Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase

Verena Stresing, Pierrick G. Fournier, Akeila Bellahcène, Ismahène Benzaïd, Hannu Mönkkönen, Marc Colombel, F. Hal Ebetino, Vincent Castronovo, Philippe Clézardin

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone-stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS-dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 μM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7-fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo.

Original languageEnglish (US)
Pages (from-to)259-266
Number of pages8
JournalBone
Volume48
Issue number2
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

Fingerprint

zoledronic acid
Diphosphonates
Nitrogen
Chorioallantoic Membrane
Osteoclasts
Prostate
Endothelial Cells
Bone and Bones
Mevalonic Acid
Risedronate Sodium
farnesyl pyrophosphate
Enzymes
Bone Resorption
Pharmaceutical Preparations
Ovum
Blood Vessels
Testosterone
Chickens
Cell Proliferation
Neoplasm Metastasis

Keywords

  • Angiogenesis
  • Bisphosphonate
  • FPPS
  • Risedronate
  • Zoledronate

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Stresing, V., Fournier, P. G., Bellahcène, A., Benzaïd, I., Mönkkönen, H., Colombel, M., ... Clézardin, P. (2011). Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone, 48(2), 259-266. https://doi.org/10.1016/j.bone.2010.09.035

Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. / Stresing, Verena; Fournier, Pierrick G.; Bellahcène, Akeila; Benzaïd, Ismahène; Mönkkönen, Hannu; Colombel, Marc; Ebetino, F. Hal; Castronovo, Vincent; Clézardin, Philippe.

In: Bone, Vol. 48, No. 2, 01.02.2011, p. 259-266.

Research output: Contribution to journalArticle

Stresing, V, Fournier, PG, Bellahcène, A, Benzaïd, I, Mönkkönen, H, Colombel, M, Ebetino, FH, Castronovo, V & Clézardin, P 2011, 'Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase', Bone, vol. 48, no. 2, pp. 259-266. https://doi.org/10.1016/j.bone.2010.09.035
Stresing, Verena ; Fournier, Pierrick G. ; Bellahcène, Akeila ; Benzaïd, Ismahène ; Mönkkönen, Hannu ; Colombel, Marc ; Ebetino, F. Hal ; Castronovo, Vincent ; Clézardin, Philippe. / Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. In: Bone. 2011 ; Vol. 48, No. 2. pp. 259-266.
@article{45668faaf6474585a56b98030d9aef4d,
title = "Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase",
abstract = "Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone-stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS-dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 μM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7-fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo.",
keywords = "Angiogenesis, Bisphosphonate, FPPS, Risedronate, Zoledronate",
author = "Verena Stresing and Fournier, {Pierrick G.} and Akeila Bellahc{\`e}ne and Ismah{\`e}ne Benza{\"i}d and Hannu M{\"o}nkk{\"o}nen and Marc Colombel and Ebetino, {F. Hal} and Vincent Castronovo and Philippe Cl{\'e}zardin",
year = "2011",
month = "2",
day = "1",
doi = "10.1016/j.bone.2010.09.035",
language = "English (US)",
volume = "48",
pages = "259--266",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase

AU - Stresing, Verena

AU - Fournier, Pierrick G.

AU - Bellahcène, Akeila

AU - Benzaïd, Ismahène

AU - Mönkkönen, Hannu

AU - Colombel, Marc

AU - Ebetino, F. Hal

AU - Castronovo, Vincent

AU - Clézardin, Philippe

PY - 2011/2/1

Y1 - 2011/2/1

N2 - Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone-stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS-dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 μM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7-fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo.

AB - Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone-stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS-dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 μM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7-fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo.

KW - Angiogenesis

KW - Bisphosphonate

KW - FPPS

KW - Risedronate

KW - Zoledronate

UR - http://www.scopus.com/inward/record.url?scp=78650976566&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650976566&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2010.09.035

DO - 10.1016/j.bone.2010.09.035

M3 - Article

VL - 48

SP - 259

EP - 266

JO - Bone

JF - Bone

SN - 8756-3282

IS - 2

ER -