Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma.
Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma.
Scavelli
Claudio
C
Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare, 11, I-70124 Bari, Italy.
Di Pietro
Giulia
G
Cirulli
Teresa
T
Coluccia
Mauro
M
Boccarelli
Angela
A
Giannini
Teresa
T
Mangialardi
Giuseppe
G
Bertieri
Raffaello
R
Coluccia
Addolorata Maria Luce
AM
Ribatti
Domenico
D
Dammacco
Franco
F
Vacca
Angelo
A
D000328:Adult; D000368:Aged; D001483:Base Sequence; D015153:Blotting, Western; D017077:Culture Media, Conditioned; D017931:DNA Primers; D004164:Diphosphonates / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D010641:Phenotype; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D000077211:Zoledronic Acid
D017077:Culture Media, Conditioned; D017931:DNA Primers; D004164:Diphosphonates; D007093:Imidazoles; D042461:Vascular Endothelial Growth Factor A; C012258:mevastatin; D000077211:Zoledronic Acid; D008148:Lovastatin; D040262:Receptors, Vascular Endothelial Growth Factor