title: Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid.
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 for 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 4 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.
authors.affiliation: Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Misso
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Maria
authors.initials: M
authors.lastname: Castellano
authors.forename: Federica
authors.initials: F
authors.lastname: De Cicco
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069448:Denosumab; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053245:RANK Ligand; D000069448:Denosumab; D000077211:Zoledronic Acid