zoledronate. Clodronate had no effect on HUVEC adhesion, migration, and survival nor did it enhanced TNF cytotoxicity. Taken together these data demonstrate that zoledronate sensitizes endothelial cells to TNF-induced, caspase-independent programmed cell death and point to the FAK-PKB/Akt pathway as a novel zoledronate target. These results have potential implications to the clinical use of zoledronate as an anti-angiogenic or anti-cancer agent.
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Bisphosphonates suppress proliferation, adhesion, migration, and survival of endothelial cells in vitro and induce endothelial apoptosis in vivo.
“these agents have also been shown to suppress the proliferation, adhesion, migration, and survival of endothelial cells in vitro (147, 148) while inducing endothelial cell apoptosis in vivo (149).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [148]
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- Authors
- Bezzi, M., Hasmim, M., Bieler, G., Dormond, O., & Rüegg, C.
- Affiliations
- University of Lausanne (CH)
- Corresponding author
- Rüegg, Curzio
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 278
- Issue
- 44
- Pages
- 43603-43614
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2031276908
- Cited by
- 139
- References
- 91
- Citations by year
- 2023: 1 · 2022: 3 · 2021: 1 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 6 · 2015: 8 · 2014: 7 · 2013: 8 · 2012: 7
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (63752)
- Topics
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- zoledronic acid, bisphosphonates, clodronate, endothelial cells, TNF-α, programmed cell death, caspase-independent cell death, angiogenesis, focal adhesion kinase, Akt signaling, integrin αvβ3, endothelial cell adhesion, endothelial cell migration, focal adhesions, stress fibers, interferon-gamma, NF-κB, Src kinase, anti-angiogenic therapy, cancer therapy
- MeSH terms
- Zoledronic Acid, Adenoviridae, Cell Adhesion, Cell Membrane, Cell Movement, Cell Survival, Cells, Cultured, Clodronic Acid, Diphosphonates, Coloring Agents, Endothelium, Vascular, Enzyme Activation, Flow Cytometry, Humans, Imidazoles, Microscopy, Fluorescence, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Tumor Necrosis Factor-alpha, Umbilical Veins, Cell Death, Apoptosis, Annexin A5, Protein Serine-Threonine Kinases, Electroporation, Angiogenesis Inhibitors, Integrin alpha5beta1, Integrin alphaVbeta3, Endothelial Cells, Proto-Oncogene Proteins c-akt, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesion Kinase 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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