Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid

Gabriella Misso, Manuela Porru, Antonella Stoppacciaro, Maria Castellano, Federica De Cicco, Carlo Leonetti, Daniele Santini, Michele Caraglia

Research output: Contribution to journalArticle

Abstract

Denosumab (Dmab) and zoledronic acid (ZOL) are antiresorptive agents, with different mechanisms of action, that are indicated for delaying the onset of skeletal-related events in patients with bone metastases from solid tumors. Clinical and preclinical data suggest that ZOL may have also anti-angiogenic activity; however, the effects of Dmab (a fully humanized antibody against the receptor activator of nuclear factor kappa B ligand) on angiogenesis are largely unknown. The objective of this study was to compare the potential anti-angiogenic activity of Dmab with that of ZOL in preclinical models. Dmab (0.31 to 160 μM) had no effect on the viability of human MDA-MB-436 and CG5 breast cancer cells or human umbilical vein endothelial cells (HUVECs) and no effect on tubule formation or invasion of HUVECs. In contrast, ZOL (0.31 to 160 μM) decreased the viability of breast cancer and HUVECs in a time- and concentration-dependent manner and also inhibited HUVEC tubule formation and invasion. In vivo, ZOL (20 μg/mouse three times a week for three consecutive weeks) inhibited angiogenesis in Matrigel plugs and inhibited the growth and neo-angiogenesis of CG5 xenografts in athymic nude mice. In contrast, Dmab (10 mg/kg twice a week for four consecutive weeks) had no effect on Matrigel vascularization or xenograft growth in this model. These findings support the potential antiangiogenic and anticancer activity of ZOL in vitro and in vivo and further suggest that Dmab does not have antiangiogenic activity. Additional studies are needed to elucidate the potential anticancer activity of Dmab.

Original languageEnglish
Pages (from-to)1491-1500
Number of pages10
JournalCancer Biology and Therapy
Volume13
Issue number14
DOIs
Publication statusPublished - Dec 2012

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Keywords

  • Acid 10.4161/cbt.22274
  • Angiogenesis
  • Anticancer
  • Breast cancer
  • Denosumab
  • HUVEC
  • RANKL
  • Zoledronic

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Misso, G., Porru, M., Stoppacciaro, A., Castellano, M., De Cicco, F., Leonetti, C., Santini, D., & Caraglia, M. (2012). Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid. Cancer Biology and Therapy, 13(14), 1491-1500. https://doi.org/10.4161/cbt.22274